SUPRAMOLECULAR COORDINATION CHEMISTRY OF PHOSPHORUS,
ARSENIC, ANTIMONY, AND BISMUTH WITH ORGANOTHIOLATES
by
VIRGINIA MAY CANGELOSI
A DISSERTAnON
Presented to the Department of Chemistry
and the Graduate School of the University of Oregon
in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy
September 201 0
11
University of Oregon Graduate School
Confirmation of Approval and Acceptance of Dissertation prepared by:
Virginia Cangelosi
Title:
"Supramolecular Coordination Chemistry of Phosphorus, Arsenic, Antimony, and Bismuth with
Organothiolates"
This dissertation has been accepted and approved in partial fulfillment of the requirements for
the Doctor of Philosophy degree in the Department of Chemistry by:
James Hutchison, Chairperson, Chemistry
Darren Johnson, Member, Chemistry
Catherine Page, Member, Chemistry
Michael Haley, Member, Chemistry
Scott Bridgham, Outside Member, Biology
and Richard Linton, Vice President for Research and Graduate Studies/Dean of the Graduate
School for the University of Oregon.
September 4, 2010
Original approval signatures are on file with the Graduate School and the University of Oregon
Libraries.
III
An Abstract of the Dissertation of
Virginia May Cangelosi
in the Department of Chemistry
for the degree of
to be taken
Doctor of Philosophy
September 2010
Title: SUPRAMOLECULAR COORDINATION CHEMISTRY OF PHOSPHORUS,
ARSENIC, ANTIMONY, AND BISMUTH WITH ORGANOTHIOLATES
Approved:
Darren W. Johnson
The ever-expanding field of suprarnolecular chemistry has recently incorporated
use of the main group ions. This dissertation presents a suprarnolecular approach to the
coordination chemistry of the Group 15 elements, with a special emphasis on arsenic
(As). Arsenic is ubiquitous in our environment, contaminates the drinking water of large
human populations, and is a worldwide health concern. Arsenic's legendary toxicity is
thought to be due to its thiophilicity and the stability of arsenic-thiolate bonds within
proteins. Chapter I is a review of the current literature on the kinetics, thermodynamics,
and supramolecular chemistry of the As(III)-thiolate bond and reveals that the stability
and lability of the bond make it well-suited for supramolecular chemistry. The remainder
of the dissertation explains our supramolecular design strategies for the As(III) ion with
thiolate ligands, then expands the approach to the Group 15 elements phosphorus,
antimony, and bismuth.
IV
Chapter II presents an approach to controlling diastereoselectivity in the self-
assembly of supramolecular AszLzCh macrocycles using intramolecular steric
interactions. Chapter III expands upon this approach by using intermolecular steric
interactions to control diastereoselectivity and dimer formation of AszLzClz macrocycles.
Chapter IV gives insight into the self-assembly of these AszLzClz macrocycles by
identifying several reaction intermediates and kinetic mistakes that form eluring the
course of the reaction. In Chapter V the application of our design strategy to the heavier
Group 15 elements of antimony and bismuth is shown through the presentation of EzL3
cryptands (E = As, Sb, Bi). Additionally, a Group 15 "transmetallation" reaction is
explained which allows, for the first time, the preparation of the elusive PzL3 cryptand.
Chapter VI further examines the transmetallation reaction, the solution isomerism of the
EzL3 cryptands, and presents three heterometallic EE'L3 cryptands. Finally, Chapter VII
briefly concludes this dissertation and provides some potential future directions for the
project.
This dissertation includes co-authored material and previously published results.
CURRICULUM VITAE
NAME OF AUTHOR: Virginia May Cangelosi
PLACE OF BIRTH: Grand Rapids, MI
DATE OF BIRTH: November 24,1982
GRADUATE AND UNDERGRADUATE SCHOOLS ATTENDED:
University of Oregon, Eugene, OR
Albion College, Albion, MI
University of Wollongong, Wollongong, NSW, Australia
DEGREES AWARDED:
Doctor of Philosophy, Chemistry, 2010, University of Oregon
Bachelor of Arts, Chemistry, 2005, Albion College
AREAS OF SPECIAL INTEREST:
Supramolecular Chemistry
Main Group Coordination Chemistry
PROFESSIONAL EXPERIENCE:
Graduate Research Assistant, University of Oregon, 2006-2010
Graduate Teaching Fellow, University of Oregon, 2005-2010
GRANTS, AWARDS AND HONORS:
National Science Foundation GK12 Fellowship, 2007-2010
Department of Education GAANN Fellowship, 2007-2010
University of Oregon Women in Technology and Science Travel Award, 2010
American Chemical Society Travel Award, 2008
v
vi
PUBLICATIONS:
Cangelosi, V. M.; Carter, T. G.; Crossland, J. L.; Zakharov, L. N.; Johnson, D. W. "Self-
Assembled E2L3 Cryptands (E =P, As, Sb, Bi): Transmetallation, Homo- and
Heterometallic Assemblies, and Conformational Isomerism" submitted to Inorg. Chem.
Cangelosi, V. M.; Pitt, M. A; Vickaryous, W. J.; Allen, C. A; Zakharov, L. N.; Johnson,
D. W. "Design Considerations for the Group 15 Elements: The Pnictogen···1t Interaction
as a Complementary Component in Supramolecular Assembly Design" Cryst. Growth
Des. 2010, in press.
Lindquist, N. R.; Carter, T. c.; Cangelosi, V. M.; Zakharov, L. N.; Johnson, D. W.
"Three's Company: Co-crystallization of a Self-Assembled S4 Metallacyclophane with
Two Diastereomeric Metallacycle Intermediates" Chem. Commun. 2010,46,3505-3507.
Cangelosi, V. M.; Zakharov, L. N.; Crossland, J. L.; Franklin, B. c.; Johnson, D. W. "A
Surprising "Folded-In" Conformation of a Self-Assembled Arsenic-Thiolate Macrocycle"
Cryst. Growth Des. 2010,10, 1471-1473.
Cangelosi, V. M.; Zakharov, L. N.; Johnson, D. W. "Supramolecular "Transmetalation"
Leads to an Unusual Self-Assembled P2L3 Cryptand" Angew. Chem., Int. Ed. 2010, 1248-
1251.
Cangelosi, V. M.; Carter, T. c.; Zakharov, L. N.; Johnson, D. W. "Observation of
Reaction Intermediates and Kinetic Mistakes in a Remarkably Slow Self-Assembly
Reaction" Chem. Commun. 2009, 5606-5608.
Allen, C. A; Cangelosi, V. M.; Zakharov, L. N.; Johnson, D. W. "Supramolecular
Organization Using Multiple Secondary Bonding Interactions" Cryst. Growth Des. 2009,
9,3011-3013.
Cangelosi, V. M.; Zakharov, L.N.; Fontenot, S. A; Pitt, M. A; Johnson, D. W. "Host-
Guest Interactions in a Series ofAS2~ChMacrocycles" Dalton Trans. 2008, 3447-3453.
Cangelosi, V. M.; Sather, A c.; Zakharov, L. N.; Berryman, O. B.; Johnson, D. W.
"Diastereoselectivity in the Self-Assembly of AS2~ChMacrocycles is Directed by the
As-1t Interaction" Inorg. Chem. 2007,46,9278-9284.
Carter, T. G.; Vickaryous, W. J.; Cangelosi, V. M.; Johnson, D. W. "Supramolecular
Arsenic Coordination Chemistry" Comments on Inorg. Chem. 2007,28,97-122.
VB
ACKNOWLEDGMENTS
First and foremost I would like to thank my advisor Darren Johnson for the
support and encouragement he has provided me throughout the last five years. His
excitement for chemistry is contagious and the mentoring he provided is indispensible.
He has managed to build a very fun and supportive lab environment by not ignoring the
importance of interpersonal relationships and team building with barbeques, poker, and a
little lab competition (aka fantasy football). I've especially appreciated the unquestioning
acceptance that he has shown me over the last several months while lab work has been
impossible. Additionally, I would like to thank my thesis committee chair Jim Hutchison
and members Mike Haley, Cathy Page, and Scott Bridgham for their guidance and time.
I also appreciate the quick, insightful, and kind feedback on crystals from Lev Zakharov.
His structures have been an integral part of my research and this project could not have
advanced without them. Funding from the Department of Education GAANN, NSF
GK12, and the University of Oregon are acknowledged.
I have been lucky to work with an eclectic group of lab mates whom have helped
me to grow professionally and personally. Specifically, I have enjoyed input and help
from the toxics group: Tim Carter, Sean Fontenot, and Jake Vickaryous. Corinne Allen
went above-and-beyond what I expected of her as "my undergrad" and I look forward to
seeing her future success. Finally, in the last couple months, Justin Crossland has been a
great help in wrapping up several key experiments.
viii
Outside of my lab, I have been privileged to befriend a number of motivational,
inspirational, and fun cohorts. My fellow classmates made the first two years of grad
school hoop-jumping a lot more enjoyable. I've enjoyed getting some outside
perspective from Lallie McKenzie and Elsa Johnson. The professional development and
mentoring that I have gotten from Women in Graduate Sciences members, specifically
Suzanne Buck, has been appreciated.
Lastly, I would like to thank my friends and family. I'm glad to have spent much
of my free time with Rachel and Charlie Swor and Lauren and Ian Moody. My parents,
Mark and Gloria, and my siblings, Margie, Carrie, Terry and Elena, have been very
supportive over the last five years. Finally, John, thank you for sharing Oregon with me.
To John and our final grad school experiment. I hope she turns out like her dad.
ix
TABLE OF CONTENTS
Chapter Page
1. KINETICS, THERMODYNAMICS, AND STRUCTURE OF THE
ARSENIC(III)-THIOLATE BOND. 1
General Overview............. 1
Introduction...... 2
Kinetics of the As(III)-Thiolate (As-S) Bond 6
Kinetics of Small Biomolecule-Arsenic Adducts 6
Kinetics of the As-S Bond Within Nanoreactors 7
Kinetics of As-S Bonds Within Proteins......................................................... 9
Thermodynamics of the As(III)-Thiolate (As-S) Bond......................................... 12
Thermodynamics and Kinetics of Inversion at the As-Center 18
Preferred Geometries for As(III)-Thiolate Complexes 23
Trithiolate Complexes 25
Halo-Arsenic Dithiolate Complexes 29
Organic Dithiolate Complexes 32
Heteroatom-Arsenic Dithiolate Complexes 34
Non-Trigonal Pyramidal Geometries 36
Protein Mimics and Supramolecular Arsenic-Thiolate Chemistry............ .... ....... 39
Protein Mimics.. 39
Supramolecular Chemistry 42
---_._- - ---.
x
XI
Arsenic-Containing Cryptands , 43
Arsenic-Containing Macrocycles 46
Higher-Order Structures........................... 53
Conclusions 55
Bridge to Chapter 11................ 55
II. DIASTEREOSELECTIVITY IN THE SELF-ASSEMBLY OF AszLzClz
MACROCYCLES IS DIRECTED BY THE As-n INTERACTION 57
Introduction. 57
Results and Discussion.......................................................................................... 59
Mechanism of Interconversion........................................................................ 68
Conclusion................. 71
Experimental Section.............. 71
General Procedures 71
Synthetic Procedures...... 72
2,6-bis(bromomethyl)naphthalene 72
2,6-bis(mercaptomethyl)naphthalene 72
Asz(Lz,6)ZClz 73
1,5-bis(bromomethyl)naphthalene 73
1,5-bis(mercaptomethyl)naphthalene 74
Asz(LI,5)ZClZ 74
l,4-bis(bromomethyl)naphthalene 74
· ------------------
XlI
1,4-bis(mercaptomethyl)naphthalene 75
Asz(L1,4)zCh 75
X-Ray Crystallography 76
Bridge to Chapter III 78
III. HOST-GUEST INTERACTIONS IN A SERIES OF SELF-ASSEMBLED
AszLzCh MACROCYCLES 79
Introduction.............. 79
Results and Discussion.......................................................................................... 81
anti-Aszl zClz 84
anti-Asz2zClz 87
Asz3zCh........................................................................................................... 88
[(Asz3zCh)z'Guest] Dimers 89
anti-Asz3zClz 92
Structural Trends in AszLzCh Macrocycles 92
Conclusion............................................................................................................. 94
Experimental Section............................................................................................ 94
General Procedures......................................................................................... 94
Synthetic Procedures 95
4,4'-bis(mercaptomethyl)biphenyl 95
Aszl zClz , '" 95
4,4'-bis(mercaptomethyl)-trans-stilbene 96
Chapter
xiii
Page
Asz2zClz 97
1,4-dimethoxy-2,5-bis(mercaptomethyl)benzene 97
As232Ch 98
Volume Calculations using GRASP 98
X-Ray Crystallography 99
Disorder in Crystal Structures 100
Measurement of Bend in Biphenyl Ligand 101
Bridge to Chapter IV.............................................................................................. 102
IV. OBSERVATION OF REACTION INTERMEDIATES AND KINETIC
MISTAKES IN A REMARKABLY SLOW SELF-ASSEMBLY REACTION 103
Introduction............................................................................................................ 103
Results and Discussion 105
Conclusion............................................................................................................. 110
Experimental Section............................................................................................. 111
General Procedures.......................................................................................... 111
Synthetic Procedures........................................................................................ 111
As2La2Ch.................................................................................................... 111
As2Lb2Ch 111
As2LCCl4 112
Mass Spectrometry Experiments 112
X-Ray Crystallography 113
Chapter
XIV
Page
Bridge to Chapter V 114
V. "SUPRAMOLECULAR TRANSMETALLATION" LEADS TO AN
UNUSUAL SELF-ASSEMBLED P2L3 CRYPTAND 115
Introduction 115
Results and Discussion.......................................................................................... 116
Conclusion............................................................................................................. 123
Experimental Section 124
General Procedures 124
Synthetic Procedures 124
Bi2L3 124
Sb2L3 125
As2L 3 125
P2L3............................................................................................................ 126
X-Ray Crystallography 127
Bridge to Chapter VI 128
VI. SELF-ASSEMBLED E2L3 CRYPTANDS (E = P, As, Sb, Bi):
TRANSMETALLATION, HOMO- AND HETEROMETALLIC
ASSEMBLIES, AND CONFORMATIONAL ISONIERISM 129
Introduction........................................................................................................... 130
Results and Discussion.......................................................................................... 131
Symmetric and Asymmetric E2L3 Cryptands.................................................. 131
xv
Chapter Page
Solid-State Structures................................................................................. 133
Solution Structures 136
Mechanism of Ligand Flipping 142
Heterometallic EE'L3 Cryptands 143
Conclusion 147
Experimental Section 148
General Procedures.......................................................................................... 148
Synthetic Procedures 149
AsSbL3 149
AsBiL3 149
PSbL3 150
X-Ray Crystallography 150
Crystallographic Data for AsSbL3·CH3CN 152
Crystallographic Data for AsBiL3·2(CHCh) 152
Crystallographic Data for SbPL3·CH3CN 152
Bridge to Chapter VII 153
VII. CONCLUSIONS AND FUTURE OUTLOOK 154
Introduction 154
Potential Future Directions 155
Transmetallation Reactions.............................................................................. 155
Chapter
xvi
Page
Guest Inclusion................................................................................................ 156
Self-Sorting 156
APPENDICES............................................................................................................. 158
A. ADDITIONAL NMR SPECTROSCOPY AND MALDI MASS
SPECTROMETRY DATA FOR THE SELF-ASSEMBLY OF AszLzCh
MACROCYCLES 158
B. SUPPLEMENTARY DATA FOR THE CHARACTERIZATION OF
GROUP IS-CONTAINING CRYPTANDS 165
REFERENCES............................................................................................................ 182
xvii
LIST OF FIGURES
CHAPTER I
1. Structure of 4-sulfophenylarsonous acid (13) and kinetic scheme showing
binding of arsenic within pore to give isomeric products 14~A and 14~B 8
2. Recombinant human a-domain and ~-domain 10
3. Cartoon and stick representations of the X-ray crystal structure of 36................. 25
4. Cartoon and stick representations of the X-ray crystal structure of 37................. 26
5. Stick-representations of the X-ray crystal structures of 38, 39, and 40 27
6. Cartoon and stick-representation of the X-ray crystal structure of 41.................. 28
7. Cartoon and stick-representation of the crystal structure of 42............................ 29
8. Stick-representations of crystal structures of 43,45,46,44, and 47 31
9. Cartoon and stick representations of 48 32
10. Cartoon and stick representations of 49 " 32
11. Cartoon and stick representations of the X-ray crystal structure of 50.......... ....... 33
12. Cartoon and stick representation of the X-ray crystal structure of 30.................. 35
13. Cartoon and stick representations of the X-ray crystal structure of 55 36
14. Stick representations of the X-ray crystal structures of 56,57, and 58................. 38
15. Cartoon and stick representations of the X-ray crystal structure of 59................. 38
16. Cartoon representation of synthesis of As-coordinated three-helix coil (60) 40
17. Representations of the X-ray crystal structure of 61............................................. 41
18. Cartoon representation of AsCIII) binding to an a-helix 42
-~ ._-~~~._-------
xviii
Figure Page
19. Cartoon and stick representations of the X-ray crystal structure of 62................. 44
20. Cartoon and stick representations of the X-ray crystal structure of 63 45
21. Transmetallation reaction and the X-ray crystal structure of 64........................... 46
22. Representations of the X-ray crystal structure of syn-66 and anti-66................... 47
23. Representations of the X-ray crystal structures of 67,68, and 69........................ 48
24. Representations of the X-ray crystal structures of 70 and 71 49
25. Representations of the X-ray crystal structures of 72 50
26. Representations of the X-ray crystal structures of 73,74,75, and 76.................. 51
27. Cartoon and stick representations of the X-ray crystal structures of 77............... 53
28. Cartoon and stick representations of the X-ray crystal structures of 78............... 54
29. Representations of the X-ray crystal structures of cis-79 and trans-79 54
CHAPTER II
1. Partial ball and stick models showing two conformations......... 60
2. Representations of single-crystal X-ray structures................................................ 61
3. Methylene region of the IH NMR spectra of As2L2Clz macrocycles.................... 64
4. Variable temperature IH NMR spectra for As2(L1,4h Clz macrocycles................. 66
5. Variable temperature IH NMR spectra for AS2(L2,6hClz macrocycles................. 67
6. Representations of three conformers of As2(L1,4)2Clz'C6~ 70
CHAPTER III
1. Representation of single-crystal X-ray structure of anti-As2bClz........................ 84
- _ ..- - _._----------
XIX
Figure Page
2. Representations of single-crystal X-ray structure of anti-As222Ch, 88
3. Representations of single-crystal X-ray structure of inclusion complexes 91
4. Representations of single-crystal X-ray structure of anti-As232Cb 93
5. Representations of the disorder in the X-ray crystal structures 101
CHAPTER IV
1. X-ray crystal structure representations.................................................................. 105
2. CH2 region of IH NMR spectra............................................................................. 107
CHAPTER V
1. X-ray crystal structures of As2L 3, Sb2L3, and BhL3 ............................................. 117
2. IH NMR spectra for As2L 3, Sb2L3 , and BhL3 118
3. IH NMR spectra for the reaction of Sb2L 3 with AsCh 120
4. lH and 31p NMR spectra of P2L 3........................................................................... 121
5. X-ray crystal structure of P2L3 122
CHAPTER VI
1. X-ray crystal structures of symmetric cryptands................................................... 133
2. Overlayed X-ray crystal structures of P2L3 and BhL3 135
3. Crystal structures of AsCh, SbCh, and BiCh cocrystallized with
hexamethylbenzene 136
5. Representations of symmetric E2L 3 and E2L3-asym 138
Figure
xx
Page
6. Liquid chromatography mass spectrometry data 139
7. X-ray crystal structures of AsSbL3, AsBiL3, and PSbL3...................................... 145
8. IH NMR spectra of PSbL3, AsSbL3, and AsBiL3................................................. 146
- --- ---------------
XXI
LIST OF TABLES
Table Page
CHAPTER II
1. Crystallographic Data and Refinement Parameters for As2(L2,6)2Cb,
As2(L1,5)2CI2, As2(L1,4)2Cb'CHCh, and AS2(LI,4)2CI2'C6H6 62
2. Selected Bond Lengths and Angles....................................................................... 63
CHAPTER III
1. Crystallographic Data and Refinement Parameters for As212Cb, As222Cb,
and As232Cb 83
2. Selected Bond Lengths (A) and Angles (0) 85
CHAPTER VI
1. Select Distances and Bond Angles for E2L3 Cryptands........................................ 134
2. Select Distances and Bond Angles for EE'L3 Cryptands 145
-- -- - -._---------
XXll
LIST OF SCHEMES
Scheme Page
CHAPTER I
1. Reaction of alkyl-spaced dithiols with lewisite in pigeon brain mince................. 13
2. Ligand-exchange reaction of AS(GS)3 (8) with DMSA (18) 14
3. Competition experiment of DMSA with DTE 14
4. Reaction of sodium arsenite with cysteine 15
5. Reaction of sodium arsenite with glutathione 15
6. Stability constants of complexes reported by Wilcox 17
7. Pyramidal inversion of ethylmethylphenylarsine.................................................. 19
8. Inversion by the breaking/reforming of As-S bond 19
9. Inversion by the breaking/reforming of As-Cl bond............................................. 20
10. Inversion of 32 20
11. Inversion of 33 21
12. Inversion of 34 22
13. Inversion of 35 23
14. Synthesis of 59 39
15. Intermediates in the self-assembly of As2L2Cb macrocycles 52
xxiii
Scheme Page
CHAPTER II
1. The self-assembly of AszLzCh macrocycles......................................................... 58
2. Proposed mechanism for intramolecular disproportionation . 70
CHAPTER III
1. The self-assembly of AszL2Ch macrocyc1es......................................................... 82
CHAPTER IV
1. Ligands and AszL2Ch macrocycles.... 105
2. Self-assembly of AszL2Ch 108
CHAPTER V
1. The self-assembly of E2L3 cryptands 117
2. Transmetallation of Sb2L 3 to AszL 3 ...................................................................... 119
CHAPTER VI
1. Self-assembly of EzL 3 cryptands........................................................................... 132
2. Transmetallation of Sb2L 3 ..................................................................................... 132
xxiv
LIST OF CHARTS
CHAPTER I
1. Common arsenic species 4
2. Structures of glutathione (7) and AS(GS)3 (8)....................................................... 5
3. Biomolecules used in kinetic experiments by Zahler and Cleland....................... 7
4. Common geometries and conformations for As(III)thiolate compounds...... ....... 24
5. Trithiolate structures 27
6. Halo-arsenic dithiolate rings structures................................................................. 30
7. Cartoon representations of structures 51, 52, 53, and 54...................................... 34
8. S(C6~ShAsX structures 56-58............................................................................ 37
9. Kinetic mistakes observed in the self-assembly of AS2~Chmacrocycles........... 53
CHAPTER IV
1. Oligomeric kinetic mistakes. 110
CHAPTER I
KINETICS, THERMODYNAMICS, AND STRUCTURE OF THE ARSENIC(III)-
THIOLATE BOND
General Overview
This dissertation describes the supramolecular chemistry which occurs between
rigid dithiol and dithiolate ligands and the Group 15 elements (P, As, Sb, and Bi). The
majority of the work in this document focuses on the utilization of the dynamic arsenic-
thiolate bond for self-assembly, but later chapters (V and VI) apply these lessons to
phosphorus, antimony and bismuth as well. Chapter I sets the stage for the utilization of
the As(III)-thiolate bond in self-assembly by reviewing the kinetics, stability, preferred
structure, and published supramolecular chemistry of the bond. Chapters II and III
(published, co-authored) describe how steric interactions can be used to promote
stereoselectivity in the self-assembly of arsenic-containing macrocycles. Chapter IV
(published, co-authored) explores the self-assembly process, giving insight into the
kinetics of the As-S bond and supramolecular assembly. Chapters V (published, co-
authored) and VI (co-authored) apply these lessons in As-S chemistry to other Group 15
elements. The reactivity, dynamic solution behavior, and structures of a series of Group
1
215 element-containing cryptands are described. Chapter VII is a brief conclusion that
further ties together these chapters and suggests some potential future experiments.
Chapter I surveys the literature on the As(III)-thiolate bond. The strength and
lability of this bond are implicated in the toxicity of arsenic, yet the mechanism(s) of
arsenic toxicity are not fully understood. This chapter begins with a brief overview of
arsenic as a worldwide drinking water contaminant and the implications of arsenic
contamination on human health. Next, the kinetics and thermodynamics of the As(III)-
thiolate bond are reviewed. It is revealed found that the bond is kinetically labile, but
thermodynamically stable. The following section explores the preferred geometry of
As(III)-thiolate complexes by presenting a representative sample of crystal structures
containing As(lII)-thiolate bonds. Finally, the use of the As(III)-thiolate bond in protein
mimics and supramolecular assemblies is reported.
Introduction
Arsenic (As) is infamous for its toxicity and its presence in drinking water is a
worldwide health problem. There have already been several excellent reviews on
arsenic's toxicity, 1,2 distribution,3 water chemistry,4 and metabolism.5 Here, we will
review the As(III)-thiolate bond, thought to playa critical role in arsenic's toxicity.
Specifically, we aim to learn about the stability and lability of the As(lII)-thiolate (herein
referred to as As-S) bond by looking at relevant examples from the literature that report
on the kinetics, thermodynamics and structure of the bond. While many examples are
3pulled from the biochemical literature, this is not an exhaustive review of biologically
relevant As-containing molecules. This chapter will wrap with an overview of how the
As-S bond has been used in supramolecular design strategies.
Arsenic is the 20th most common element on the planet3 and, consequently, is
ubiquitous in the environment. Arsenic occurs naturally in over 300 types of minerals,
many of which also contain sulfur, and is released into the air and water during natural
weathering processes.6 Once a part of the groundwater cycle, arsenic can easily spread.
Dangerously high levels of arsenic in drinking water7 are a worldwide problem,
especially affecting highly populated regions in Asia, Europe, and North and South
America.2,4,8 The World Health Organization recommends a maximum of 10 J.lg As per
liter of drinking water, yet these limits are severely exceeded in many natural water
sources, including, but not limited to, those in Bangladesh,9,10 Vietnam,l1 and the western
and New England regions of the United States of America.12
While arsenic is naturally occurring, it can also be introduced into a local
environment by human activities such as coal burning,13 mining,14 and the use of poultry
litter as a fertilizer. 15 Arsenic has also been used medicinally throughout history.16
Currently, it can be found in treatments for African sleeping sickness (melarsoprol)17 and
acute promyelocytic leukemia (arsenic trioxide).18 Unfortunately, treatment with arsenic-
containing drugs is not without risk. In fact 4-8% of individuals treated with melarsoprol
die from the treatrnent. 19 Acute exposure to arsenic is fatal, hence its use as a poison,16,20
even to this day.21 However, many more people are affected by long term exposure to
4low levels of arsenic in their drinking water. In 2000, a risk assessment was carried out
investigating bladder, liver and lung cancer caused by exposure to arsenic in drinking
water. It was found that consumption of water containing 50 Ilg/L arsenic led to an
increased risk of cancer and, therefore, a limit set at that level is not protective of human
health.22 Regular exposure to arsenic in drinking water has been correlated with
increased rates of skin, liver, kidney, colon, bladder, and lung cance?3 as well as lesions
on the hands and feet,24 hematologic disorders, diabetes, developmental and neurological
disorders, and cardiovascular disease.2s
Arsenic toxicity has been shown to be heavily dependent on its speciation.4 In an
aqueous environment, arsenic typically exists as the arsenate (As(V» species H3As04 (1),
H2As041- (2), and HAsol- (3) (Chart 1).26 However, in vivo, arsenate is reduced to
arsenite (As(III» (4) which is more toxic.2? In humans, arsenite is known to go through a
series of methylation steps, with monomethylarsenite (MMA, 5) and dimethylarsenite
(DMA, 6) being excreted in urine (Chart 1)?8 Methylation is not necessarily a
detoxification pathway, though; MMA is known to be more toxic than arsenite.29
0 0 0
II II II
HO"6HOH HO·~s·OH HO'~s-O- HO"6~H H3C"6:'pH H C,,~sOH0- 0- 3 CH3
1 2 3 4 MMA DMA5 6
Chart 1. Common arsenic species.
5While arsenic's toxicity is legendary, its mechanism of toxicity is not well
understood, probably because arsenic interacts with so many different biomolecules in
vivo. Arsenic is very thiophilic and strong As(III)-thiolate bonding between arsenite and
cysteine has been known and studied since at least the 1920s,3°,31 Glutathione (GSH, 7)
is thought to play an important role in arsenic detoxification (Chart 2)?7 Consequently
As(III)-GSH adducts, such as AS(GS)3 (8) have been well studied32-34 by NMR3S and
mass spectrometry.36,37
o ~SHHOOC~ ~~COOH
- N
NH2 H 0
glutathione (GSH)
7
H2N.., COOH
J(COOH
HN--4o
0:t:\ H~O
HOOC,,-NH NH
S'As"'S ~
o ~ 0 ~,.NH2HOOC~ (~~ COOH~ N'f( '1
NHz H 0 COOH
As(GSh
8
Chart 2. Structures of glutathione (7) and AS(GS)3 (8).
Arsenic can cause changes to the secondary structure of cysteine-containing
proteins upon binding,38 inhibiting their functions. 39 Arsenic has been shown to bind to
metallothionein,40-48 hemoglobin,49 ArsR protein,SO,Sl galectin-1 and thioredoxin
peroxidase II,52,53 GLUT4,54 tubulin and Actin.55 In 2009, Yan and co-workers used an
6affinity selection technique to identify over 70 proteins in human lung carcinoma cells
alone that bind arsenic.56 This chapter summarizes the current understanding of the As-S
bond - knowledge that is vital to understanding arsenic's mode of toxicity.
Kinetics of the As(III)-Thiolate (As-S) Bond
The rates by which As(IlI)-thiolate complexes react are important for
understanding As-toxicity and its use in supramolecular assemblies. However, there are
limited examples of in-depth kinetic analysis of the As-S bond.
Kinetics for Small Biomolecule-Arsenic Adducts
One of the first experiments on the kinetics of the As-S bond was carried out by
Zahler and Cleland in the late 1960s.57 Rate constants for the formation and dissociation
of complexes of biologically-relevant dithiols (Chart 3) with arsenite were measured in
the course of designing a sensing assay for disulfide groups. For dithiothreitol (DTT, 9)
the rate constant for complex formation was found to be kon =4.7 X 102 sec-IM-I and the
rate constant for complex dissociation was found to be koff =1.5 X 10-4 sec-I. Similarly,
these rate constants were found to be k on = 4.5 X 102 sec-IM-I and k off = 1.7 X 10-4 sec-I for
dithioerythritol (DTE, 10), k on =1.2 X 103 sec-IM-I and 5.7 x 10-4 sec-I for 1,3-
dithioglycerol (11), and k on = 3.0 X 102 sec-IM-I and koff = 7.7 X 10-5 sec-I for 1,2-
dithioglycerol (12). It should be noted that these rates were calculated for the complex
formation which includes two As-S bonds and, in the case of DTT and possibly the
7others, an intramolecular As-O bond.58 Individual As-S bond formation and dissociation
are expected to be significantly faster, especially if the second As-S bond forms
cooperatively.
QH QH
H~SH HS~SH HS~OH HS~SHS -
OH OH SH OH
DTT DTE 1,2-dithioglycerol 1,3-dithioglycerol
9 10 11 12
Chart 3. Biomolecules used in kinetic experiments by Zahler and Cleland.57
Kinetics of the As-S Bond Within Nanoreactors
Recently, rate constants have been obtained by Bayley and co-workers for the
formation and dissociation of As-S bonds using single-molecule techniques.59•6o By
binding 4-sulfophenylarsonous acid (13) (Figure la) to a cysteine residue at position 117
within an a-hemolysin pore, kinetic measurements were carried out on the reversible
formation and dissociation of the As-S bond. In their first experiment, the pore was
modified to contain just one cysteine residue59 and rate constants were found to be kon =
2.0 X 104 M-1s-1for the forming of an As-S bond and korr =1.4 S-l for the breaking of that
bond. This gave an overall formation constant of kr =1.4 x 104 M-1at 24°C. These rate
constants were for a single As-S bond and are markedly faster than those observed for the
multiple bonds involved in complex formation by Zahler and Cleland.57
a) H¢H
8°3-
13
b)
fj
____ As,
p""" \ '··OH
S R
14-A
8
Figure 1. Structure of 4-sulfophenylarsonous acid (13) (a) and kinetic scheme showing
binding of arsenic within pore to give isomeric products 14-A and 14-B (b).6o
Moving the cysteine residue to position 137 revealed that two isomers (14-A and
14-B) formed upon reaction of 13 with the nanoreactor (Figure Ib).6o These isomers
formed with slightly different rate constants of kon =1.4 X 104 and 5.9 x 103 M-ls-l and
dissociated with rate constants of koff =1.5 and 0.40 sol for 14-A and 14-B, respectively.
The overall formation constants of kf =9.3 X 103 and 1.5 x 104 M-l are similar to that
observed when the cysteine residue was at position 117. These rate constants were
expected to be similar to those in solution and, to test this, the authors carried out
magnetization-transfer NMR spectroscopy experiments on a 2: 1 GSH-4-
sulfophenylarsonous acid adduct. A rate constant of 4.7 S·l at 30 DC was found for GSH
exchange, which was approximately the same as the rate of As-S bond dissociation in the
nanoreactor.
9Kinetics ofAs-S Bonds Within Proteins
As-toxicity is usually linked to the loss of cellular function that occurs upon As-
cysteine binding in folded proteins. Arsenite (4), MMA (5), and an aryl arsenical bind
cysteine residues in unfolded proteins preferentially over aSH (7), likely leading to a loss
in protein function. 61 The reaction of reduced riboflavin binding (Rib) protein with
excess MMA was monitored by fluorescence quenching on a stopped-flow instrument
and it was found that 60% of the decrease in fluorescence occurred in the initial fast
phase of the reaction. Pseudo-first order conditions yielded a second-order association
rate constant of 2.35 x103M-1s-1. This was on the same order of magnitude as the rates
found by Bayley and co-workers for As-S bond formation in a nanoreactor.60
Significant work has been carried out on the consequences of binding of arsenic
to metallothioneins,41-48 but only those with contributions to the kinetics of the As-S bond
will be discussed here. The recombinant human metallothioneiil (rhMT) isoform la
protein binds arsenic in the a (AS3Scysll) and ~ (AS3Scys9) domains (Figure 2). Time- and
temperature-resolved electrospray mass spectrometry was used to conduct a complete
kinetic analysis of the reaction of these isolated domains with As(III).62 At pH 3.5 and
room temperature, the individual rate constants were found to be 5.5, 6.3, and 3.9 M-1s-1
for the first, second, and third binding events to the a-domain and 3.6, 2.0, and 0.6 M-1s-1
for the ~-domain. These rate constants are significantly slower than those in the unfolded
Rib proteins61 and Bayley's nanoreactor.60 Respectively, the activation energies were
measured at 7.9,6.9, and 5.5 kcal/mol for the a-domain and 7.6,8.4, and 6.9 kcal/mol for
10
the ~-domain. In each case, the activation entropies were negative (between -30.4 and -
39.4 kcal/mol) and the activation enthalpies were positive (between 4.8 and 7.9 kcal/mol)
giving very consistent activation free energies of between 16.3 and 17.4 kcal/mol at 25
cys cys ser cys s Iu ser a a
et aSR fO apn cys cys ser cys c 5 ro me
s cys ser asn cys 5 CYS U 5 cys S
etas fO ncssercysaatrb)
aa
aa
aa
ala
scsvacys
ys
ys
alaY-a"""a""a""la.i::a"'a
a)
Figure 2. Recombinant human a-domain (a) and ~-domain (b).62
Next, this electrospray mass spectrometry analysis was extended to the complete,
two domain rhMT isoform 1a protein and the results were compared to those for the
isolated domains.63 It was found that the complete protein binds As(III) faster initially
and that each successive binding event occurs slower, which implies a non-cooperative
mechanism. Sequential rate constants for the binding events were found to be k = 25, 24,
29,14,8.7, and 3.7 M-1s-1. The authors attributed the faster binding in the complete
protein to the larger number of binding sites for arsenic (six compared to three for each
domain). Activation energies were found to be 3.3 kcal/mol for the first event and 5.3
kcal/mol for each subsequent event. Again, the activation entropies were negative
(between -33.0 and -42.5 kcal/mol) and the activation enthalpies were positive (between
11
2.9 and 6.0 kcal/mol) giving very consistent activation free energies of between 15.3 and
16.5 kcal/mol at 25°C. The authors concluded that increasing the number of equivalent
binding sites in a protein increased the rate at which metals bind, implying that
metallothionein may have evolved two sites in order to scavenge metals more efficiently.
The two domain F. vesiculosus metallothionein, found in seaweed, was also
subjected to kinetic analysis upon As-binding.64 Rate constants of 19.8 and 1.4 M-1s-1
were found for the y domain and 16.3,9.1 and 2.2 M-1s-1 for the Pdomain and the authors
concluded that the length of the interdomain linker in multi-domain metallothioneins had
a direct effect on the rate of binding metals. Again, there were similar activation energies
(8.1 and 7.9 kcal/mol for the y domain and 7.6, 8.4, and 6.5 kcal/mol for the Pdomain)
with an average of 7.6 kcallmol. Activation entropies (between -26.8 and -36.6 kcal/mol
with average ~S* =-30.8 kcallmol), activation enthalpies (between 6.0 and 7.9 kcallmol
with average ~H* =7.2 kcallmol), and activation free energies (between 15.5 and 17.2
kcallmol with average ~G* = 16.5 kl/mol) were similar to those found for the transition
state in the human form of the protein.
More recently, this kinetic analysis has been extended to two three-domain
proteins: recombinant PPP and aaa human metallothionein la, which contain 27 and 33
cysteine residues respectively.65 Arsenic binding was found to be noncooperative at 198
K, with rate constants of 40, 36, 37, 26, 27, 17, 12, 6, and 1 M-1s-1 for the PPP protein and
52,45, 46, 42, 38, 36, 29, 25, 14, and 6 M-1s-1 for the aaa protein.
12
Thermodynamics of the As(III)-Thiolate (As-S) Bond
As with the kinetic studies, much of the thermodynamic data on the As-S bond
comes from biologically-relevant examples. In addition to measuring rate constants,
Zahler and Cleland measured dissociation constants for arsenite-dithiolate adducts during
the design of their free thiol sensing assay (Chart 3).57 These dissociation constants can
be converted to stability constants for comparison to the more recent literature. They
concluded that, surprisingly, the five-membered ring adduct with 1,2-dithioglycerol (11)
was the most stable with K = 3.8 X 106M-1, followed by two seven-membered ring
adducts with OTT (9) (K =3.0 x 106 M-1) and OTE (10) (K =2.7 x 106M- 1). Finally, the
six-membered ring adduct with 1,3-dithioglycerol (12) was the least stable (K =2.0 x 106
M-1). It has since been shown that the As-OTT complex is actually bicyclic in structure,
not the seven-membered ring that the authors proposed. This does not mean that there is
any problem with the stability constants reported for these complexes, but that
correlations between ring size and stability cannot be drawn.
These results directly contradict Whittaker's previous experiments in which
dithiols (15) with varying spacer lengths were tested to see which would reactivate
pigeon brain pyruvate oxidase most effectively after poisoning with lewisite (16)
(Scheme 1).66 Stability constants were not reported, but the relative stability of the
lewisite-adducts (17) with rings of varying size were reported. The authors concluded
that rings containing five, six, and 9-13 atoms were the most stable. Larger rings and
those containing seven or eight atoms were the least stable. However, disulfides in the
13
pigeon brain mince could have oxidized dithiols to varying degrees and dithiobutane has
the lowest redox potential of the series giving a possible explanation for the discrepancy
in S-As-S-containing ring stabilities. Several monothiols were found to be less stable
than the rings and the enzyme-lewisite adduct.
HS~SH + CI~AsCI
I
n ~ 0-12 CI
15 Lewisite16
pigeon brain
•
Scheme 1. Reaction of alkyl-spaced dithiols with lewisite in pigeon brain mince.66
The relative stabilities of several other monothiolate and dithiolate adducts of
arsenite have also been reported. NMR spectroscopy showed exchange when
dimercaptosuccinic acid (DMSA, 18) was added to a solution of a (glutathione)3-arsenite
complex (AS(GS)3) (8) (Scheme 2),35,67 further establishing the greater stability of
dithiolate-arsenite adducts over monothiolate-arsenite adducts.68 Additionally, DMSA
was shown to form a more stable complex (19) (five-membered ring) with arsenite than
was DTE (10) (seven-membered ring) (Scheme 3). This is in agreement with both Zahler
and Cleland's57 and Whittaker's66 results.
8SH
+ Hooc0coOH
SH
DMSA
18
·OOC COO·
rS' /SXAs-S S-As
-OOC S' H 's COO·
'OOC COO·
As2(DMSAh
19
14
Scheme 2. Ligand-exchange reaction of AS(GS)3 (8) with DMSA (18).35,67
SH
HOOC0cOOH
SH
18
OH
+ HS~SH
OH
10
-----l..~ Asz(DMSAh
pH =6.5
19
Scheme 3. Competition experiment of DMSA (18) with DTE (10).35,67
While these results indicate that monothiolate-arsenic adducts are not as stable as
dithiolate adducts, they are still thought to be an important part of the arsenic
detoxification route in many animals. Studying the stability of glutathione adducts with
arsenite and MMA in rat bile revealed that neither AS(GS)3, nor CH3As(GS)z, is stable
under physiological conditions.69 However, As-treated rats had increased concentrations
of glutathione present in their bile and it was found t.~at both adducts were stabilized in a
GSH concentration-dependent manner.
15
In 2004, Pereira-Maia et al. monitored potentiometric and spectroscopic titrations
of cysteine (20) and glutathione (7) with sodium arsenite. The stability constants for the
adducts that formed were log K =29.84 for AS(CyS)3 (21), log K =12.01 for
As(Cys)(OHh- (22), log K =32.0 for AS(GS)33- (8), and log K =10 for As(GS)(OH)l-
(23) (Schemes 4 and 5).70
'S
I
As
0- S.... 'S-.
~ ,I "', NH +," / 3o ' -o~
NH3+ 0
21
....
pH = 2-8.4
log K::; 29.84
o
+H N \I
3 ~O-
"SH
cysteine (CysH)
20
pH::; 8.5-10
log K = 12.01
...
o
H2N~0_
"s
I
AsHO.... 'OH
22
Scheme 4. Reaction of sodium arsenite with cysteine.7o
Scheme 5. Reaction of sodium arsenite with glutathione.7o
H1N,.,COO'
NaAs02
pH::; 8.5-10 ... HN 0
logK::; 10 00,
(NH S~s,OH
COO' OH
23
o (SH
oil[ Na_As02 'OOC~N~~"-./'"COOH
pH - 2-8.4 NH + H 0
log K::; 32.0 3
glutathione (GSH)
7
8
16
These stability constants are inconsistent with those reported the following year
by Wilcox et al. for the As(GS)l- (8).71 Using near-UV absorption spectroscopy and
isothermal titration calorimetry (ITe), the thermodynamics of arsenite and MMA
coordinated by GSH (7), DMSA (18), dihydrolipoic acid (DHLA, 24), and DTT (10)
(Scheme 6) were quantified. Based on their spectroscopic data, they concluded that
neither arsenite nor MMA formed particularly stable complexes (8, 25) with GSH (fJ =
1.0 X 107 for arsenite and fJ =2.3 X 107 for MMA), but that arsenite and DHLA do form a
very stable 2:3 complex (26) (fJ =4 X 1018). Other than this arsenite-DHLA adduct,
MMA complexes (K = 2.7 x 105 for 1:1 complex with DMSA (27), K = 3.2 X 106 for 1:1
complex with DHLA (28), and K =2.0 x 106 for 1:1 complex (29) with DTT) were found
to be more stable than arsenite complexes (fJ =5 x 109 for 1:2 complex with DMSA (19),
fJ = 4 X 1018 for 2:3 complex (26) with DHLA, and K = 1.1 X 106 for 1:1 complex (30)
with DTT).
17
25
27
MMA
__-----.,..... CH~s(DMSA)
K=1.0x107
o ~SHNaAs02 II H MMA~ 6HOOC~N N,-"""COOH .. CH~s(GSh
fJ=1.8 x 10 NH2 H 0 j3=1.3x107
glutathione (GSH)
7
SH
HOoc0cOOH
SH
OMSA
18
8
19
As(GSh
NaAs02
As(DMSA)2 .....~f-----
Ij= 8.3 x 108
NaAs02
As2(DHLAh .....f-----
j3= 4 x 1018
26
rY(CH2)4COOH
SH SH
DHLA
24
MMA
__-----.,..... CH~s(DHLA)
K=1.1 x107
28
As(OTT) ....1-----
K= 9.5 x 105
30
OH
- SHHS~
OH
OTT
10
MMA
------l..... CH~s(DTT)
K = 8.2 x 105
29
Scheme 6. Stability constants of complexes reported by Wilcox.7 ! All values are taken
from ITC data except for Asz(DHLA)3.
Calorimetric data was obtained under almost identical conditions and the binding
constants compare well with those obtained by spectroscopy (jJ =1.8 x 106 for 8, p=8.3
X 108 for 19, p=2.1 X 105 for 26, and K =9.5 X 105 for 30, p=1.3 X 107 for 25, K =1.0
X 107 for 27, K =1.1 X 107 for 28, and K = 8.2 X 105 for 29). The most glaring
discrepancy between UV and ITC results are the stability constants calculated for 26, but
the authors conclude that ITC cannot accurately account for the 2:3 stoichiometry and
that the optical data is more accurate in this case. ITC also revealed thermodynamic
18
parameters for the formation of each of these As(Ill)-thiolate complexes. In general, it
was found that formation became increasingly entropically unfavorable as ring size was
increased. However, in each case the formation of the As-S bonds was exothermic and
the formation of the complexes was favorable.
As previously mentioned, these results do not agree with those reported by
Pereira-Maia et a1.70 However, the stability constant reported here by Wilcox for 30 (K =
1 x 106) does agree closely with that reported by Zahler and Cleland (K =3 x 106 M-1),
despite the use of very different methods of measurement.57 Wilcox's measurements also
agree with previous observations that DMSA will extract As(IlI) from glutathione.35,67
Glutathione will form fully saturated complexes of arsenite, MMA, and DMA on
a size-exclusion column with glutathione buffer under conditions resembling those within
hepatocyte cytoso1.32,33 Temperature-dependent retention behavior of these arsenic
compounds revealed that the As-S bonds in CH3As(SG)2 (25) and (CH3hAs(SG) are
more stable than those in As(SGh (8).
Thermodynamics and Kinetics of Inversion at the As-Center
In some cases, As(III)-thiolate complexes exist as stereoisomers due to the
stereochemistry at the As-center. The lone pair of electrons on As(III)R3compounds is
stereochemically active due to the high barrier to inversion. Pyramidal inversion of this
lone pair of electrons is known to be higher in energy in arsines than in amines or
phosphines.72,73 The first experimental measurement of the pyramidal inversion energy
19
of an arsine was carried out on ethylmethylphenylarsine (31) and found to be ~Gt =42-
46 kcallmol at 218°C (Scheme 7).74 This is significantly higher than the energy
requirement that had been previously calculated for lone pair inversion in arsines.75•76 A
rate constant of 1.4 x 10-6 sec-l was reported for the pyramidal inversion.
AGi = 42-46 kcal/mol
decalin
Scheme 7. Pyramidal inversion of ethylmethylphenylarsine (31).74
While pyramidal inversion is very slow, inversion at the arsenic center can also
occur by the breaking and reforming of bonds to arsenic. In As(III)-S and As(III)-CI
complexes, inversion can occur through the breaking and reforming of AS_S60,77,78
(Scheme 8) or As-CC9 (Scheme 9) bonds, respectively. Either of these routes to
inversion is expected to be faster and lower in energy than inversion of the lone pair.
Scheme 8. Inversion by the breaking/reforming of As-S bond.
20
Scheme 9. Inversion by the breaking/reforming of As-CI bond.
The first experimental measurements of the energy of inversion for compounds
containing As-S bonds was carried out on several dithiarsolanes using 1H NMR
spectroscopy.80 Here, the barriers were measured assuming coalescence at the highest
temperature attained (197°C). However, coalescence, or even line broadening, was not
actually observed and consequently the reported values for the barrier to inversion are
lower limits and the actual barriers can be expected to be significantly higher. The lower
limit was measured as i1G:j: = 26 kcallmol for both PhAs(SCH2CHMeS) (32) in
cWoroform and PhAs(S-i-C3H7)2 in benzene (Scheme 10).
AG:t: > 26 kcal/mol
..
Q
r,;jAs" ..~---1
w \'~.
S CH3
5-32
Scheme 10. Inversion of 32.80
21
Compounds with stereoisomers at the As-center are not necessarily energetically
equivalent. Configurational isomers of arsenicals with different thermodynamic
stabilities have been reported81 as have several examples79,82,83 of isomeric As-containing
macrocycles. The latter will be discussed in detail in the "Supramolecular Arsenic
Chemistry" section below.
In order to study the interconversion of stereoisomers, six-membered S-As-S-
containing heterocycles were examined.77 When crystals of the (2RS,4RS)-33 isomer
were dissolved in chloroform, they slowly (over several days at room temperature)
converted to an equilibrium mixture consisting of 84% of that isomer and 16% of the
(2SR,4RS)-33 isomer (Scheme 11). In methanol, this conversion was much faster and
gave a final ratio of 85:15, corresponding to a 8.Go =1.0 ± 0.2 kcallmol and an inversion
energy of 8.Gt =26 kcallmol at 25°C. Again, it was concluded that inversion occurred
through the breaking and reforming of As-S bonds, not pyramidal inversion at the As-
center. Because the rates of inversion were faster in methanol than in chloroform, the
authors interpreted the inversion to occur by acid catalysis.
oY AG:I: = 26 kcal/mol&JA~§.:3:(CH2)4COOH ::;o~r=========!~
(2RS,4RS)-33
Scheme 11. Inversion of 33.77
e
UA!"~(CH2)4COOHI Sh-
(2SR,4RS)-33
22
Five- and six-membered isomeric rings containing S-As-S units were found to
interconvert.78 A double irradiation NMR experiment was used to obtain rate constants
for interconversion between the geometric isomers. The phenyldichloroarsine adduct of
1,3-dimercapto-2-propanol, 34, was found to exchange with rates of k1 = 0.419 S-1 and k2
=1.588 S-1 at 298 K (Scheme 12). Activation energies for this exchange were measured
at 10.25 kcaVmol for Eal and 8.83 kcaVmol for Ea2• For the 1,2-dimercaptopropane
adduct, 35, rates of kl = 0.975 S-I and k2 = 2.273 S-1 at 295 K and activation energies of
13.66 kcaVmol for Eal and 13.36 kcaVmol for Ea2 were measured (Scheme 13), revealing
that the five-membered ring is slightly more stable than the six-membered ring.
Additionally, it was found that the exchange rates increased with increasing concentration
of adduct or Hel and were affected by the addition of excess phenyldichloroarsine, but
not by excess ligand. In both cases inversion occurred through the breaking and
reforming of an As-S bond.
trans-34
Scheme 12. Inversion of 34.78
k1 =0.419 5.1
Ea1 = 10.3 kcal/mol
k2 = 1.588 5.1
Ea2 = 8.83 kcal/mol
cis-34
Q
<9A~~CH3
cis-35
Scheme 13. Inversion of 35.78
k1 = 0.975 S·1
Ea1 = 13.7 kcal/mol
k2 =2.273 S-1
Ea2 = 13.4 kcal/mol
..
e
crA~ S--7'-..CHI S::::..-' 3o
trans-35
23
The kinetic analysis of the As-S bond within a nanoreactor by Bayley et al. also
contained data on the rate constants for inversion between the two isomers.6o They found
that inversion occurred slowly relative to the breakdown of the As-S bond and less than
8% of all bond-breaking and forming events resulted in inversion. Inversion between
isomers 14-A and 14-B occurred with rate constants of kAB =7.1 X 10-2 and kBA =4.9 x
10-2 S-1 (as compared to koff =1.5 and 0.4 S-I) (Figure 1). The authors concluded that the
process of inversion was based on an As-S bond breaking/reforming mechanism.
Preferred Geometries for As(III)-Thiolate Complexes
200484 and 200585 searches of the Cambridge Structural Database (CSD) revealed
only 59 examples of crystal structures in which an As(lIl) ion was coordinated by one or
more organic thiolate ligands. Of these, only 14 contained an As(III) ion that was also
bonded to a carbon. This chapter will not cover every structure in the database, but will
present a representative set of examples. These examples show that when bound by
thiolates, As(lIl) typically has a predictable trigonal pyramidal coordination geometry
which features a stereochemically active lone pair of electrons (Chart 4, left). However,
24
secondary bonding interactions (SBls) between arsenic86 and aryl rings87-90 or
heteroatoms such as oxygen,85 sulfur,91,92 or the halogens93 can cause distortion of this
preferred geometry. Extreme distortion results in a trigonal bipyramidal geometry around
the arsenic atom (Chart 4, left center).
e R1 eI .. \R3 ) R ~ R RAs., ([)As -120° /AS., \/ t!I/ \ "/R3 I ..~ \"'/8R1 R 8 8 I~2 V90° I I R 8 8
-90-100° R R
Trigonal Trigonal
exo endoPyramidal Bipyramidal
Chart 4. Common geometries (left) and conformations (right) for As(III)thiolate
compounds.
Arsenic can also sit in either an endo or exo position relative to the ligands bound
to it (Chart 4, right). When in the exo position, the lone pair of electrons on arsenic is
relatively exposed as a result of the positioning of the thiolate ligands. In the endo
configuration, the lone pair is "protected" and points in the same direction as the S-C
bonds of the thiolate ligands. Examples of arsenic in both the endo and exo positions
have been observed and in each case may result from steric bulk or SBls. Like so many
features of crystal structures, the positioning of arsenic could also be a simple
consequence of crystal packing forces. The following examples of As(III)-thiolate
complexes are organized based on the identity of the atoms bound directly to arsenic.
The vast majority of examples come from X-ray crystal structures, but NMR, JR, and
25
EXAFS spectroscopy have all be used to glean structural information of arsenic
complexes.
Trithiolate Complexes
The X-ray crystal structure of tri(phenylthio)arsine (36) shows that it is C3-
symmetric and has an As-S bond length of 2.24 Aand a S-As-S angle of 96° (Figure 3).94
The As-center sits in the endo conformation, possibly because this orientation minimizes
steric interactions between the ligands. A comparison was drawn between the C3 solid-
state structure to the time-average C3v solution structure in which the As-center is also
believed be in the shielded endo conformation.95
b)
Figure 3. Cartoon (a) and stick (b) representations of the X-ray crystal structure of 36.94
The treatment of N-(2-mercaptoethyl)-1,8-naphthalimide with AsCh and base
gave 37 (Figure 4).85 The final structure of 37 is trigonal pyramidal but somewhat
distorted due to steric interactions which allow only one weak As···O SBI with arsenic to
26
form. This interaction causes no elongation of the As-S bonds (2.23, 2.24, and 2.24 A),
but the S-As-S bond angles are far from equal (95, 96, 106°). The endo conformation of
the As-center in this example may result from this SBI.
a)
~.,.:...... .'....,. ..
.'
Figure 4. Cartoon (a) and stick (b) representations of the X-ray crystal structure of 37.85
Recently, the structures of three new trithiolate arsenic complexes were reported
(Chart 5, Figure 5).96,97 Compound 38 contained two five-membered rings linked
covalently by an -SCH2CH2S- unit with As-S distances ranging between 2.23 and 2.27 A
and S-As-S bond angles between 93 and 102°.96 The longest bonds and widest angles
around arsenic involved those sulfur atoms that were not a part of a ring system.
Compound 39 contained three pentafluorophenylthiolate ligands bound to arsenic (Chart
5, Figure 5)96 Unlike its non-fluorinated analogue 36,94 this complex did not crystallize
with C3 symmetry. Instead, unequal S-As-S angles of 88, 98, and 99° were reported.
Additionally, As-S distances (2.26-2.27 A) were slightly longer than in 36 (2.24 A),
27
suggesting that electronic effects can influence the length of As-S bonds. In the solid
state structures of both 39 and 36, the As-center was in the endo conformation.
/SJS-As
S ~ 'sC~s-s
S
38
o:S, Q Q /SX)I ~s-S S-S S-As.. Ih S S h
40
Chart 5. Trithiolate structures.96,97
a)
Figure 5. Stick-representations of the X-ray crystal structures of 38 (a), 39 (b), and 40
(C).96,97
A third structure, 40, was reported separately (Chart 5, Figure 5).97 Here, an
unusual disulfide linkage was tethered between two arsenic centers. Angles and
distances around the As-center were very similar to those observed in 38, with As-S bond
28
lengths of 2.23, 2.25, and 2.29 A and S-As-S angles of 92, 103, and 104°. The slightly
wider bond angles for 40 were likely due to the difference in length of the hydrocarbon
backbones between 39 and 40. 38,39, and 40 had trigonal pyramidal geometry and the
As-centers in 38 and 40 were in the exo conformation.
The simple arsenic trithiolate complex 41 was prepared by the treatment of 2-
mercaptomethylnaphthalene with AsCh (Figure 6) in the presence ofbase.98 As-S
distances (2.23, 2.24, 2.25 A) and S-As-S angles (95, 98, 102°) were in the typical range
for a trigonal pyramidal arsenic center. Asymmetry around the As-center resulted from
SBIs in the solid state. A single As···x SBI to one ligand and x-x stacking of the
naphthalene rings were observed. Here, the As-center is in neither the exo nor the endo
conformation, with two ligands positioned toward the arsenic lone pair and one
positioned away from it.
a) b)
s~~s.AsIVV
.;:;.;:; su
41 lJ
Figure 6. Cartoon (a) and stick-representation (b) of the X-ray crystal structure of 41.98
In each of the examples reported above, As-S distances were between 2.23 and
2.29 A and S-As-S angles were between 92 and 106°. When no SBIs were present in the
29
solid state, the bond angles were equal, or close to it, and the geometry was clearly
trigonal pyramidal. SBIs distorted the symmetry and angles around the As-center, giving
the geometry some degree of trigonal bipyramidalism. The structures suggested that
there is no general preference for either the endo or exo conformation at the As-center in
trithiolate complexes. In each case the observed orientation seemed to be due to steric
interactions, SBIs, or crystal packing forces, although some subtle electronic "donor-
acceptor" type interactions may be involved.
Halo-Arsenic Dithiolate Complexes
While preparing 37, crystals of 42 were also isolated (Figure 7). Here, As-S bond
lengths of 2.22 and 2.23 Awere observed. These were just slightly shorter than the As-S
bonds in 37, likely a result of the electron-withdrawing ability of the chloride ligand. The
S-As-S of 92° was smaller than those observed in 37, probably because the steric bulk of
chlorine caused S-As-CI bond angles of 98 and 101°.85 The As-center is in the endo
conformation and arsenic is involved in one short As.. ·Q SBI.
b)
Figure 7. Cartoon (a) and stick-representation (b) of the crystal structure of 42.85
30
Five new XAs(SRS) structures where X =Cl or I and R =(CH2)z, (CH2)3, or
(CH2C6~CH2)were recently reported (Chart 6, Figure 8).96 These five, six, and seven-
membered S-As-S ring complexes allowed insight into the effects of halogen identity and
ring size. Compound 43, a five-membered ring with chloride substitution on arsenic, had
an S-As-S angle of 93° and S-As-Cl angles of 98°. Replacement of chloride with iodide
gave compound 44. Here, the angles were very similar to those in 43, showing that
identity of the terminal halide had very little effect on the structure of the ring, despite
being in the axial position. The six-membered, chlaro-substituted compound 45 had a
significantly wider S-As-S bond angle of 102°, suggesting slight ring strain. Again, there
were similar bond angles in the iodinated compound 46. In the seven-membered ring 47,
a S-As-S bond angle of 105° suggested increased ring strain. Based on these
observations, strain increased with ring size. These results were in line with previous
observations that in S-As-S-containing ring systems, five-membered rings are more
stable than seven-membered rings.35,67 In each case, arsenic was trigonal pyramidal and
exo and the halide was found to be in the axial position with respect to the ring, likely
due to the anomeric effect.
S
X-As J
's
43 X= CI
44X= I
x-~:J
45X =CI
46X= I
S)OCI-A~ IS ~
47
Chart 6. Halo-arsenic dithiolate rings structures.96
31
d)
Figure 8. Stick-representations of crystal structures of 43 (a), 45 (b), 46 (c), 44 (d), and
47 (e).96
A different polymorph of 43 was previously reported which had slightly different
angles and distances. As-S bonds were 2.19 and 2.23 A, the S-As-S angle was 93.SO, and
the S-As-CI angles were 98 and 100°.99
In the solid-state, a greater range of bond distances and angles is exhibited by
halo-arsenic dithiolate complexes than by trithiolate complexes. This could be a
consequence of steric and electronic differences between substituents and/or the ring
strain observed in many of the examples. As-S distances between 2.19 and 2.27 A, S-As-
S angles between 87 and 105° and S-As-X angles between 97 and 101° were typical. The
identity of the halide, X, did not seem to affect bond distances and angles, but ring size
did. Again, both endo and exo conformations were observed at the trigonal pyramidal
As-centers.
--------- --- --
32
Organic Dithiolate Complexes
Organic dithiolate arsenic complexes containing CAsS2 units have been
structurally characterized to some degree. As-S distances of 2.25 and 2.26 A, an S-As-S
angle of 99°, and S-As-C angles of 95 and 96° were observed in the crystal structure of
1,3-dithia-2-phenylarsino-[3]ferrocenophane (48).100 These measurements show that
despite its close proximity to arsenic, the ferrocene unit did not affect arsenic's exo
trigonal pyramidal geometry (Figure 9). The X-ray crystal structure of a tolylarsenic-
BAL (British Anti-Lewisite) complex (49) (Figure 10) revealed a five-membered ring in
which the As-S distances (2.23 A) ,S-As-S angle (93°) and S-As-C angles (98 and 101°)
were in the typical range. 101 Arsenic, in the endo position, did not take part in any SBIs,
despite the availability of the alcohol oxygen.
a)np~
~A~ Fe
S~
48
Figure 9. Cartoon (a) and stick (b) representations of 48.100
Figure 10. Cartoon (a) and stick (b) representations of 49.101
33
The biologically relevant structure of a phenyl As-lipoic acid derivative, 50,
contained an ASS2C3 six-membered ring in the chair conformation.77 The As-center was
in the exo conformation and the phenyl group on arsenic was in the expected axial
position (Figure 11). This example reiterates the axial preference for substituents on the
arsenic atom in rings that was seen above for compounds 43_47.96,97 This preference has
also been observed in solution for six-membered rings containing S-As-S or O-As-O
units. IOZ In the solid state structure of 50 there were no SBIs involving arsenic which was
in the endo conformation with trigonal pyramidal geometry. The bond lengths and angles
around arsenic fell into the typical range for aryl-AsSz moieties. As-S distances of 2.23
A, an S-As-S angle of 99°, and S-As-C angles of 99 and 101 ° were observed.
Figure 11. Cartoon (a) and stick (b) representations of the X-ray crystal structure of
50.77
In each case reported above, the geometry at arsenic was trigonal pyramidal. For
organic dithiolate arsenic complexes, As-S distances in the range of 2.23 to 2.26, S-As-S
angles between 93 and 99°, and S-As-C angles between 95 and lOP were typical. Both
endo and exo conformations were observed. It should be noted that these angles and
34
distances seem to be typical for the CAsSz trigonal pyramidal unit, even if the sulfur atom
is not part of a thiolate ligand. For instance, the As-S distances in realgar (AS4S4) are
2.21 Aand in arsenic trisulfide (ASZS3) are 2.25 A. I03 A table of known As-S bond
lengths in cluster compounds has been previously reported and will not be discussed
here. I04 However, a few more recent examples will be. The phenyl arsenic sulfide
tetramer (51) has As-S distances of 2.26 A, S-As-S angles of 1020 and S-As-C angles of
94 and 96 (Chart 7).105 Due to the steric crowding of four phenyl units, each occupies an
equatorial, rather than axial position. The crystal structure of diphenyldiarsenic trisulfide
(52) has As-S distances of 2.25 A, an S-As-S angle of 980 , and S-As-C angles of 100 and
1010 .106 Rings 53 and 54 have similar structural features. 107
52 53 54
Chart 7. Cartoon representations of structures 51,105 52,106 53,107 and 54. 107
Heteroatom-Arsenic Dithiolate Complexes
The X-ray crystal structure of the As-OTT adduct (30) showed that, surprisingly,
the complex was not the seven-membered ring hypothesized by Zahler and Cleland,57 but
35
a bicyclic structure in which one of the oxygens on DTT was bound directly to arsenic
(Figure 12).58 Despite the strain in 30, As-S bond distances were typical (2.23 and 2.24
A). However, the bond angles were affected by the strain and by SBIs between arsenic
and the sulfur atoms on neighboring molecules. This resulted in a geometry around
arsenic that was intermediate between trigonal pyramidal and octahedral. The S-As-O
angle in the five-membered ring was only 89°, while the S-As-O angle in the six-
membered ring was significantly wider at 97°. The S-As-S angle in the seven-membered
ring was 101°. Based on these results, it seems possible that the arsenite complexes of
dithioerythritol (10), 1,2-dithioglycerol (11), and 1,3-dithioglycerol (12) also have
covalent bonds between an oxygen atom within the ligand framework and bicyclic
structures.
a) HhH b) OHffi
s" /s s,?/s
As As
I
OH 30
Figure 12. Cartoon representation of the incorrect57 (a) and correct (b) structures of the
As-DTT adduct 30. Stick representation of the X-ray crystal structure of 30 (C).58
36
Burford and co-workers have mainly focused their efforts on the preparation and
characterization of arsonium cations which are beyond the scope of this review.
However, they have also presented several examples of crystal structures containing As-S
units in neutral molecules.99,108,109 In 55, the N,S,Cl coordination-sphere around arsenic
was slightly distorted from trigonal pyramidal by a SBI with chlorine in a neighboring
molecule (Figure 13).108 The As-S bond length was unaffected (2.20 A).
a)
Figure 13. Cartoon (a) and stick (b) representations of the X-ray crystal structure of
55.108
Non-Trigonal Pyramidal Geometries
A series of As(III)-thiolate containing metallocanes (eight-membered rings:
X(CHzCHzS)zAsR, X =0 or S) with a range of trigonal pyramidal to trigonal
bipyramidal geometries has been reviewed previously by Moya-Cabrera et al. 110 and will
not be repeated here. However, since Moya-Cabrera's review was published, the crystal
structures of a series of S(C6~S)zAsXwhere X =CI (56), Br (57), and I (58) were
reported (Chart 8, Figure 14).111 The primary coordination spheres have the classic
37
trigonal pyramidal geometry. However, intramolecular transannular S~As SBIs gave
the complexes trigonal bipyramidal geometries. The authors evaluated the influence of
the S~As interaction on the geometry using the donor-acceptor bond length method
described by Holmes112-11 4 and the Pauling-type bond order of that interaction.1l5-117
They found that the complexes actually had hybrid geometries and were each between
64-67% trigonal bipyramidal and 36-33% trigonal pyramidal. The S~As bond orders
were between 0.19 and 0.21. As-S distances were long for halo-arsenic dithiolate
complexes, between 2.27 and 2.29 A. The S-As-S angles were wide, between 103 and
104°, likely a steric effect of the S~As SBI. Finally, S-As-X angles were between 87
and 88°. The small difference in angles here indicates that the identity of the halogen had
only a slight effect on bond angles and distances.
Q
s sfit' A~v.-s/ 'Sr
57
a) c)
38
Figure 14. Stick representations of the X-ray crystal structures of 56 (a), 57 (b), and
58. 111 S~As secondary bonding interactions are shown with dashed lines.
The X-ray crystal structure of the unusual, biologically-relevant, four-coordinate
As(III)-N,S complex 59 (Figure 15) was recently reported. 1I8 Upon treatment with
AsCi), an N,S-containing benzothiazoline ligand (60) reacted to form 59 (Scheme 14).
The equatorial plane of 59 included N, I, and the lone pair, while the axial positions were
occupied by S and N, making the geometry at the As-center trigonal bipyramidaL The
As-S bond distance of 2.29 Awas similar to those observed in three-coordinate thiolate
complexes. The equatorial location of the lone pair in this structure was consistent with
other four-coordinate As(III)-thiolate structures. I 19-123
a) rY b)
~~N-As0'''1 -.~. _.--''-'::: SI~
59
Figure 15. Cartoon (a) and stick (b) representations of the X-ray crystal structure of 59.
The axial N-S bond is represented by a dotted line. I 18
260
Scheme 14. Synthesis of 59.
1) 2 NaH, AsCI3
THF,RT
2) Nal
(CH3hO/CH2CI2
..
rrl('~~
N-As +
~S"I
VS9
39
Protein Mimics and Supramolecular Arsenic-Thiolate Chemistry
Protein Mimics
Arsenic has been shown to bind a number of cysteine-containing proteins, but As-
protein adducts are difficult to study. One way around this problem is to study As-
polypeptide interactions in protein mimics. 124,125 The well-studied peptide helix bundles
from the TRI family are known to aggregate in two-helix bundles at low pH and three-
helix bundles at high pH. 126 Cysteine was substituted onto the peptide at position 16 and
an excess of sodium arsenite was added at both low and high pHs (Figure 16). For both,
electrospray and MALDI mass spectrometry showed that the product was the three-helix
coiled coil bound to arsenic (60), suggesting that the trigonal binding preferences of
arsenic can overcome the preference of the peptide to exist as a two-helix bundle at low
pH. An As-S bond length of 2.25 A was determined by EXAFS spectroscopy. Similar
results were obtained when using a peptide substituted in position 12 despite unfavorable
rotameric forms of the cysteine in this position. These results demonstrate that the
40
thiophilicity of arsenic is great enough to cause distortion and aggregation in certain
biopolymers. 127
HS
pH = 5.5 or 8.5
60
Figure 16. Cartoon representation of synthesis of As-coordinated three-helix coil
(60).124,125
Using a slightly different peptide, Coil Ser with cysteine in position 9 (CSL9C),
Pecoraro et al. were able to determine the crystal structure of the triply bound
As(CSL9C)3 (61) to 1.8 A resolution (Figure 17a).128 A mean As-S distance of 2.28 A
and S-As-S angles of 91, 92, and 88° were found. These angles are slightly smaller than
those observed for typical small molecule trithiolate arsenic complexes and this could be
due to peptide aggregation or side chain rotamer effects. The As-center was in the endo
conformation within the coiled coil, with arsenic's lone pair of electrons and the cysteine
carbons all lying below the plane of the sulfur atoms (Figure 17b). While this
conformation is not uncommon in small molecule As(lII)-thiolate complexes,85,94 the exo
conformation is also often observed.96-98 This is a rare example of a structurally
characterized As-containing biomolecule and the environment around arsenic matches
that proposed for arsenic in Ars-R and Ars-D arsenic-resistance regulatory proteins.50
41
Figure 17. Representations of the X-ray crystal structure of 61 from the top down (a)
and side (b).128
The effects of arsenic binding to a single a-helix has also been reported.129 A
family of peptides with two cysteine residues in the i, i+ I, i+2, i+3, and i+4 positions was
treated with MMA and the structural effects of 1:1 binding were studied by circular
dichroism (CD) spectroscopy. Destabilization and structural alteration were found to
occur in all cases except for the helix with residues in the i, i+4 positions (Figure 18). In
this case, stabilization was found to occur by enhancement of the helical structure.
Dissociation constants were found to range from 1.5-19.8 x 10-9M, suggesting that the
location of the cysteine residues had little effect on the tight As-binding regardless of the
structural consequences. Association constants ranging from 1.1-2.8 x 104 M-1s-1were
also reported.
,S
HO-As
's
Stabilized
As(11I )
...
As(III)_~S
- S-As
OH
Destabilized
42
Figure 18. Cartoon representation of As(ITI) binding to an a-helix causing stabilization
or destabilization depending on location of cysteine residues. 129
The effects of arsenic binding to modified ~-hairpins has also been studied.38
Four model hairpins, each with a cysteine incorporated at two positions, were treated
with MMA and studied by CD, NMR, and UV-vis spectroscopy. It was found the arsenic
binding could stabilize or destabilize the hairpin structure. Similarly to the results for 0.-
helical binding, this stabilization/destabilization was dependent on the location of the
cysteine residues. Binding was found to occur rapidly. Association rate constants were
measured between 1.0-2.2 x 104M-1s-1no matter the location of residues or structural
reorganization upon binding. Equilibrium dissociation constants of 1.3-10.6 x 10-9 M
were also reported.
Supramolecular Chemistry
Supramolecular chemistry is the study of dynamic molecules assembled of
multiple components through reversible interactions. 130,131 These interactions are often
hydrogen bonds132.133 or labile metal-ligand bonds,134,135 but can also include 1t_1t,136
cation-1t,137 and CH_1t138 interactions and take advantage of hydrophobic and solvophobic
43
effects. 138 Typically, the design of metal-organic assemblies involves incorporation of
the highly studied and well-behaved transition metals. However, a recent resurgence of
the main group elements139,140 has led to interest in the use of main group ions in metal-
directed self-assembly. 141
As a component in supramolecular assemblies, As(III) has much to offer. In
addition to the favorable thermodynamics and kinetics of the As-S bond discussed earlier
in this chapter, arsenic can take part in secondary bonding interactions with heteroatoms
such as oxygen,85 sulfur,91,92 and the halogens,93 as well as with electron-rich aromatic
rings through As···n interactions.87-9o Finally, trigonal pyramidal bonding geometries and
endohedral functionality are unusual in slipramolecular assemblies. As(III) supplies
both. 142
Arsenic-Containing Cryptands
The first reported use of As(III) as a directing ion for supramolecular self-
assembly involved the treatment of a rigid phenyl-spaced dithiolate ligand (L2-) with
Aseb, resulting in the formation of As2L3 (62) in high yields (Figure 19).84 This showed
for the first time that the As-S bond is labile enough for the self-assembly of discrete
species. This example also has several interesting features. First, in the crystal structure,
each As-center was in the endo conformation with its lone pairs of electrons pointing
directly into the cavity. This could have been due in part to favorable As···n interactions
with the ligands. Second, the cryptand was remarkably stable; air, water, excess ligand,
44
competing metal ions, and even heating to reflux in CHCh in the presence of
trifluoroacetic acid or p-toluenesulfonic acid caused no decomposition or reaction. This
suggests that the supramolecular chelate structure imparted additional stability onto the
assembly beyond what was expected for the individual As-S bonds. The observed As-S
bond lengths of 2.25 A and S-As-S angles of 95° were within the typical range for non-
constrained S-As-S units, showing that the chelating effects of the ligands did not disturb
the geometry around the As-center.
a)
Figure 19. Cartoon (a) and stick (b) representations of the X-ray crystal structure of
62.84
Since this initial discovery, the structures of two other AszL3 cryptands have been
reported. The preparation of 63, a cryptand with an extended diphenylmethane spacer,
allowed comparison of the crystal structure (Figure 20) with a DFT-calculated structure
run at the B3LYP/6-31 +G* level. 143 These two structures were shown to be very similar,
except that DFT did not predict As···1t interactions. This was not surprising, as the Bi ...1t
interaction is not correctly interpreted by DFT. l44 Again, in this crystal structure, As-S
distances between 2.23 and 2.25 Awere within the typical range. S-As-S angles ranged
45
from 91-103° showing that this structure clearly lacked the C3 symmetry of the 62. The
loss of symmetry here appeared to be due to edge-to-face aromatic interactions in the
crystal packing; NMR spectroscopy revealed a time-averaged symmetric structure in
solution.
a)
63
Figure 20. Cartoon (a) and stick (b) representations of the X-ray crystal structure of
63. 143
In the crystal structure of the naphthyl-spaced As2L3 cryptand 64, the As.. ·As
distance was very similar to that in 62, but the cavity of the assembly was far more
sterically congested (Figure 21).145 This had little effect on the endo trigonal pyramidal
geometry around the As-center. Again, As-S distances of 2.25 A and S-As-S angles of
94° were reported. This cryptand was prepared by an unconventional route; the Sb2L3
congener (65) was transmetallated with AsCh, resulting in complete conversion to As2L3.
This reaction highlighted the relative stability of the As-S and Sb-S bonds. In solution, a
small percentage of the As2L3 cryptand rearranged to a less-symmetric structure in which
one ligand was folded in the opposite direction of the other two. The conversion between
46
the symmetric and asymmetric structures likely occured when an As-S bond breaks and
reforms, again showing the lability of the As-S bond. 146 This cryptand will be described
in further detail in Chapters V and VI.
a)~1",S Sb
:::.--.. ,.,::;
S Sb
3
65 64
Figure 21. Schematic cartoon showing transmetal1ation reaction (a) and stick
representation of the X-ray crystal structure of 64 (b).145
Arsenic-Containing Macrocycles
As2L2Ch macrocycles, intermediates in the formation of As2L3 cryptands, were
prepared directly from rigid dithiolligands (H2L) and AsCi]. Crystal structures of 66, a
macrocycle prepared from the phenyl-spaced ligand used in 62, revealed that the As-
centers again were in the endo conformation and were involved in As.. ·1t interactions
(Figure 22).82 Two isomers, syn and anti, were observed in the solid state and in solution.
As-S distances of 2.22 and 2.23 A, S-As-S angles of 87 and 900 and S-As-CI angles of
100 and 101 0 were observed. These angles were similar to those previously reported for
halo-arsenic dithiolate structures.85•96 While the two isomers could be isolated separately
47
in the solid state, dissolving one in chloroform led to an equilibrium -1: 1 mixture of both
isomers within five minutes.
a)
~
s--15....s
CI
syn-66
s.....~....s
61
anti-66
Figure 22. Cartoon and stick representations of the X-ray crystal structure of syn-66
(a,c) and anti-66 (b,d).82
The syn-to-anti ratio of macrocycles 67, 68, and 69 was controlled by use of
rationally-placed steric bulk in the dithiolligands.79 A series of conformationally
isomeric naphthyl-spaced ligands were prepared and treated with AsCb resulting in
macrocycle assembly (Figure 23). Crystal structures and NMR spectroscopy revealed
diastereomeric excesses of the less sterically-congested isomers. Again, interconversion
between isomers was found to be fast (equilibrium was reached within minutes of
dissolving crystals of a single isomer). However, NMR samples heated to 135°C
showed no coalescence and EXSY experiments showed no exchange, implying that
interconversion was slow on the NMR timescale. Interconversion likely occurred
through the breaking of the As-S bond (Figure 7), but could also occur through As-CI
bond (Figure 8) breaking and reforming. As-S distances of 2.22 A, S-As-S angles of 86-
48
90° and S-As-CI angles of 97-102° were observed in each macrocycle around the endo-
positioned As(liD ions. This system is further described in Chapter II.
69
1)
68
e)
a)
Figure 23. Cartoon and stick representations of the X-ray crystal structures of 67 (a,d),
68 (b,e), and 69 (c,f).
The diastereomeric excess was similarly controlled using methyl groups to impart
steric control (Figure 24).83 In the anti 2,5-substituted macrocycle 70, the As-centers
were in the endo conformation with their lone pairs of electrons pointing directly toward
each other. As-S distances of 2.21 A, s-As-S angles of 86°, and S-As-CI angles of 100
and 102° were observed. However, in the 2,3-substituted macrocycle (71), one As-center
was not in the expected position. Rather than having its lone pair pointing directly
toward the other As(III) ion, it was folded into the macrocyclic cavity to fill the space.
Previously, this was observed in the crystal structure of a conformer of 68 not shown in
49
Figure 23.79 Even in these "folded-in" or "imploded" structures, typical bond distances
and angles were observed. For the folded in SzAsCI unit, As-S distances were 2.21 and
2.22 A, S-As-S angles were 88 0 and S-As-CI angles were 98, 101 and 104. 0
71
Figure 24. Cartoon and stick representations ofthe X-ray crystal structures of 70 (a,c)
and 71 (b,d).83
The syn-to-anti ratio of macrocycle 72 was controlled in the solid state (Figure
25a).14Z When 72 was crystallized from CHCh or C6H6, the anti-macrocycle crystallized
exclusively (Figure 25b) as a result of intramolecular steric interactions between the
chloride ligands and the methoxy groups on the organic ligand. However, when crystals
were grown from larger solvents such as toluene or p-xylene, two molecules of 72 were
found to dimerize around one solvent molecule. p-xylene filled the cavity of the dimer,
causing the bulky chloride ligands to point away from the cavity. This resulted in the
exclusive crystallization of syn-72 (Figure 25c). Toluene, which is slightly smaller than
p-xylene, was not able to fill the cavity of the dimer as effectively. Although the dimer
still formed, 72 crystallized as a mixture of syn and anti isomers (Figure 25d, only the
syn-syn dimer is shown). Overall, the size of the guest played an important role in the
50
syn-to-anti ratio of 72 as well as whether or not dimerization occurred. As-S distances in
these structures ranged from 2.13-2.24 A and S-As-S angles ranged from 87-93°. S-As-
CI had a wide range from 87-111 0. More on this diastereoselective system can be found
in Chapter III.
c)
,
f
d)
Figure 25. Cartoon (a) and stick representations of the X-ray crystal structures of anti-72
(b), [(syn-72h·p-xylene] (c), and [(syn-72h.toluene] (d).J42
Several other macrocycles which partially host aromatic guests have been
prepared from dithiolligands containing biphenyl (73) and trans-stilbene (74) spacers
(Figure 26).142 Here, As-S distances ranged from 2.11 to 2.21 A, S-As-S angles from 88-
92°, and S-As-CI angles from 95-103°. 73 and 74 are described in further detail in
Chapter III. In an attempt to increase the volume of the cavity, 1,4-
bis(mercaptoethyl)benzene was incorporated into macrocycle 75. In this structure, As-S
distances of 2.21 A, S-As-S angles of 93°, and S-A.s-Cl angles of 100 and 102° were
observed.98 The tetramethyl-substituted phenyl-spaced macrocycle 76 was also
51
reported147 with As-S distances of 2.21 and 2.22 A, S-As-S angles of 86°, and S-As-Cl
angles of 100°. This structure can be found in Chapter N.
CI(€I ~~:
Cl
a)
73
b) c)
75
d)
76
h)
I·.······'\J?#/,·,'.;'"; ....*t. _ "-" ' ..- ,.c' '<. i AP '.' '/.'" ,,",~~,' "
....../ '-/'-
Figure 26. Cartoon and stick representations of the X-ray crystal structures of 73
(a,e)/42 74 (b,t),142 75 (C,g),98 and 76 (d,h).147
In addition to structural data, AS2~Ch macrocyc1es have given insight into the
self-assembly process. 147 Most transition metal-ligand complexes form within minutes
and their assembly can only be monitored by stopped-flow experiments. As-S kinetics in
our systems are relatively slow. For example, it took a week for the assembly of AS2~Ch
macrocycles 62 and 73 to reach equilibrium. This allowed monitoring by I H NMR
spectroscopy and MALDI mass spectrometry. Intermediates (Scheme 15) and oligomeric
52
mistakes which corrected themselves over the course of the self-assembly process (Chart
9) were observed. Additionally, an AS2LC14 intennediate (77) was crystallized (Figure
27) with As-S bond distances of 2.22 A and S-As-Cl bond angles of 89 and 102°. The
large difference in angles here were caused by an As···Q SBI with the ligand's methoxy
ether. More detail on these experiments can be found in Chapter IV.
Scheme 15. Intennediates in the self-assembly of As2L2Ch macrocycles. 147
53
~S~\XrsS §S'AsCI2I~ I~ I~;;:; ;;:; ;;:;SH s--ts-sCI
Chart 9. Kinetic mistakes observed in the self-assembly of AS2L:2Ch macrocycles. 147
Figure 27. Cartoon (a) and stick (b) representations of the X-ray crystal structures of
77. 147
Higher-Order Structures
The first tetranuclear As-containing supramolecular assembly, 78, was prepared
using a tetrathiolligand. 148 In the crystal structure of this S4-symmetric As4L:2C14
metallocryptand, As-S distances of 2.22 and 2.23 A, S-As-S angles of 90°, and S-As-CI
angles of 97 and 103° were observed (Figure 28). The AsS2Cl centers in this st.ructure
were in the same endo and trigonal pyramidal conformation that is observed for every
As-containing supramolecular assembly reported to date. Two isomeric As2LCh
54
intermediates cis-79 and trans-79 were also isolated. Their crystal structures revealed
As-S distances of 2.22-2.25 A, S-As-S angles of 104-107°, and S-As-CI angles of 97-99°
(Figure 29). These intermediates contained seven-membered AsSzC4 rings that were very
similar structurally to 47. The distances and angles for 47 were within the range
observed here and in both structures the As(III) ions were trigonal pyramidal and exo.
b)
Figure 28. Cartoon (a) and stick (b) representations of the X-ray crystal structures of 78.
cis-79
c) d)
~!Jf\
\.) '-..?"
Figure 29. Cartoon and stick representations of the X-ray crystal structures of cis-79
(a,c) and trans-79 (b,d).
55
Conclusions
The kinetics, thermodynamics, structure, and supramolecular chemistry of the
As(III)-thiolate bond were reviewed. All As-S-containing biomolecules were not
comprehensively covered, but those which have reported kinetics, thermodynamics, or
crystal structures were included. It was shown that the As-S bond is labile, with rate
constants for bond formation ranging from 103_104 M-1S-I. Bond dissociation was found
to be slower and on the order of 1-10 s-I. Stability constants for As-containing complexes
were reported and the thermodynamics and kinetics of S-As-S-containing rings were
compared. It was also shown that thiolate-bound As(III) prefers a trigonal pyramidal
geometry but substituent identity and secondary bonding interactions can affect the bond
distances and angles. When SBIs were involved, trigonal bipyramidal geometries were
observed. Arsenic-containing protein mimics and the chemistry of the As-S bond in a
supramolecular context were also reviewed.
Bridge to Chapter II
Chapter I reviewed the kinetics, thermodynamics, preferred structure, and
supramolecular chemistry of the As(III)-thiolate bond. It was seen that the bond is
thermodynamically stable, yet kinetically labile enough to allow for the formation of
discrete supramolecular assemblies. The preferred geometry of As(III)-thiolate
complexes was found to be trigonal pyramidal at the As-center and the rates and
thermodynamics of inversion at the As-center were explored in the context of
interconversion between isomers. In Chapter II, a supramolecular design strategy is
applied to the As(III)-thiolate bond, allowing for the synthesis and characterization of a
series of AS2~Cbmacrocycles. The ratio of isomers is controlled by the strategic
placement of intramolecular steric bulk and the interconversion between isomers is
explored.
56
57
CHAPTERll
DIASTEREOSELECTNITY IN THE SELF-ASSEMBLY OF Asz~Ch
MACROCYCLES IS DIRECTED BY THE As-x INTERACTION
This chapter presents the diastereoselective self-assembly of a series of AszLzCh
macrocycles in which the diastereomeric excess is controlled by intramolecular steric
interactions. This co-authored work was previously published (Inorganic Chemistry,
2007,46, 9278-9284, © American Chemical Society). I The synthesis and solution
characterization of AS2(L1,shCh was carried out by Aaron C. Sather. The X-ray crystal
structures of Asz(L2,6hCh and AS2(L1,4)zCh were solved by Dr. Lev N. Zakharov and of
Asz(L1,shCh by Dr. Orion B. Berryman. Professor Darren W. Johnson provided
intellectual input and editorial assistance. I carried out the synthesis and solution
characterization of As2(L2,6hCh and AS2(L1,4hCh and wrote the manuscript.
Introduction
The use of main group ions as directing elements in metal-ligand self-assembly
reactions is rare, and few predictive design strategies for forming self-assembled
supramolecular main group compounds exist,2-4 We have recently developed a strategy
58
to synthesize self-assembled dinuclear arsenic-containing structures5,6 that are stabilized
by arsenic-1t interactions.7,8 As2L2Ch (H2L = p-bis(mercaptomethyl)benzene)
macrocyclic assemblies synthesized by this strategy exist in equilibrium as a statistical
mixture of syn and anti diastereomers (Scheme 1), in which the arsenic-1t interaction
directs the arsenic atoms into the macrocyclic cavity formed by the arene rings of the
ligands.
SH
SH
8
CI/As~
S
syn
+
S
CI I'" /Sg
8
S.... As-CI
"S
anti
HS
Scheme 1. The self-assembly of AS2~Chmacrocycles. In the syn macrocycle both
chlorine atoms are on the same side of the arsenic atoms. In the anti macrocycle the
chlorine atoms are on opposite sides of the macrocyclic cavity.
Metal-ligand self-assembly reactions that can lead to two or more possible
diastereomers typically proceed diastereoselectively.9,IO To the best of our knowledge,
only a few examples exist of metal-ligand self-assembly reactions that provide a mixture
of diastereomers: 1) in rare instances multiple diastereomeric M44 tetrahedra (T, C3 or
59
S4) exist in equilibrium,l1 and 2) diastereomeric excess (de) values have been reported in
the formation of host-guest complexes in which two enantiomers of a chiral guest have
different binding affinities within two enantiomers of a chiral host molecule. 12
We now show that the de of self-assembled arsenic-containing macrocycles can
be controlled by the appropriate choice of achiral, isomeric dithiolligands (Scheme 1).
This demonstrates the generality of our design strategy for forming AS2L2Ch macrocycles
and shows an unusual example of multiple supramolecular interactions (reversible As-S
bond formation and As-n interactions) acting in tandem to dictate the stereochemical
outcome of a self-assembly reaction.
Results and Discussion
Scheme 1 illustrates a series of isomeric bis(mercaptomethyl)naphthalene ligands
that form equilibrium mixtures of diastereomeric macrocycles when combined with
AsCI) in solution. Depending on the choice of ligand, either no de is observed (H2L2,6),
the syn-isomer is favored (H2L1,4) or the anti-isomer (H2L1,s) is favored. The
naphthalene rings of these ligands provide added steric bulk to the macrocyclic cavity
(compared to H2L), which forces either the chlorine or sulfur atoms into close proximity
with these aromatic backbones (Figure 1). The repulsive interaction between the
electron-rich chlorine atoms coordinated to arsenic and the aromatic rings of the ligand
causes the diastereomer that positions the chlorine atoms farthest away from the arene
rings to form in excess. The result is a predictable strategy that controls the syn-to-anti
ratio of the self-assembly reaction based on the shape of the ligand.
60
Figure 1. Partial ball and stick models showing two conformations for this molecule
with the chlorine atom pointing away from (a) and toward (b) the hydrocarbon backbone.
Possible points for steric repulsion are marked in red (with chlorine) and blue (with
sulfur).
To test the stereocontrol of these self-assembly reactions, three regioisomers of
bis(mercaptomethyl)naphthalene were prepared with mercaptomethyl substituents in the
2,6-, 1,5- and l,4-positions. It was predicted that HzL1,5 would give mostly anti-product,
HzL1,4 would give mostly syn-product, and HzL2,6 would show no preference. These
predictions result from the minimization of unfavorable steric repulsions (Figure 1b)
exhibited in both anti-Asz(L1,5hClz and syn-Asz(L1,4)zClz in which the chlorine atoms are
directed away from the sterically-congested macrocyclic cavity (Figure 2). Conversely,
Asz(L2,6hClz should show no such preference: the chlorine atom is directed away from
the macrocycle in both diastereomers. When AsCi} is added to a chloroform solution of
each ligand, AszLzClz macrocycles self-assemble in each case, showing that our design
strategy;,6 for forming these macrocycles is general despite the differences in geometry of
these ligands.
a) c)
61
Figure 2. ORTEP (30% probability ellipsoids), wireframe, and space filling
representations of single-crystal X-ray structures for anti-As2(L2,6hCh (a,d,g), anti-
As2(L1,5hCh (b,e,h) and syn-As2(L1,4hCh·CHCh macrocycles (c,f,i). Carbon is shown
in black, hydrogen in white, sulfur in yellow, chlorine in green, and arsenic in purple.
The ligands are planar within 0.02 A. The angle between the averageflanes of the ligands
is 28 A in As2(L1,4hCh·CHCh and 0 A in As2(L2,6hCh and AS2(L1, hCb. Hydrogens
(a,b,c) and cocrystallized CHCh (c,f,i) are omitted for clarity, and only one of the six
As2(L1,4hClz macrocycles contained in the asymmetric unit is shown for brevity (c,f,i).
Single crystal X-ray diffraction studies confirm that each macrocycle consists of
two arsenic atoms spanned by two bridging ligands that create a cavity that is roughly 6 A
across (Figure 2, Tables 1 and 2). Each arsenic atom also remains coordinated by a lone
chlorine atom that is not displaced when the reactions are performed in the absence of
base.5,6 Each structure reveals that As-x interactions are influencing the stereochemistry
of the assemblies by directing arsenic, and thus its coordination sphere, into the
macrocyclic cavities of the complexes. Only one of the two possible diastereomers of
each macrocycle crystallizes out of chloroform: anti-As2(L2,6hCh (Figure 2a,d, Table 1),
62
anti-As2(Ll,5hClz (Figure 2b,e), and syn-As2(Ll,4hClz·CHCha (Figure 2c,f, Table 1).
Although the As···As distances in these structures vary widely (7.45,5.64 and 4.66 A,
respectively), the As···C distances between the As atom and the nearest C atom in the
naphthalene rings (3.30, 3.22 and 3.14 A, respectively) consistently indicate the presence
of AS-1t interactions (Table 2).8,14
Table 1. Crystallographic Data and Refinement Parameters for AS2(L2,6hClz,
As2(Ll,5hClz, As2(L1, hClz.CHCh, and As2(Ll,4hClz·C6H6.
AS1(L~,OhCll As1(L1':>hCh AsiLJ'''hCl1· As1(V''')lCh·
CHCl3 C6H6
empirical formula CU H1oAslChS4 C14HzoAs2ClzS4 CZ~HZIAszC15S4 C30Hz6AszClzS4
formula weight 657.38 657.38 776.75 735.49
temperature (K) 153(2) 173(2) 173(2) 173(2)
wavelength (A) 0.71073 0.71073 0.71073 0.71073
space group P211n nIle P-l P211n
a ) 6.395(1) 6.813(4) 19.313(4) 10.3332(7)
b ) 19.675(4) 19.08(1) 19.923(4) 34.375(2)
e ( ) 10.967(2) 10.277(6) 24.508(5) 17.859(1)
a (0) 90 90 78.110(4) 90
on 106.817(3) 107.79(1) 78.860(5) 98.965(1)
y (0) 90 90 89.183(5) 90
volume (N) 1320.8(5) 1272.5(14) 9050(3) 6266.3(7)
Z,Z' 2,0.5 4,1 12,6 8,2
Dcalcd (mg/m j ) 1.653 1.716 1.710 1.559
Ii (cm'l) 0.3061 0.3177 0.2951 0.2590
Nmeasd 10816 6949 102535 53433
N ind [Riot] 2322 [0.0264] 2750 [0.0816] 39214 [0.0953] 11027 [0.0315]
N obs [I> 2o{l)] 1904 1632 19406 9741
no. of params 145 145 1937 708
goodness-of-fit on FL 1.053 1.037 0.981 1.260
Rl/wR2 [I > 2o{l)] 0.0486/0.1226 0.0816/0.1779 0.0687/0.1278 0.0577/0.1155
Rl/wR2 (all data) 0.0603/0.1314 0.148210.2138 0.1577/0.1646 0.0657/0.1185
a syn-As2(Ll,4hClz crystallizes exclusively out of chloroform with six macrocycles present in the
asymmetric unit. The six syn-macrocycles vary slightly in their conformations. A full description of the
structural details and refinement are in the Experimental Section. A roughly 3:1 mixture of syn-to-anti-
Asz(Ll,4hCl2,C6H6 crystallizes out of benzene. Full details of the modeling of the disorder are contained in
the Experimental Section.
63
Table 2. Selected Bond Lengths (A) and Angles CO).
ASz(L:l,6hClz Asz(Ll,5hClz
As(1)-S(l) 2.1987(16) As(1)-S(2A) 2.210(3)
As(1)-S(2) 2.2078(15) As(1)-S(1) 2.215(3)
As( l)-Cl(1) 2.2494(18) As( l)-Cl(1) 2.237(3)
S(1 )-As(1 )-S(2) 89.33(6) S(2A)-As(1)-S(1) 85.81(10)
S(1 )-As(1 )-Cl(1) 100.42(7) S(2A)-As(1 )-Cl(l) 100.99(12)
S(2)-As(1)-Cl(1) 98.74(6) S(1 )-As(1 )-Cl(1) 102.16(11)
C(1)-S(l)-As(1) 99.4(2) C(1)-S(1 )-As(1 ) 102.1(3)
C( 12)-S(2)-As(1A) 98.89(19) C(12)-S(2)-As(1A) 102.1(3)
syn(1 )-Asz(L1,4h Clz·C6H6a and syn(2)-Asz(Ll,4hClz,C6H6 and
anti(1 )-Asz(L1,4hClz,C6H6' anti(2)-Asz(Ll,4hClz,C6H6'
As(1A)-S(4A) 2.208(2) As(1)-S(1) 2.2021(15)
As(1A)-S(1A) 2.2109(17) As(1)-S(4) 2.2077(16)
As(1A)-Cl(1A) 2.255(2) As(1 )-Cl(1 ) 2.223(2)
As(2A)-S(2A) 2.2112(19) As(2)-S(2) 2.2158(15)
As(2A)-S(2B) 2.055(15)
As(2A)-S(3A) 2.2027(17) As(2)-S(3) 2.2198(16)
As(2A)-S(3B) 2.167(12)
As(2A)-Cl(2A) 2.2757(19) As(2)-Cl(2) 2.261(3)
As(2A)-CI(2B) 2.295(14) As(2)-CI(2 ') 2.286(4)
S(4A)-As(1A)-S(1A) 87.07(7) S(1)-As(l)-S(4) 89.68(6)
S(4A)-As(1A)-Cl(1A) 101.01(10) S(1 )-As(1 )-C1(1) 100.71(9)
S(1A)-As(1A)-Cl(1A) 102.42(9) S(4)-As(1)-Cl(1) 99.84(9)
S(2A)-As(2A)-S(3A) 89.31(7) S(2)-As(2)-S(3) 88.06(6)
S(2B)-As(2A)-S(3B) 100.6(6)
S(2A)-As(2A)-CI(2A) 96.91(8) S(2)-As(2)-Cl(2) 101.75(8)
S(2B)-As(2A)-CI(2B) 100.4(7) S(2)-As(2)-CI(2 ') 103.85(10)
S(3A)-As(2A)-CI(2A) 100.14(8) S(3)-As(2)-CI(2) 97.00(11)
S(3B)-As(2A)-CI(2B) 99.7(6) S(3)-As(2)-CI(2 ') 97.93(11)
C(1A)-S(1A)-As(1A) 101.5(2) C(1)-S(1)-As(1) 100.0(2)
C(12A)-S(2A)-As(2A) 98.4(2) C(12)-S(2)-As(2) 101.33(19)
C(12A)-S(2B)-As(2A) 97.6(2)
C( 13A)-S(3A)-As(2A) 101.3(2) C(13)-S(3)-As(2) 99.3(2)
C(13A)-S(3B)-As(2A) 107.3(2)
C(24A)-S(4A)-As(1A) 100.3(2) C(24)-S(4)-As(1) 98.1(2)
a This structure contains two macrocycles in the asymmetric unit, both of which are
disordered over syn and anti conformations (denoted syn(l), anti(l), syn(2) and anti(2)).
anti(1) and anti(2) refer to the two conformers of the anti-macrocycle present in the
disordered structure (see Figure 6). The structure anti(2) results from disorder of the
chlorine atom that is bonded to As(2) over two sites: CI(2) and CI(2'). The structure
anti(l) results from disorder of the chlorine and sulfur atoms bonded to As(2a) in the
other macrocycle. The bond distances and angles for the anti-isomers are italicized in the
table.
--- ----------------
64
Table 2 (continued).
Data from only one of SIX conformers IS shown for brevIty.
ASz(LJ,'f)zClz.CHCI30
As(I)-S(4) 2.216(2) S(I )-As(l )-CI(I) 100.78(10)
As(l)-S(I) 2.227(2) S(3)-As(2)-S(2) 88.77(8)
As(l )-CI(I) 2.246(2) S(3)-As(2)-CI(2) 100.43(9)
As(2)-S(3) 2.224(2) S(2)-As(2)-CI(2) 101.88(9)
As(2)-S(2) 2.227(2) C(I )-S( l)-As(l) 99.9(3)
As(2)-CI(2) 2.240(2) C(l2)-S(2)-As(2) 99.2(3)
S(4)-As(l )-S(I) 89.53(8) C(13)-S(3)-As(2) 99.0(3)
S(4)-AsO)-CI(I) 100.39(9) C(24)-S(4)-As(l) 100.2(3)
0
Each macrocycle exists as a mixture of diastereomers in differing amounts, in
solution. A nearly equal mixture of syn- and anti-Asz(L2,6hCh macrocycles is observed
in solution (de =9%) by I H NMR spectroscopy (Figure 3a). The I H NMR spectrum of
this mixture reveals that the methylene protons of each diastereomer appear as an AB
quartet.
a)
b) 4.40! 4.20 !~
c) 4.60 4.40 4.20
I I
4,80
!
It
I I
4,60
--I i I
4AOppm
Figure 3. Methylene region of the IH NMR spectra (in ppm) of AszL2Ch macrocycles
with arrows marking the least thermodynamically stable isomers. The equilibrium
mixtures of syn- and anti-Asz(L2,6hCh (a), Asz(LI,5hCh (b), and Asz(LI,4)ZCh (c) at 25
°C are shown.
65
In the 1H NMR spectrum obtained by dissolving single crystals of anti-
Asz(L1,5)2Ch, it is clear that there is a large excess of one diastereomer, presumably the
anti-isomer (Figure 3b).b The de was calculated to be 85%, although the low solubility of
the complex, as shown by the noisy NMR spectrum (obtained from an overnight scan of a
saturated solution on a 600 MHz spectrometer), leads to a high error in this value.
A large excess of syn-isomer is observed in solution for the Asz(L1,4)2Ch
macrocycles (de =90%) (Figure 3c). In this case the anti-macrocycle appears as a singlet
in the center of the syn-AB quartet. Variable temperature NMR spectroscopy revealed
that at high temperatures this singlet splits into the AB quartet expected for the geminal
methylene protons (Figure 4). At room temperature, the methylene resonances are
coincidental, and as a result do not split each other. As the temperature is raised, these
resonances shift slightly, are no longer coincidental, and split into the characteristic AB
quartet. Interestingly, as the temperature is raised the de decreases, reminiscent of
organic reactions in which de's are typically optimized by performing reactions at lower
temperatures.c,15 This indicates that the anti-macrocycle is entropically favored over the
syn-isomer. In a related supramolecular example, Stang and co-workers have reported
that a mixture of self-assembled macrocyclic dimers and trimers exists in a temperature-
dependent equilibrium favoring the entropically-preferred dimer at higher temperatures. 16
b For each macrocycle, single crystals of one diastereomer were dissolved and thermodynamic
equilibrium is quickly reached «5 min).
C This is similar to the established case of organic addition reactions, which can exhibit temperature
dependent de's when the enthalpically and entropically favored products are not the same. 15
66
*
65° ~ J lA
85°
---AA 1 M
105°
iii I Iii iii iii I
8.0 7.5
iii
4.8
iii i i
4.4 ppm
Figure 4. Variable temperature IH NMR spectra (in ppm) for Asz(L1,4)ZClz macrocycles
with the arrow marking the resonances for the methylene protons of the anti-
diastereomer. The resonance with the * corresponds to CHCI).
Variable temperature 1H NMR spectroscopic experiments were also carried out on
the AS2(L2,6)2Clz macrocycles and revealed incomplete coalescence at temperatures up to
135°C, suggesting that the interconversion between syn- and anti-isomers is slow on the
NMR timescale (Figure 5). As the sample is heated, the syn and anti resonances shift to a
point where they overlap, making a quantitative measurement of the de at temperatures
67
above 45°C impossible. EXSY experiments continued that conversion between
diastereomers is slow on the NMR timescale for both AS2(L2,6hCh and AS2(L1,4hCh at
room temperature on a 400 MHz spectrometer.
125° C
~50C
"'T"""1r-T'""'T"""1r-T'"""T""Or-T'","T1""r-T'"-r- I I I Iii I i
7.4 4.40 4.20 ppm
Figure 5. Variable temperature IH NMR spectra (in ppm) for As2(L2,6)2Ch macrocycles.
68
Mechanism ofInterconversion
We previously showed that the interconversion of syn-to-anti macrocycles is not
occurring by 1) pyramidal inversion of one As(ill) center, 2) complete ligand
dissociation, or 3) HCl-catalyzed inversion for the following reasons.6 First, the barrier to
arsine inversion is too high to occur at room temperature, making pyramidal inversion
followed by bond rotation an unlikely route for interconversion.d,17.l8 Second, complete
ligand exchange was not observed for a related mixture of AS2L2Ch macrocycles (H2L =
bis(mercaptomethyl)benzene).6 Finally, hydrochloric acid, a side-product of macrocycle
formation, is known to cause racemization of chiral arsines19,20 and was initially thought
to be involved in the interconversion of syn-to-anti macrocycles. However, when crystals
of exclusively one diastereomer are dissolved in chloroform that has been neutralized
with basic alumina to remove any traces of HCl, interconversion still occurs rapidly to
give an equilibrium mixture of diastereomers.6 Having shown that arsine inversion,
complete ligand dissociation, and HCl-catalyzed racemization are unlikely to be involved
in the interconversion of syn-to-anti macrocycles, a new mechanism based on the
disproportionation of two arsenic centers is proposed.
X-ray crystal data reveal that when crystals of AS2(Ll,4hCh are grown by slow
diffusion of pentane into benzene, they contain two conformers of both the syn-
d The barrier to pyramidal inversion was found to be 39 keal/mol for AsH3, 45 keal/mol for AsF3,17 and at
least 42 keal/mol for ehiral arsines. 18
69
macrocycle and the anti-macrocycle (Figure 6). In the anti(2)-conformer shown in Figure
6c, the chlorine atom is pointing into the cavity with an As-CI distance of 2.286(4) and a
short As-CI contact to the other arsenic center of 3.54 A. This non-bonding distance is
shorter than the sum of the van der Waals radii for arsenic and chlorine (3.80 A). Based
on this structure, and the knowledge that AsCl3 can disproportionate into AsCh+ and
A CI - e21-22· • bl th h' . f . I lds 4,' It IS reasona e at t e mterconverslOn 0 syn-to-antz macrocyc es cou
occur by disproportionation of two arsenic centers. This interconversion could occur
intramolecularly through a zwitterionic intermediate (Scheme 2), or intermolecularly. We
are currently studying this interconversion mechanism to determine 1) if the halide ligand
is involved in the interconversion, 2) how the halide ligand affects the rate of
interconversion, and 3) if the rate depends on halide concentration. Furthermore, it is
possible that partial ligand dissociation (breakage of only one As-S bond) could result in
interconversion. The results of these studies will be reported in due course.
e AsCl3 is known to disproportionate into AsCI/ and AsCI4-.21 ,22 It seems plausible that As~CI complexes
(where L =thiolate) could also disproportionate into AsL2+ and As~C12- ions. Upon the reformation of
As~CI, inversion at the arsenic center can occur. In the anionic form, either chloride ligand could leave
with equal likelihood, scrambling the stereochemistry at arsenic. Conversely, in the planar cation, the
incoming chloride could either attack above or below the plane of the complex leading to two different
configurations at arsenic. This mechanism of interconversion could occur intra- or intennolecularly in
AS2~Ch macrocycles.
a) b) c)
70
Figure 6. ORTEP (30% probability ellipsoids), wireframe, and space fillin~
representations of three conformers found in the crystal structure of As2(L1, hCh·C6H6:
syn(1)-As2(L1,4)2Ch·C6H6 (a,d,g), anti(1)-As2(L1,4)2Ch·C6H6 (b,e,h) and anti(2)-
As2(L1,4hCh,C6H6 (c,f,i) macrocycles. The ligands are planar within 0.03 A. The
dihedral angle between the average planes of the ligands in the isomers are different: 7.4
Ain anti(l)-As2(Ll,4hCh,C6H6 (b,e,h) and 36.oA in both syn- AS2(Ll,4hCh,C6H6 (a,d,g)
and anti(2)-As2(Ll,4hCh,C6H6 (c,f,i). Cocrystallized C6H6 (a-i) and hydrogens (a,b,c) are
omitted for clarity.
Scheme 2. Proposed mechanism for the intramolecular disproportionation leading to
interconversion between syn- and anti-macrocycles.
71
Conclusion
In summary, this study represents an unusual example of a self-assembly reaction
in which the de is controlled in a predictable manner through the use of achiral, isomeric
ligands. The As-x interaction acts as the directing force for the self-assembly of Asz~Clz
macrocycles that exist as an equilibrium mixture of both "syn" and "anti" diastereomers
in solution. By controlling the syn-to-anti ratio of our Asz~Clz macrocycles in solution,
we gain some understanding of how these macrocycles could act as synthons for larger
assemblies. We are currently pursuing this goal, as well as designing macrocycles with
improved diastereocontrol and studying the mechanism of syn-to-anti interconversion.
Experimental Section
General Procedures
IH NMR spectra were measured using a Varian INOVA-SOO spectrometer
operating at 500.11 MHz (Asz(L2,6)zClz and Asz(L1,4)zClz) and a Varian lNOVA-600
spectrometer operating at 599.98 MHz (Asz(L1,s)zClz). All variable temperature
experiments were carried out on the Varian INOVA-SOO spectrometer on compounds
dissolved in 1,1,2,2-tetrachloroethane-dz. Spectra were referenced using either TMS or
the residual solvent resonances as internal standards. Single crystal X-ray diffraction
studies were performed on a Broker SMART APEX diffractometer. Commercially
available reagents were used as received. All ligands were prepared following a modified
literature procedure. 13
72
IH NMR spectroscopy revealed complete transformation (>99% yield) of ligand
and AsCh to macrocycles AS2(L2,6)2Ch and AS2(L1,4hCh. (This was not measurable for
AS2(Ll,5hCh due to poor product solubility). The reported yields below are for isolated
single-crystals. Caution: Arsenic compounds are hazardous and should be handled with
care! (This accounts for the small scale of the reactions reported herein.)
Synthetic Procedures
2,6-bis(bromomethyl)naphthalene. 2,6-dimethylnaphthalene (1.34 g, 8.59
rnmol), N-bromosuccinimide (4.84 g, 25.8 mmol), benzoyl peroxide (859 mg, 0.221
mmol) and dry chloroform (50 mL) were stirred together and degassed to give a yellow
suspension. The reaction mixture was heated under N2at 55 DC for 12 h. Chloroform (25
mL) was added and the solution was washed with 2 M HCl (2 x 25 mL), then 2 M NaOH
(2 x 25 mL). The solvent was evaporated to yield an off-white powder. This powder
was purified by trituration with acetone to yield a white solid (1.34 g, 4.27 rnmol, 50%).
lH NMR (CDCh): 87.82 (s, 2H, CH), 7.82 (d, 2H, CH, J = 8.5 Hz), 7.54 (d, 2H, CH, J =
8.5 Hz), 4.67 (s, 4H, CH2).
2,6-bis(mercaptomethyl)naphthalene (H2L 2,6). 2,6-
bis(bromomethyl)naphthalene (1.09 g, 3.47 rnmol) and thiourea (803 mg, 10.6 rnmol)
were heated to reflux in 1:1 v/v CH2Ch/acetone (60 mL) for 1 h 15 min. The solvent was
evaporated and the resulting white salt was washed with acetone, dried overnight by
vacuum filtration, and then degassed. Degassed 2 M NaOH (30 mL) was transferred via
cannula onto the salt and the solution was stirred under N2at 80 DC for 2 h. The solution
73
was acidified with 6 M HCl and extracted with CHzClz (3 x 30 mL). The organic layer
was washed with 0.5 M HCI, dried with MgS04, and concentrated to yield a white solid
(510 mg, 2.31 mmol, 67%). IH NMR (CDCh): 87.78 (d, 2H, CR, J =8.2 Hz), 7.72 (s,
2H, CR), 7.48 (dd, 2H, CR, J =8.5 Hz, J =1.8 Hz), 3.91 (d, 4H, CR2, J =7.6 Hz), 1.81
(t, 2H, SR, J = 7.6 Hz).
Asz(Lz,6hCh. AsCh (6.37 pL, 0.0746 mmol) was added slowly to a solution of
HzL z,6 (16.5 mg, 0.0746 mmol) in CDCh (5 mL) to yield a solution containing only a
mixture of syn- and anti- diastereomers in a ratio of 1.7:1 after three days. Single crystals
were grown by slow vapor diffusion of pentane into a CHCh solution of Asz(LZ,6)2Clz
yielding colorless crystals after 3 days (4.7 mg, 0.0072 mmol, 19%). syn-Asz(Lz,6hClz:
IH NMR (300 MHz, CDCh) 8 7.64 (d, 2H, CR, J =8.8 Hz), 7.56 (s, 2H, CR), 7.35 (m,
2H, CR), 4.26 (ABq, CR2, 4H, J = 12.9 Hz). anti-Asz(Lz,6hClz: IH NMR (CDCh) 8 7.63
(d, 2H, CR, J = 8.5 Hz), 7.51 (s, 2H, CR), 7.38 (m, 2H, CR), 4.25 (ABq, CRz, 4H, J =
12.9 Hz).
1,5-bis(bromomethyl)naphthalene. 1,5-dimethylnaphthalene (10.0 g, 64.0
mmol), N-bromosuccinimide (34.2 g, 192 mmol) and benzoyl peroxide (1.55 g, 6.40
mmol) were dissolved in dry chloroform (250 mL) in a 500 mL 3-neck flask and
degassed. The reaction mixture was heated under Nz at 50°C for 3 h 15 min. The
solution was cooled to room temperature and half of the solvent was evaporated, causing
a white precipitate to crash out of solution. This precipitate was removed by vacuum
filtration and washed with 2 M HCI (2 x 30 mL), 2 M NaOH (2 x 30 mL), brine, and
dried with MgS04 to yield a white powder as the crude product (14.4 g, 45.9 mmol,
74
72%). IH NMR (CDCh): () 8.19 (d, 2H, CR, J = 8 Hz), 7.58 (m, 4H, CR), 4.96 (s, 4H,
CR2).
1,5-bis(mercaptomethyl)naphthalene (H2L 1,5). 1,5-
bis(bromomethyl)naphthalene (14.3 g, 45.4 mmol) and thiourea (13.9 g, 182 mmol) were
heated to reflux in acetone (500 mL) for 1 h 15 min. The solvent was removed by
vacuum filtration and the resulting white salt was washed with acetone to yield a white
salt. The salt was then placed under N2 in a 500 mL 3-neck flask equipped with a stir bar.
Degassed 2 M NaOH (300 mL) was transferred via cannula onto the salt and the solution
was stirred under N2 at reflux for 2 h. After cooling to room temperature, the solution
was acidified with concentrated HCl and extracted with CH2Ch (3 x 50 mL). The
organic layer was washed with H20, dried with MgS04, and concentrated to yield a white
solid (8.28, 37.4 mmol, 82%). IH NMR (CDCI3): () 8.04 (m, 2H, CR), 7.49 (m, 2H, CR),
4.21 (d, 4H, CR2, J =7.4 Hz), 1.88 (t, 2H, SR, J =7.4 Hz).
AS2(L1,5)2Ch. AsCh (5.13 ilL, 0.0601 mmol) was added slowly to a solution of
H2L 1,5 (13.3 mg, 0.0601 mmol) in CHCh (5 mL) and mixed well causing white crystals
to crash out of solution that were suitable for single crystal X-ray structure determination
(52.0 mg, 0.079 mmol, 35%). Sparingly soluble crystals were dissolved in CD2Ch and
the IH NMR spectrum was collected over 10 hours: IH NMR (600 MHz, CD2Ch) () 7.98
(d, CR, J =8.2 Hz), 7.37 (m, CR), 7.33 (m, CR), 7.24 (m, CR), 7.18 (m, CR), 4.51 (ABq,
CH2, J =12 Hz), 4.39, (ABq, CH2, J =4 Hz).
1,4-bis(bromomethyl)naphthalene. 1,4-dimethylnaphthalene (4.42 g, 28.3
mmol) was dissolved in dry chloroform (150 mL) and degassed. Under active N2, N-
75
bromosuccinimide (15.0 g, 84.5 mmol) and benzoyl peroxide (690 mg, 2.85 mmol) were
added and the suspension was degassed to give a yellow suspension. The reaction
mixture was heated under N2at 55 DC for 6 h. The solution was cooled to room
temperature and then washed with 2 M HCI (2 x 15 mL), 2M NaOH (2 x 20 mL), brine,
and dried with MgS04. The solvent was evaporated to yield an off-white powder as the
crude product (9.50 g, 28.3 mmol, >99%). IH NMR (CDC!)): 08.22 (m, 2H, CH), 7.67
(m, 2H, CH), 7.49 (s, 2H, CH), 4.94 (s, 4H, CH2).
1,4-bis(mercaptomethyI)naphthalene (H2L1,4). 1,4-
bis(bromomethyl)naphthalene (4.00 g, 12.7 mrnol) and thiourea (2.92 g, 38.5 mmol) were
heated to reflux in 3:2 v/v CHC!)/acetone (250 mL) for 16 h. The solvent was removed
by vacuum filtration and the resulting white salt was washed with acetone and dried for 1
h 30 min by vacuum filtration to yield a pale yellow salt (5.92 g, 12.7 mmol, >99%). The
salt was then placed under N2in a 500 mL 3-neck flask equipped with a stir bar.
Degassed 2 M NaOH (200 mL) was transferred via cannula onto the salt and the solution
was stirred under N2 at 80 DC for 2 h. After cooling to room temperature, the solution
was acidified with concentrated HCI and extracted with CH2Ch (3 x 50 mL). The
organic layer was washed with H20, dried with MgS04, and concentrated to yield a
yellow solid (2.06, 9.31 mmol, 73%). IH NMR (CDC!)): 08.14 (m, 2H, CH), 7.60 (m,
2H, CH), 7.38 (s, 2H, CH), 4.19 (d, 4H, CH2, J == 7.0 Hz), 1.88 (t, 2H, SH, J == 7.0 Hz).
AS2(L1,4hCh. AsCh (17.4 ilL, 0.203 mmol) was added slowly to a solution of
H2L1,4 (45.0 mg, 0.203 mmol) in CHCh (15 mL) and mixed well to yield a solution of
syn and anti diastereomers in a ratio of 20: 1. Slow diffusion of pentane into a chloroform
76
solution of the complex yielded clear, colorless crystals that were suitable for structure
determination using single crystal X-ray diffraction methods (6.9 mg, 0.010 mmol, 10%).
Single crystals were also obtained by slow diffusion of pentane into a benzene solution of
the complex. Single crystals were dissolved in CDC!): syn-As2(L1,4hCh: IH NMR (500
MHz, CDC!)) 8 8.03 (m, 4H, CR), 7.53 (m, 4H, CR), 7.32 (s, 4H, CR), 4.58 (ABq, 16H,
CH2, J =13.2 Hz). anti-As2(L 1,4hCh: IH NMR (500 MHz, CDC!)) 8 8.00 (m, 4H, CR),
7.47 (m, 4H, CR), 7.28 (s, 4H, CR), 4.57 (s, 16H, CH2).
X-Ray Crystallography
All data was collected on a Bruker SMART APEX CCD diffractometer using Mo
Ka radiation at 153 K (AS2L2,62Ch) or 173 K (As2(L1,shCh, AS2(Ll,4hCh·CHC!) and
As2(L1,4hCh,C6H6). The crystallographic data, details of the data collections, and
refinements of the structures are given in the CIF files. The absorption corrections for
each structure were applied by SADABS. The structures were solved using direct
methods or the Patterson function, completed by subsequent difference Fourier syntheses,
and refined by full matrix least-squares procedures on F2. In each of the structures, all
non-H atoms were refined with anisotropic thermal parameters except the disordered C
and CI atoms in solvent CHC!) molecules in As2(Ll,4hCh. H atoms were treated in
calculated positions. All calculations were performed by the Bruker SHELXTL package.
Some additional comments about the X-ray structure of AS2(L1,4hCh·CHC!)
should be noted. The crystal structure of this compound was determined as triclinic
77
(space group P-l, unit cell a =19.313(4), b =19.923(4), c = 24.508(5) A, a= 78.110(4),
13= 78.860(5), Y= 89.183(5)° with six symmetrically independent structural units, each
containing the macrocycle and one CHCh molecule. Checking these crystals for possible
twins by CELL_NOW23 showed that the crystals could contain a twin which consists of
four domains with the same unit cell (a =10.494, b =17.351, c =17.616 A, (X= 105.80,
13= 92.98, Y= 95.98~ but different orientations. Our attempts to solve this structure as a
twin or in a monoclinic system failed (the fact that parameters a, b and angles ~ 13 are
close to each other indicates such a possibility). However, it was possible to solve and
perform refinements to the crystal structure of As2(L1,4)2Ch·CHCh in space group P-l
with six independent molecules. All non-H atoms in As2(L1,4hCh-CHCh were refined
with anisotropic thermal parameters. The geometry of all six independent molecules, the
anisotropic thermal parameters for each of the atoms, and the packing of the molecules in
the crystal structure are all reasonable. Four of the six symmetrically independent solvent
CRCb molecules are disordered over two positions with opposite orientations. All six
macrocyclic molecules have a syn-configuration and the geometrical parameters in all of
the molecules are close. The X-ray data for AS2(Ll,4hCh·CHCb confirm the connectivity
and stereochemistry of this macrocycle as reported in the manuscript.
There are two symmetrically independent molecules AS2(Ll,4hCh in the crystal
structure of AS2(Ll,4hCh,C6H6. One of the CI atoms in one of them and the S2AsCI
fragment in another one are disordered over two positions (in ratio 41/59 and 88/12,
respectively) corresponding to anti-As2(Ll,4hCh, and syn-As2(L1,4)2Ch' isomers,
78
respectively. Thus the X-ray data show that both anti- and syn-isomers are in the crystal
structure of Asz(L1,4hCh,C6H6.
Crystallographic Information Files for each of these structures are available on the
ACS website at pUbs.acs.org.
Bridge to Chapter III
Chapter II reported on a series of AszLzCh macrocycles prepared from
constitutionally isomeric naphthalene dithiolligands. The diastereomeric excess, or syn-
to-anti ratio, was controlled by the ligand choice; intramolecular steric interaction
resulted in preference for one isomer over the other. In Chapter III, several different
AszLzCh macrocyclic complexes are reported. In one example, the syn-to-anti ratio is
controlled intermolecularly, through steric interactions in the solid state. In the absence
of a suitable guest molecule, the macrocycle crystallizes as the anti isomer exclusively.
However, if toluene or p-xylene is present during the crystallization process, two
macrocycles dimerize around one solvent molecule, creating an inclusion complex. p-
xylene causes the exclusive crystallization of the syn isomer, while inclusion of the
smaller toluene molecule results in a mixture of syn and anti conformations.
79
CHAPTER ill
HOST-GUEST INTERACTIONS IN A SERIES OF SELF-ASSEMBLED AszLzCh
MACROCYCLES
This chapter presents solid-state evidence for the diastereoselective self-assembly
of a series of AszLzCh macrocycles in which the diastereomeric excess is controlled by
intermolecular steric interactions with solvent molecules. This co-authored work was
previously published (Dalton Transactions, 2008,3447-3453, © Royal Society of
Chemistry).l Sean A. Fontenot performed the synthesis of Asz(l)zCh and Asz(2)zCh and
assisted in writing the manuscript. X-ray crystallography was carried out by Dr. Lev N.
Zakharov. Dr. Melanie A. Pitt performed calculations on cavity volumes. Professor
Darren W. Johnson provided intellectual input and editorial assistance. I synthesized
each isomer of Asz(3)zCh, performed cavity volume calculations, and wrote the majority
of the manuscript.
Introduction
The use of main-group elements as components in metal-ligand supramolecular
assemblies is not common, and has led to new structure types that are inaccessible using
the more traditional transition metals.z Self-assembled from metal ions and multidentate
80
organic ligands, metal-ligand supramolecular assemblies are dynamic systems,3-6 often
capable of encapsulating guest molecules within their three-dimensional cavities. The
walls of these cavities usually consist of phenyl rings causing the cavity interiors to be
highly hydrophobic, an environment that can differ significantly from that of the solvent
outside the cavity. It is difficult, but also of great interest, to spice up these bland
interiors by preparing cavities with endohedral functionality.? Guest molecules can
interact specifically with inward-directed functional groups,8 potentially increasing the
selectivity of the cavity and the likelihood of reaction or catalysis within that cavity.
Unfortunately, endohedral functionalization is synthetically very challenging. Gibb and
co-workers have demonstrated this challenge by showing that reactive sites on the
exterior of a cavitand are more likely to react than reactive sites within the cavitand.9,10
As one elegant example of inward-directed functionality, Rebek and co-workers have
prepared bowl-shaped cavitands with functional groups that dangle over the bowl-
opening,11-13 allowing them to trap reactive intermediates that are not normally
observable on the NMR timescale. 14
While many of these systems require extensive synthesis, self-assembled arsenic-
ligand supramoleculara,15 structures provide easy access to inherently endohedrally-
functionalized hosts: the As(ill) lone-pairs point into the host's cavity. We are exploring
inclusion complexes of these hosts that are uniquely suited for unusual host-guest
interactions.
a These self-assembled supramolecular systems could also be reasonably described as dynamic covalent
systems.
81
Arsenic(llI) has an unusual, but predictable, trigonal pyramidal coordination
geometry that features a stereochemically active lone-pair when coordinated by sulfur-
based ligands. Our laboratory has shown that this geometry can be targeted in the self-
assembly of AszLzClz macrocycles (where L =a rigid dithiolate) from AsCl3 and dithiol
ligands. 16-17 In the solid state, the arsenic atoms in these macrocycles sit within the
macrocyclic cavity, partially due to the As-n interaction. This causes the lone-pair of
electrons on each arsenic atom to point directly into the cavity, which, when combined
with the electron-rich aromatic ligand walls, results in a Lewis-basic interior for the
macrocyclic cavity. Unfortunately, all AszLzClz macrocycles reported to date are too
small to host any guest molecules, and no interactions of potential guests with the unusual
Lewis-basic interiors of these cavities have been observed. In this chapter, the single
crystal X-ray structures for three macrocycles with larger cavities are reported, and their
inclusion complexes with aromatic guests are described. In one case, guest inclusion
drives the crystallization of the sterically-hindered isomer of a macrocycle into a dimeric
"capsule" around that guest.
Results and Discussion
AsCh and dithiolligands Hz1, Hz2, and Hz3 self-assemble into syn- and anti-
AszLzCh macrocycles (Scheme 1). These macrocycles were crystallized as inclusion
complexes with a variety of aromatic guests (Table 1). In each case it was found that
guest inclusion does not affect the As-n interaction, an attractive electrostatic interaction
between Lewis-acidic As(llI) and Lewis-basic aromatic rings. 18-ZO While the presence of
82
this interaction results in arsenic lone pairs within the macrocyclic cavities, the strong As-
7t interactions shelter the lone-pairs from interacting with the guests. However, guests do
dictate their host's structure, and in fact, host-guest interactions can even be used to
provide diastereocontrol in the self-assembly reactions in some cases.
SH
SH
syn
+
S
CI I'\. /Sf]
e
/As-CI
S "-S
anti
H~OMe
Meo~.
SH
H23
Scheme 1. Self-assembly of AszLzCh macrocycles. In the syn-AszLzCh macrocycles,
both chlorine atoms are on the same side of the macrocyclic cavity while in the anti-
AszLzCh macrocycles, the chlorine atoms are on opposite sides.
83
Table 1. Crystallographic Data and Refinement Parameters for AS2hCh, As222Ch, and
As232Cl2.
~ [As212Ch [anti-As222Ch anti-As232Ch ~ [(syn-As232CI2)2 ~ [(syn-
·toluene] ·benzene] ·toluene] As232Chh·
v-xylene]
!Formula C21H2oAsClS2 C38H34As2CI2S4 C2oH24As2Ch C23.50H28As2Ch C24H29As2Ch
°4S4 04S4 °4S4
!Formula weight 446.86 839.63 677.37 723.44 730.45
tremperature (K) 173(2) 173(2) 173(2) 173(2) 173(2)
Wavelength (A) 0.71073 0.71073 0.71073 0.71073 0.71073
Crystal system Triclinic Monoclinic Triclinic Monoclinic Monoclinic
Space group P-1 P2/c P-1 P21 P21/c
a (A) 9.3876(7) 15.404(7) 8.4805(11) 13.8813(13) 13.9458(17)
b (A) 9.6322(8) 6.395(3) 9.3290(12) 9.8378(9) 9.8297(12)
r (A) 12.0300(9) 19.576(8) 9.6719(12) 21.764(2) 21.814(3)
a (0) 107.6460(10) 90 117.4210(10) 90 90
Vi CO) 99.3000(10) 104.071(5) 101.198(2) 90.202(2) 90.784(2)
b' (0) 101.4170(10) 90 98.034(2) 90 90
!Volume (N) 987.09(13) 1870.5(14) 642.79(14) 2972.1(5) 2990.0(6)
~,Z' 2, 1 2,0.5 1,0.5 4,2 4, 1
!Dcalcd (mg/m") 1.503 1.491 1.750 1.617 1.623
I! (cm- I ) 0.2070 0.2179 0.3158 0.2738 0.2722
~'(OOO) 456 856 340 1460 1476
~rystal size (mm) 0.18 x 0.16 x 0.19 x 0.14 x 0.27 x 0.14 x 0.32 x 0.26 x 0.08 0.18 x 0.14 x
0.12 0.02 0.10 0.10
ITndex ranges -12S;hS;12, -18S;hS;18, -10 S; h S; 10, -17 S; h S; 17, -13 S;hS; 17,
-12 S; k S; 12, -7S;kS;7, -11 S;ks. 11, -12 S; k S. 12, -8 S. k S; 12,
-15<1<15 -23 S; 1< 23 -12S;1S; 12 -27 < 1S. 27 -27 S; 1S; 26
!Reflections 11379 12553 5920 33472 14607
ollected
ndependent 4453 [0.0211] 3268 [0.1 021] 2713 [0.0131] 12933 [0.0186] 6483 [0.0309]
eflections [Riot]
lData/restraints/ 4438/0/318 3268/0/208 2713/0/193 12933/111643 6483/4/371
parameters
KJoodness-of-fit 1.103 1.122 1.031 1.045 1.134
bnF2
R1IwR2 0.0382/ 0.0897/ 0.0280/ 0.0516/ 0.0713/
[l> 2a(l)] 0.0876 0.2091 0.0692 0.1469 0.1340
!R1IwR2 (all data) 0.0450/ 0.1412/ 0.0316/ 0.0615/ 0.0985/
0.0910 0.2356 0.0713 0.1550 0.1440
Largest diff. ~eak 0.926; -0.489 1.294; -1.428 0.661; -0.399 1.155; -0.772 1.037/-1.096
and hole/e k
84
4,4'-Bis(mercaptomethyl)biphenyl (Hzl) was designed to form macrocycles with
cavities that are tall enough along the As-As axis to host small guest molecules. Aszl zClz
was prepared by mixing Hzl with AsCb in toluene. X-ray quality crystals of the [anti-
Aszl zClz·toluene] inclusion complex were obtained by the slow diffusion of hexanes into
a toluene solution of AszlzClz.b In the crystal structure, the observed AS-Caryl distances,
the shortest of which is 3.24 A, reveal intramolecular As-x interactions (Figure la).
However, no interactions between the arsenic atoms and the toluene guest molecule are
observed. The distances (-3.5 A) between the closest carbon atoms in the biphenyl
a) C"· <;;1"
,,";~~2~~;:..r
·'A,nAJ A.n,~.eli"C\\~l~ "
\ ;)-ooo"j~ ;n~,~--::J~\"Q{-~~~~'~f::-;~_:-:~~'~-""-:'1(~~~- ';~ic')
b)
Figure 1. ORTEP (30% probability ellipsoids) representation of single-crystal X-ray
structure of anti-AszlzClz (a) and space-filling representation (b) of single-crystal X-ray
structure of the [Aszl zCh·toluene] inclusion complex. Only one position for disordered
groups is shown for clarity.
b Crystals were obtained only when toluene or benzene were present, although the crystals grown from
benzene were not of X-ray quality. The following solvents did not yield single crystals; presumably, they
were not appropriately sized to serve as guests: CH2Ch, CHCh, p-xylene, mesitylene, and THF.
85
ligands and toluene indicate the presence of 1t-1t stacking between host and guest. The
biphenyl ligands bow out slightly, presumably to accommodate the toluene guest. A
search of the Cambridge Structural Database21 reveals that this degree of bending is
within the observed range for biphenyl moieties in known structures. All S-As-S, S-As-
CI, and C-S-As angles are within the typical range observed for AS2~CI2macrocycles
(Table 2).15,17
Table 2. Selected bond lengths (A) and angles e).
[(syn-As232Chh·toluene] [(syn-As232CI2h·p-xylene]
As(I)-S(I) 2.203(2) As(I)-S(1 ) 2.2140(2)
As(I)-S(4) 2.214(2) As(1)-S(3) 2.199(2)
As( I)-CI(l ) 2.248(2) As( 1)-CI( 1) 2.246(2)
As(2)-S(2) 2.220(3) As(2)-S(2) 2.245(5)
As(2)-S(3) 2.244(3) As(2)-S(4) 2.218(5)
As(2)-CI(2) 2.232(3) As(2)-CI(2) 2.235(7)
As(2A)-S(2A) 2.13(2) As(2A)-S(2) 2.105(2)
As(2A)-S(3A) 2.13(3) As(2A)-S(4) 2.177(1)
As(2A)-CI(2A) 2.336(1) As(2A)-CI(2A) 2.24(2)
As(3)-S(5) 2.192(2) S(3)-As(1)-S(I) 87.80(8)
As(3)-S(8) 2.212(2) S(3)-As(1 )-CI(1) 103.22(1)
As(3)-CI(3) 2.247(2) S(1 )-As(1 )-Cl(1) 100.27(8)
As(4)-S(7) 2.201(3) C(1)-S(l)-As(1) 100.1(2)
As(4)-S(6) 2.209(3) C(1I)-S(3)-As(1) 102.4(3)
As(4)-Cl(4) 2.248(3) S(4)-As(2)-S(2) 87.58(2)
As(4A)-S(6A) 2.13(5) Cl(2)-As(2)-S(2) 101.8(2)
As(4A)-S(7A) 2.32(3) S(4)-As(2)-CI(2) 102.8(3)
As(4A)-Cl(4A) 2.254(2) C(8)-S(2)-As(2) 103.0(3)
S(I)-As(I)-S(4) 87.79(8) C(18)-S(4)-As(2) 101.7(3)
S(1)-As(l)-CI(1) 102.93(1) S(2)-As(2A)-S(4) 92.3(7)
S(4)-As(1 )-Cl(1) 100.74(9) S(2)-As(2A)-CI(2A) 99.9(8)
86
Table 2 continued.
C( 1)-S(1 )-As(1) 102.5(3) S(4)-As(2A)-Cl(2A) 86.7(2)
C(18)-S(4)-As(1) 99.5(2) C(8)-S(2)-As(2A) 103.7(4)
S(2)-As(2)-S(3) 88.47(1) C(18)-S(4)-As(2A) 105.6(6)
S(2)-As(2)-CI(2) 100.14(1)
S(3)-As(2)-CI(2) 101.88(1) [As212C12·toluene]
C(8)-S(2)-As(2) 100.0(2) As(1)-S(1) 2.1922(9)
C(11 )-S(3)-As(2) 101.4(3) As(1)-S(2) 2.2125(9)
S(3A)-As(2A)-S(2A) 93.0(8) As(1)-CI( 1) 2.2524(9)
S(2A)-As(2A)-Cl(2A) 93.1(6) As(1)-S(1A) 2.185(6)
S(3A)-As(2A)-Cl(2A) 88.4(8) As(1 )-S(2A) 2.110(6)
C(8)-S(2A)-As(2A) 100.7(3) As(1)-C1(1A) 2.464(8)
C(1l)-S(3A)-As(2A) 103.2(3) S(1 )-As(1 )-S(2) 88.19(3)
S(5)-As(3)-S(8) 88.47(9) S(1)-As(1)-Cl(1) 101.63(4)
S(5)-As(3)-CI(3) 102.02(1) S(2)-As(1)-CI(1) 101.23(4)
S(8)-As(3)-CI(3) 99.47(9) C(1)-S(1)-As(1) 103.37(1)
C(21)-S(5)-As(3) 103.1(3) C(14)#1-S(2)-As(1) 101.12(1)
C(38)-S(8)-As(3) 100.3(2) S(1A)-As(1)-S(2A) 92.4(3)
S(7)-As(4)-S(6) 87.83(1) S(1A)-As(1 )-CI(1 A) 94.9(3)
S(6)-As(4)-Cl(4) 100.64(1) S(2A)-As(1 )-Cl( 1A) 95.4(3)
S(7)-As(4)-Cl(4) 101.94(1) As(1)-S(1A)-C( 1) 104.5(3)
C(28)-S(6)-As(4) 103.7(3) As(l)-S(2A)-C(14A)#1 93.1(3)
C(3l)-S(7)-As(4) 102.3(3)
S(6A)-As(4A)-S(7A) 86.8(1) [anti-As222Ch·benzene]
S(6A)-As(4A)-Cl(4A) 110.8(1) As(1)-S(1) 2.204(3)
Cl(4A)-As(4A)-S(7A) 105.9(1) As(1)-S(2) 2.213(3)
C(28)-S(6A)-As(4A) 94.3(5) As(1)-Cl( 1) 2.244(4)
C(31 )-S(7A)-As(4A) 99.4(5) S(1)-As(1)-S(2) 87.52(1)
S(l)-As(1)-Cl(1) 102.69(2)
anti-As232Cl2 S(2)-As(1 )-Cl(1) 98.77(2)
As(1)-S(1) 2.2182(7) C(1)-S(1)-As(1) 102.9(4)
As(l )-S(2)#3 2.2018(8) C(16)#2-S(2)-As(1) 99.5(4)
As(1 )-Cl(1) 2.2586(8)
S(2)#3-As(1 )-S(1) 86.76(3)
S(2)#3-As(1 )-Cl(1) 101.50(4)
I
S(1)-As(1)-Cl( 1) 102.73(3)
C(1 )-S(1)-As(l) 102.92(9)
C(1 0)-S(2)-As(1 )#3 103.85(1)
Symmetry Codes: #1-x+2, -y+2, -z+2; #2-x, -y+l, -z; -x, -y, -z+2. Disordered atoms in
the second positions are indicated with the symbol A.
87
4,4'-Bis(mercaptomethyl)-trans-stilbene (H22) is longer than H21 and was
designed to form macrocycles with even taller cavities. As222Ch was prepared by mixing
H22 with AsC!) in CH2Ch. X-ray quality crystals of [anti-As222Clrbenzene] were
obtained by the slow diffusion of benzene layered on top of a CH2Ch solution of
macrocycle.c The crystal structure reveals the presence of intramolecular As-x
interactions as evidenced by short AS-Caryl contacts, the shortest of which is 3.23 A
(Figure 2a). A slight bowing of the stilbene ligands is observed, allowing guest inclusion.
No unusual bond angles are observed (Table 2) suggesting that there is not much strain
imposed on the macrocycle by the guest molecules. One benzene molecule per
macrocycle is present, but is shared with a neighboring macrocycle, so that each
macrocycle partially hosts two guests and each guest is partially encapsulated by two
macrocycles (Figure 2c). Alternating macrocycles and benzene molecules form infinite
chains of x-x stacked host-guest assemblies (Figure 2b).
C Crystals were not obtained when an aromatic solvent mOlecule was not present. The crystals grown from
benzene were of X-ray quality, but those obtained from toluene, mesitylene, and p-xylene were not. The
following solvents were not appropriately sized to serve as guests: CH2Ch, CHCh, THF, DCE, TCE.
88
a)
Figure 2. ORTEP (30% probability ellipsoids) representations of single-crystal X-ray
structure of anti-As222Ch (a) and the packing diagram of [anti-As222Ch·benzene] along
the macrocyclic axis (b). Space-filling representation of single-crystal X-ray structure of
the [anti-As222Ch·benzene] inclusion complex (c).
1,4-Dimethoxy-2,5-bis(mercaptomethyl)benzene (H23) was designed to be used in
the preparation of macrocyc1es that are wide but not tall. The methoxy groups on this
ligand expand the macrocyclic cavity. As232Clz was prepared by mixing H23 with AsCI)
in chloroform, benzene, toluene, or p-xylene. The solvent used for crystallization
89
becomes the guest in the inclusion complex and dictates whether anti-As232Clz, [(syn-
If As232Ch is crystallized from p-xylene a [(syn-As232Clzh'p-xylene] inclusion
complex is observed (Figure 3). In this structure, the organic ligand backbones are at a
slight angle (31.5°) to each other resulting in an opening of one side ofthe macrocycle
and a closing of the other. The chlorine ligands of syn-As232Clz are directed toward the
sterically hindered closed end of the macrocycle, which defines the tapered end of a bowl-
shaped structure. The open ends of two adjacent macrocycles are sandwiched together to
form a cavity with an interior volume of ca. 216 A3.e.22 Within each macrocycle, the two
organic ligands can be eclipsed (methoxy groups on both ligands aligned) or staggered,
and both species exist within the crystal structure (the disorder was modeled showing
73% of the eclipsed structure is present). For ease of viewing, only the eclipsed
structures are shown.
If As232Ch is crystallized from toluene a mixture of homo- and hetero-dimers
d The following molecules were screened as guests, but were not found to drive dimer formation: p-
dimethoxybenzene, hydroquinone, p-benzenedimethanol, p-xylenediarnine, phenol, bromobenzene,
iodobenzene, mesitylene, 1,2,3-trimethylbenzene, cyclohexane, 1,4-cyanobenzene, and m-xylene. In each
case, either the anti-Asz3zClz macrocycle or nothing crystallized from solution. Crystallization from 0-
xylene resulted in an [(Asz3zClzh·o-xylene] dimer that was highly disordered in the solid state.
e Cavities were measured using solvent (1.4 A) surfaces. The cavity volume was estimated as the difference
between the volume of the [(syn-Asz3zClzh·p-xylene] host-guest complex and the volume of the p-xylene
guest. By this calculation, p-xylene fills 46% of the cavity.
90
structure of these dimers is very similar to that of the [(syn-As232Chh-p-xylene] dimer
with a 29.9° angle between the organic ligand backbones and an interior volume of ca.
184 A3•f •22 With the decrease in symmetry in the guest molecules fromp-xylene to
toluene comes a decrease in the symmetry of the dimer. While [(syn-As232Ch)z'p-
xylene] is disordered only in the orientation of the methoxy groups and the position of a
As-CI fragment, the toluene-containing dimer contains a mixture of syn and anti
macrocycles, disordered methoxy groups, and a disordered toluene guest (see
Experimental section for details on the modelling of the disorder).
Guest inclusion in the dimer can be accomplished without destroying the strong
As-x interaction. The shortest AS-Caryl contact (3.26 A and 3.22 A for toluene and p-
xylene guests respectively) is significantly less than the sum of the van der Waals radii for
arsenic (2.0 A) and a phenyl carbon (1.7 A). The As-As distances (4.83 and 4.86 Afor
toluene guest and 4.89 and 4.74 A for p-xylene guest) within each macrocycle of the
dimer are significantly longer than the As-As distance in the anti-macrocycle (see below),
showing that the macrocycle is sufficiently flexible to accommodate guest molecules.
The guest molecules are oriented in the cavity to best fill the space with the methyl
groups on each guest pointing into the cavity of one or both components of the dimer
(Figure 3b,d). There are no obvious x-x or Cll-x interactions between the host and guest
molecules - only van der Waals interactions.
f Cavities were measured using solvent (1.4 A) surfaces. The cavity volume was again estimated as the
difference between the volume of the [(syn-As232CI2h·toluene] complex and the volume of toluene. By this
calculation, toluene fills 45% of the cavity.
91
c)
l
\
d)
/
I
I
-1.
\
I
Figure 3. ORTEP (30% probability ellipsoids) and space-filling representations of the
single-crystal X-ray structure of [(syn-As232Chh'p-xylene] (a,c) and [(syn-
As232Chh·toluene] (b,d) inclusion complexes. Only one position for disordered groups
is shown for clarity.
92
anti-Asz3zClz
If appropriately-sized guest molecules are not present during the crystallization
process, anti-As232Ch crystallizes exclusively. anti-As232Ch is observed when crystals
are grown from chloroform or benzene, both of which are apparently too small or of the
wrong shape to satisfactorily fill the cavity of the (As232Chh dimer. In the anti-As232Ch
solid-state structure (Figure 4a), the two organic ligands that make up the macrocycle are
parallel and the methoxy groups of each ligand are aligned. The chlorine ligands on each
arsenic atom are directed away from the sterically bulky methoxy groups. The expanded
cavity is filled by the methoxy groups of neighboring macrocycles and face-to-face n-n
stacking occurs between neighboring macrocycles (Caryl-Caryl distance of 3.56 A) (Figure
4b-c).
In this structure, the As-n interaction is completely unaffected by guest molecules
as none are present. The AS-Caryl distance of 3.11 A for anti~As232Ch is the shortest
contact for any As2kCh macrocycle that has been reported to date. 15,1? This As-n
interaction is shorter, and presumably stronger, than those previously observed because
the aryl rings in this system are more electron rich due to the electron donating methoxy
substituents.
Structural Trends in AszLzClz Macrocycles
Analysis of the five crystal structures obtained for AS2hCh, As222Ch, and
As232Ch gives insight into the ability of these macrocycles to host guest molecules. Each
macrocycle is too small to completely encapsulate a guest molecule, but is large enough
93
to partially host one while maintaining As-1t interactions. As222Ch has a longer cavity
than As2hCh and this difference in size is reflected in the number of solvent molecules
that each can host. While AS212Ch partially hosts one toluene molecule, each AS222Ch
macrocycle partially hosts two benzene molecules. In either case guest inclusion results
in a slight bowing of the organic ligands. In the As232Ch macrocycle, the organic ligands
do not deviate from planarity to accommodate a guest molecule, but rather the
macrocycle walls tilt out of parallel allowing one end of the macrocyclic cavity to open
up and a guest molecule to fill the void. In each case it is shown that guest inclusion
dictates the structure-and in some cases drives diastereoselectivity in the self-
assembly--of the macrocycle.
a)
b) F.t.... '..!i.C"".•' ,...~.'.'},') c)
(' --. <,
.. '\' r;
<, ~- .. i L, ,; '-"-JIL/~.~',
... (, ..' ,....1","", c:" ' , .. "
/~.'- . :"~ ;'. --} (~-"
cc 'J" ,-l~ c '::
Figure 4. ORTEP (30% probability ellipsoids) representation of single-crystal X-ray
structure of anti-As232Ch (a). Stick representation showing the packing of anti-As232Ch
in the crystal structure from top (b) and side views (c).
94
Conclusion
In this paper, five new X-ray crystal structures were presented for three new
AszLzClz macrocycles. In each example, appropriately sized aromatic solvent molecules
fill the macrocyclic cavity. In the case of Asz3zClz, choice of guest molecule allows
stereocontrol over which diastereomer is crystallized. Larger guest molecules (toluene, p-
xylene) are encapsulated by an [(Asz3zClzh·guest] inclusion complex, while smaller guest
molecules (chloroform, benzene) are too small to fill the dimer cavity forcing anti-
Asz3zClz to crystallize exclusively. When the guest is p-xylene, the dimer consists of
only anti macrocycles, and when the guest is toluene, the structure contains and mixture
of anti-anti and syn-anti dimers. We have shown that larger dithiolligands will
predictably form expanded ASzLzCh macrocycles with spacious cavities; even larger
ligands are needed for complete encapsulation of a guest or the formation of kinetically
stable inclusion complexes in solution. We will continue these studies by exploring the
possibility of "threading" a guest molecule through the cavity of these macrocycle to
make rotaxanes and synthetically linking macrocycles to give larger assemblies.
Experimental Section
General Procedures
IH NMR spectra were measured using a Varian INOVA-300 spectrometer
operating at 299.935 MHz. J values are given in Hz. Commercially available reagents
were used as received. Hzl z3 and Hz3z4,z5 were prepared following modified literature
procedures. Complete transformation (>99% yield) of ligand and AsCb to macrocycles is
95
revealed by IH NMR spectroscopy. Isolated single-crystal yields are reported. Caution:
Arsenic compounds are highly toxic and should be handled with care!
Synthetic Procedures
4,4'-bis(mercaptomethyl)biphenyl (H21). Procedure is modified from that
which was previously reported.23 4,4'-bis(chloromethyl)biphenyl (2.00 g, 7.96 mmol)
was dissolved in solution of absolute ethanol (30 mL) and acetone (4 mL). Thiourea
(1.31 g, 17.2 mmol) was added and the solution was heated to reflux for 3 hours. The
off-white precipitate was filtered, washed with acetone, and dried under vacuum (3.01g,
7.46 mmol, 93%). A 3-neck round bottom flack was charged with this precipitate (1.04
g, 2.58 mmol), equipped with a stir bar and condenser, and placed under a N2 atmosphere.
Degassed 2 M NaOH (30 mL) was added via cannula and the mixture was heated to 80
°C for 4 hours. The cloudy solution was cooled to room temperature and degassed 4 M
HCI (20 mL) was added via cannula. Precipitate formed as the acid was added and pH
paper was used to verify that the solution was acidic (pH < 3). The reaction mixture was
extracted with CH2Ch (3 x 20 mL) and the combined organics were dried over sodium
sulfate and evaporated to dryness to yield a white powder (373 mg, 1.51 mmo1, 59%).
()H(300 MHz; CDC!]; Me4Si) 7.54 (d, 4 H, CH, J 4.5), 7.39 (d, 4 H, CH, J 7.8),3.79 (d, 4
H, CH2, J7.5), 1.80 (t, 2 H, SH, J7.5); ()c(75 MHz; CDCh) 140.4, 139.7, 128.6, 127.5,
28.9, which matched the values reported in the literature.
AS212Ch. AsC!] (4.0 I!L, 0.047 mmol) was added to H21 (12.7 mg, 0.0475 mmo1)
96
in toluene (4 mL). Gold-colored X-ray quality crystalsg of the anti macrocycle were
obtained after 5 days by the diffusion of hexanes into this solution at 4 °c (1.5 mg, 4.1
Ilmol, 17%). Dissolving the crystals yields a solution of both syn and anti macrocycles.
~H(300MHz; CDCh; Me4Si) 7.13 (d, 8 H, CH, J 7.8), 7.04 (d, 8 H, CH, J 9.3),4.24
(ABq, 4 H, CH2, J 13),4.23 (ABq, 4 H, CH2, J 13).
4,4'-bis(mercaptomethyl)-trans-stilbeneh,26 (H22). 4,4'-bis(bromomethyl)-trans-
stilbene27,28 (903 mg, 2.69 mmol) was dissolved in solution of absolute ethanol (20 mL)
and acetone (3 mL). Thiourea (613 mg, 8.06 mmol) was added and the solution was
heated to reflux for 4 hours. The off-white precipitate was filtered, washed with acetone,
and dried under vacuum (1.07 g, 2.07 mmol, 77%). A 3-neck round bottom flask was
charged with this precipitate (200 mg, 386 mmol), equipped with a stir bar and
condenser, and placed under a N2atmosphere. Degassed 2 M NaOH solution (30 mL)
was added via a cannula, and the resulting mixture was heated to 80°C for 4 hours. The
cloudy solution was cooled to room temperature, and degassed 4 M HCI (20 mL) was
added via a cannula. Precipitate formed as the acid was added and pH paper was used to
verify that the solution was acidic (pH < 3). The reaction mixture was extracted with
CH2Ch (3 x 20 mL) and the combined organics were dried over sodium sulfate and
evaporated to dryness to yield a white powder (43.0 mg, 158 mmol, 41 %). mp 156.4-
158.1 °C; ~H(300MHz; CDCh; Me4Si) 7.46 (d, 4 H, CH, J 8.1),7.31 (d, 4 H, CH, J 8.1),
g eeDe reference number 676182.
h While use of this ligand has been reported previously,26 no synthetic details or characterization data is
available.
-------
97
7.07 (s, 2 H, HC=CH), 3.74 (d, 4 H, CH2, J 7.2), 1.76 (t, 2 H, SH, J 7.2); 8c(75 MHz;
CDC!) 140.7, 136.3, 128.6, 128.3, 127.0,29.0; m/z (£1) 272 (58%, M+), 239 (100, M-
SH), and 206 (58, M - 2 x SH).
As222Ch. AsC!) (4.0 /lL, 0.047 mmol) was added to a solution ofH22 (12.7 mg,
0.0475 mmol) in CH2Ch (4 mL). Pale yellow X-ray quality crystalsi were obtained after
5 days by layering of benzene on top of this CH2Ch solution at 4 °C (1.0 mg, 2.5 /lmol,
12%). Dissolving the crystals yields a solution of both syn and anti macrocycles. 8H(300
MHz; CDC!); Me4Si) 7.07 (d, 8 H, CH, J7.5), 7.01 (d, 8 H, CH, J7.2), 6.97 (s, 4 H,
HC=CH), 4.17 (ABq, 4 H, CH2, J 13), 4.16 (ABq, 4 H, CH2, J 13).
1,4-dimethoxy-2,S-bis(mercaptomethyl)benzene (H23). Procedure is modified
from that which was previously reported. 3D 1,4-bis(methoxy)-2,5-
bis(chloromethyl)benzene (251 mg, 1.07 mmol) and thiourea (275 mg, 3.62 mmol) were
heated to reflux in acetone (40 mL) for 4 h. The solvent was evaporated to yield an off-
white salt. The salt was transferred to a 3-neck round-bottom flask and placed under N2.
Degassed 2 M NaOH (50 mL) was transferred via cannula onto the salt and the solution
was stirred under N2 at 80°C for 7 h. This solution was acidified using 6 M HCI under
N2, then extracted with CH2Ch (4 x 20 mL). The organic layer was washed with water
(25 mL) and brine (25 mL) and the solvent was evaporated to yield a white solid (120 mg,
0.521 mmol,49%). 8H(300 MHz; CDC!); Me4Si) 6.81 (s, 2 H, CH), 3.85 (s, 6 H, CH3),
i eeDe reference number 676181.
98
3.71 (d, 4 H, CH2, 17.9),1.96 (t, 2 H, SH, 17.9), which matched the values reported in
the literature.
As232Ch. AsCh (15.3 flL, 0.179 mmol) was added to a solution of H23 (41.2 mg,
0.179 mmol) in p-xylene (10 mL) to yield a mixture of four macrocycle isomers.
Colorless single crystals of [(syn-As232Ch)2'p-xylene]j were grown by the slow diffusion
of pentane into ap-xylene solution of As232Ch after 6 days (5.19 mg, 3.55 flmol, 7.9%).
oH(300 MHz; CDCh; Me4Si) 6.80 (m, 2 H, CH), 4.52 (m, 4 H, CH2), 3.79 (m, 6 H, CH3).
Replacing p-xylene with toluene or chloroform as the solvent yielded
[(As232Ch)2·toluene]k and anti-As232Ch,1 respectively.
Volume Calculations using GRASP31
The cavity volume of the [(As232Ch)2·toluene] dimer was also calculated using
the software package GRASP and found to be 164 A3. The large apertures in the plane of
the sulfur atoms were "capped" for the calculation by the addition of a non-covalently
bound anthracene units on each side. This "capping" is expected to cause the volume to
be slightly underestimated.
j eeDe reference number 676184.
k eeDe reference number 676185.
I eeDe reference number 676183.
99
X-Ray Crystallography
All X-ray diffraction data were collected on a Bruker Smart Apex difractometer at
173 K using MoKa. radiation (1 = 0.71073 A). Absorption corrections were applied by
SADABS.29 Crystal structures were solved by direct methods. The crystal structure of
[(syn-As232Chh'p-xylene] was determined to be in the monoclinic space group P2dc.
Crystals of [(As232Chh·toluene] are also monoclinic with unit cells that are close to that
of [(syn-As232Cbh·p-xylene]. However, for the crystal structure of [(As232Cb)2·toluene]
there are several hundred non-zero hkl-type reflections which are inconsistent with a c
glide plane. Therefore, the structure was solved in space group P21• The collected data
suggested that the crystal of [(As232Cbh·toluene] was a racemic twin with a 30/70 ratio
of the two phases. The disorder presumably arises from the mismatched symmetry of the
macrocycle and the solvent guest molecules in [(As232Cbh·toluene] and [(syn-
As232Cbh·p-xylene], the latter of which is centrosymmetric. Two ofthe four S2AsCI
fragments in [(As232Cb)2·toluene] are also disordered over two positions with opposite
orientations of the As-CI bonds. Thus in the structure there are two types of molecules
with syn and anti configurations in 88:12 and 91:9 ratios for the two independent
molecules. Toluene guest molecules in [(As232Cbh·toluene] are disordered over two
positions in a 50:50 ratio. One of two AsCI fragments in each macrocycle in [(syn-
As232Cb)2'p-xylene] is also disordered over two positions. In contrast to
[(As232Cb)2·toluene], all molecules in [(syn-As232Cbh'p-xylene] have a syn
configuration. The disorder of the AsCI group in [(syn-As232Cb)2·p-xylene] results from
the two positions for the As atom, one above and one below the average plane of the
100
connected -CHzS···SCHz- groups. The -OMe groups in [(Asz3zClzh·toluene] and [(syn-
Asz32Clzh'p-xylene] are disordered over two positions corresponding to two opposite
orientations for the benzene rings of the ligand, resulting in macrocycles that are eclipsed
or staggered. The ratios of the occupancies for these two positions are 73:27 in [(syn-
As232Chh·p-xylene] and 84: 16 and 62:38 for the two symmetrically independent
molecules in [(As232Ch)2·toluene]. In [anti-As2hCh·toluene] both S2AsCI fragments are
disordered over two positions with opposite orientations of the As-CI bonds in a ratio of
82/18. Non-H atoms in all structures were refined with anisotropic thermal parameters. H
atoms in [(As232Ch)2·toluene], [(syn-As232Ch)2·p-xylene] and [anti-As222Ch·benzene]
were refined in calculated positions in a rigid group model. In [anti-As232Ch] and [anti-
As212Clz·toluene] H atoms were found on the residual electron density map and refined
with isotropic thermal parameters, except those at the CH2 groups connected to the
disordered fragments which were treated in calculated positions. Disordered fragments
were refined with restrictions; standard distances of bonds were used in the refinement as
targets for corresponding chemical bonds and atoms disordered in similar positions were
refined with the same thermal parameters. All calculations were performed using the
Broker SHELXTL 6.10 package.32
Disorder in Crystal Structures
Disorder in the crystal structures is shown in Figure 5.
101
d)
Figure 5. ORTEP (30% probability ellipsoids) representations of the disorder of the
macrocyc1es in the X-ray crystal structures of Aszl zCh (a), [(Asz3zChh'p-xylene] (b),
and [(Asz3zChh·toluene] (c). Ball and stick representation of the disorder of toluene in
the X-ray crystal structure of [(Asz3zChh·toluene] (d).
Measurement ofBend in Biphenyl Ligand
The bend of the biphenyl ligands in the X-ray crystal structure of AszhCh was
compared to that of 4,4' -substituted biphenyl moieties in other molecules. To measure
102
this bend, the ligand was represented as a set of five lines, drawn between the following
carbons: C1-C2, C2-C5, C5-C8, C8-Cll, Cll-C14. The angles formed at the
intersections of these lines were measured using the Bruker SHELXTL 6.10 software.3Z
A Cambridge Crystal Structure DatabaseZl search yielded 91 structures containing the
4,4' -substituted biphenyl moiety and the measurement procedure was repeated on a
selection of similar structures. These measurements yielded angles similar to those found
in Aszl zClz.
Bridge to Chapter IV
Chapters II and ill reported the synthesis and characterization of AszLzClz
macrocycles in which the syn-to-anti ratio was controlled by steric bulk intra- or
intermolecularly. The self-assembly of these macrocycles in the observed ratios is
necessarily a dynamic process that involves the self-correction and reassembly of pieces
to get to the thermodynamically stable product. In Chapter N, this self-assembly process
is monitored and analyzed using IH NMR spectroscopy, MALDI mass spectrometry, and
X-ray diffraction. Several intermediates to the final product are observed and
characterized, suggesting multiple pathways to the final product. Additionally,
oligomeric "kinetic mistakes" are observed which are corrected during the self-assembly
process.
103
CHAPTER IV
OBSERVATION OF REACTION INTERMEDIATES AND KINETIC MISTAKES IN
A REMARKABLY SLOW SELF-ASSEMBLY REACTION
This chapter presents solution and solid-state evidence for several intermediates
and oligomeric "mistakes" that form during the normal course of metal-ligand self-
assembly. This co-authored work was previously published (Chemical Communications,
2009, 5606-5608, © Royal Society of Chemistry).! MALDI mass spectrometry was
carried out by Dr. Timothy G. Carter. Dr. Lev N. Zakharov performed all X-ray
crystallography experiments. Professor Darren W. Johnson provided intellectual input
and editorial assistance on the manuscript. I performed all synthesis, crystal growth,
NMR studies, and wrote the manuscript.
Introduction
Self-assembly is the most efficient route to prepare discrete supramolecules,2.3 but
the complexity of the dynamic self-assembly process is still poorly understood.4 It is
generally accepted that this process involves the correction of misconnections and
random oligomeric errors, quickly leading from kinetic intermediates to the discrete,
thermodynamic product. Despite this widespread assumption, there exist only a few
104
examples of the observation of oligomeric errors ("kinetic mistakes") and in these cases
they are not structurally characterized.s Additional examples involving the observation of
self-assembly intermediates exist, but because most of these reactions between metals
(M) and organic ligands (L) occur spontaneously and quickly, it is difficult to observe
kinetic intermediates that form prior to the final thermodynamic product.6 Intermediates
have been observed during the titration of one component (M or L) into the other, but this
approach is limited in that only the equilibrium product of each titration is observed in
solution.7•8 Rarely are kinetic intermediates stable enough to isolate from solution.8•9
Since the speed by which self-assembly reactions occur precludes the observation
of intermediates and kinetic mistakes, slowing down the process could allow a better
understanding of metal-directed assembly. This may ultimately lead to the ability to
incorporate design features and specific properties into supramolecular assemblies with
greater predictability. Paradoxically, for the self-assembly of discrete species to occur in a
reasonable amount of time, fast kinetics are required in the forming and breaking of
individual supramolecular interactions (typically either labile metal-ligand bonds or H-
bonds). In this chapter, we describe the relatively slow self-assembly of M2Lz
supramolecular macrocycles. This reaction occurs over the course of several days which
allows for the observation and identification of several intermediate species and kinetic
mistakes along the pathway to macrocycle formation.
105
Results and Discussion
A mixture of syn and anti-As2~Chmacrocycles form in solution over the course
of several days (Scheme I) when rigid dithiolligands H2La,lO H2Lband H2Lell are
individually treated with arsenic trichloride. X-ray quality crystals of syn-As2Lb2Ch were
grown by diffusion of pentane into a solution of AS2Lb2Ch in chloroform. The crystal
structure (Figure la,b) reveals an As-As distance of 4.45 Aand a distance of 4.26 to 7.45
Abetween the methyl carbons on opposite ligands, leaving a small cavity that is devoid
of a guest.
R1~",SHR' AsCI,
Q .-
R2 R1
SH
H2La; R1 = R2 = H
H2Lb; R1 = R2 = CH3
H2Lc; R1 =OCH3 , R2 =H
Scheme 1. Ligands and AS2~Ch macrocycles. Both chlorine atoms are on the same side
of the macrocyclic cavity in the syn macrocycle and on opposite sides in the anti
macrocycle.
c)
Figure 1. X-ray crystal structure representations of As2(LRhCh (stick) (a), As2(Lb)2Ch
(van der Waals radii) (b), and As2LcCl4 (stick) (c).
106
When As2L 3 2Ch (43 ) and As2Lb2Ch (4b) are prepared in d-chloroform, the
reaction progress can be monitored by observing the changes to the methylene region of
the IH NMR spectrum (Figure 2 for 43 and Appendix A for 4b). In each case, as H2L is
consumed, its resonances are replaced with those corresponding to several different
reaction intermediates. These, in turn, are replaced with the resonances for 4, the fully
formed macrocycles. While several of the methylene region resonances overlap, it was
possible to identify three of these intermediate species by symmetry. The first species
observed upon treatment of H2L with AsCh is HL(AsCh) (1), which appears as a doublet
for the unbound (CH2SH) end and a singlet for the bound (CH2S(AsCh)) end. The next
observed species is HL(AsCI)LH (2) which appears as an ABq for the bound
«CH2ShAsCI) end and a doublet for the unbound (CH2SH) end, which is coincidental
with the resonance for H2L or 1. The third species that can be identified by IH NMR is
L(AsChh (3), which appears downfield as a singlet since the ligand symmetrically spans
two As centers.
107
1a 2a H La H La
a 3:Ra 4a 4a2a 4a 4a 2~
-...AA- ...... ... ..
1a 1
b J. ~ A.A-A.J. U
c All ~ AL.N. )J
d JL M-f/L. A.L.Jv. U
e ,J j: ~ J1f ~ tf "A.;AZA ~9
I I I I
4.40 4.20 4.00 3.80 ppm
Figure 2. CHz region of IH NMR spectra of reaction of HzL8 with AsCi) after 35 (a), 81
(b), 122 (c), 186 (d), 366 (e), 1378 (f), and 5650 (g) minutes. Structures of 18 _48 are
shown in Scheme 2.
The identities of1b - 4b were also confirmed by MALDI-MS ([1b+Na+2Ht,
394.9, calc 394.9; [2b+Na+4Ht, 587.0, calc 587.1; [3b+Nat, 536.8, calc 536.8;
[4b+Nat, 690.9, calc 690.9), when AszLzClz was prepared from HzLb• These species
could either be intermediates or kinetic mistakes that are corrected in the self-assembly of
AszLzClz (4). It is possible that the self-assembly reaction is occurring simultaneously
through several competing pathways, as outlined in Scheme 2.a,b
a Unfortunately the slow kinetics and complexity of the reaction do not allow for the measurement of rate
constants. EXSY NMR experiments were carried out on the reaction of AsCh with a monofunctional
model ligand (2-mercaptomethylnaphthalene) at 120 DC, but no ligand exchange was observed.
b 2 and 3 could be both intermediates and kinetic mistakes.
108
a: R1 =R2 =H
b: R1 =R2 =CH3
c: R1=QCH3, R2 = H
Scheme 2. Self-assembly of As2LzCh.
While the overlapping resonances of H2L, 1, 2, 3, and AS2LzCh (4) make it
difficult to accurately integrate the NMR spectra, it is clear that at least one additional
discrete species exists in solution,c likely a larger oligomeric kinetic mistake. These
kinetic mistakes could easily fonn reversibly in the free-for-all chaos of the self-assembly
reaction and then equilibrate to As2LzCh. After 5 minutes, and under the same
conditions as the NMR experiments, several oligomeric species (Chart 1) were identified
by MALDI-MS ([Sb+Na+2Ht, 728.9, calc 728.9; [6b+Nat, 870.7, calc 870.7;
[7b+Na+4Ht, 921.0, calc 921.0; [Sb+Na+2Ht, 1062.8, calc 1062.9; [9b+Na)+, 1206.7,
calc 1204.7). After 30 minutes, they are no longer observed. These species could be
C The ABqs in the lH NMR corresponding to 23 and 43 overlap. However, before the signal for 43 becomes
prominent, the asymmetry of the signal is clear, suggesting an overlapping resonance. The signal for 2b is
clearly an ABq (see Appendix A).
109
expected to have IH NMR resonances that overlap with the other intermediates. We do
not know for sure that every one of these oligomeric species is present in solution during
the reaction, as they could be formed as a concentration effect upon evaporation of the
MALDI sample, yet after 30 minutes they are no longer observed by MALDI. It is clear
that some kinetic mistakes are corrected during the course of the reaction because
everything remains soluble and all resonances except those for AszkCb disappear
eventually. These oligomeric species observed by MALDI MS are the most likely
culprits.
The isolation of compounds 1-3 was unsuccessful until prepared with a ligand
containing additional coordinating groups (methyl ether in HzLc). While macrocycle was
typically isolated by crystallization of the reaction mixture of HzLC and AsCh, one
attempt led to the isolation of 3c (Figure Ic). The intermediate is stabilized by As.. ·Q
secondary bonding interactions lZ and crystal packing is dictated by the As· ..1t
interaction. 13 This experiment further supports the idea that structure 3 is an intermediate
or a kinetic mistake in the self-assembly of AszkCh.
110
x2SS~\%S §S'ASCI2I~ I~ I~U U USH S..... ts....S8b CI
Chart 1. Oligomeric kinetic mistakes.
Conclusion
In conclusion, we have shown a metal-directed self-assembly reaction in which
several intermediates and kinetic mistakes can be identified. This provides insight into
the complexity of the self-assembly process-as revealed by the multiple possible
pathways-even for a simple dinuclear species. While most self-assembly reactions
occur too quickly to observe without stopped-flow kinetics, the dynamic covalentl4 nature
of the As-S bond and the steric bulk of the ligands make this reaction slow enough to
observe by IH NMR, providing exquisite structural detail. This shows that
supramolecular chemistry based on main group elements not only leads to new structure
types,15 but also can add valuable insight into the nature of self-assembly, which could be
applicable to understanding the formation of nanoparticles, 16 polymers I? and
monolayers l8 by self-assembly.
111
Experimental Section
General Procedures
Commercially available reagents were used as received. Literature procedures
were followed to prepare H2La,19 H2Lb,20 and H2Lcy Caution: Arsenic compounds are
hazardous and should be handled with caution! IH NMR spectra were measured using a
Varian INOVA-300 spectrometer. Spectra were referenced using the residual CHCh
solvent resonance as an internal standard.
Synthetic Procedures
As2La2Ch (4a). 1,4-bis(mercaptomethyl)benzene (H2La, 16.1 mg, 94.9IJ.mol) was
dissolved in 2.0 mL CDCi) in a scintillation vial. In a separate vial, AsCi) (94.8 IJ.mol,
8.09 IJ.L) was dissolved in 2.0 mL CDCh. The AsCh solution was added to the solution
containing ligand and mixed well (T = 0). An aliquot was transferred to an NMR tube
and monitored by 1H NMR.
As2Lb2Ch (4b). 1,4-bis(mercaptomethyl)durene (H2Lb, 14.0 mg, 61.8 p,mol) was
dissolved in 4.0 mL CDCh in a scintillation vial. AsCh (61.8 p,mol, 5.28 IJ.L) was added
and the solution was mixed well (T =0). An aliquot was transferred to an NMR tube and
monitored by IH NMR spectroscopy (see Appendix A for spectra). Colorless X-ray
quality crystals were grown by the slow diffusion of pentane into a CHC!) solution of
As2Lb2Cbo Crystallographic Data: C24H32As2ChS4, M =669.48, 0.16 x 0.14 x 0.10 mm,
T =293 K, Triclinic, space group P-l, a =8.4667(7) A, b =10.6932(9) A, c =
17.0485(15) A, a =87.852(2)0,P =77.066(2)°, y =68.0790(10)°, V =1393.8(2) A3, Z =
112
2, Dc =1.595 Mg/m3,,u =2.901 mm-1, F(OOO) =680, 20max =27.00°, 15620 reflections (-
lO::S h::S 10, -13::S k::S 13, -21 ::s l::s 21),6027 independent reflections [Rint = 0.0306], Rr
=0.0624, wR2 =0.1638 and GOF =1.033 for 6027 reflections (298 parameters) with I >
2a(!), R r =0.0945, WR2 =0.1892 and GOF =1.033 for all reflections, max/min residual
electron density +1.741/-0.704 eA3, CCDC: 741267.
AS2LcCI4 (3C). AsCh (3.44 ilL, 0.0404 mmol) was added slowly to a solution of
2,5-bis(mercaptomethyl)-I,4-dimethoxybenzene (H2Lc) (9.30 mg, 0.0404 mmol) in
CHCh (4 mL) and mixed well. An aliquot of the solution was transferred into a vial and
layered with pentane. Slow diffusion of pentane into this solution yielded colorless
crystals after one week. Crystallographic Data: ClOHr2As2C402S, M = 519.96, 0.27 x
0.22 x 0.14 rnm, T =173(2) K, monoclinic, space group P2r/c, a =8.1642(8) A, b =
11.7354(12) A, c =9.2996(9) A, y =106.451(2t, V =854.52(15) A3, Z =2, Dc=2.021
Mg/m3, ,u = 4.775 mm- 1, F(OOO) = 508, 20max = 28.19°, 9618 reflections (-10 ::s h ::s 10, -
13 ::s k::s 13, -21 ::s l::S 21),2030 independent reflections [Rint =0.0194], R r =0.0202, WR2
= 0.0547 and GOF = 1.039 for 2030 reflections (115 parameters) with I> 2a(!), Rr =
0.0212, WR2 =0.0554 and GOF =1.039 for all reflections, max/min residual electron
density +0.490/-0.222 eA3, CCDC: 741266.
Mass Spectrometry Experiments
Laser Desorption Ionization experiments on H2Lb with AsCh were perfonned on
a Waters Micromass Q-TOF MALDI mass spectrometer (Milford, MA USA) using V-
113
Optics in positive ionization mode. Samples were prepared by spotting NMR solutions
(CDC!)) containing the analyte directly onto the sample plate, without the use of a matrix,
at various time intervals ranging from T =0 to T =2 hrs after the addition of AsCh,
Initial spectra where nearly devoid of macrocycle 4b and contained mostly MnLm species.
After sampling at T = 30 minutes, macrocycle 4b was the prominent species detected.
Sodium adducts of the species of interest most likely resulted from the direct laser
desorption technique. Additionally, multiply protonated thiols (M+2H+Nat were
observed for species containing single thiols while (M+4H+Nat were observed for those
containing two thiols. 21 Ligands capped with arsenic (no free thiols) flew as (M+Nat
and did not contain additional protons. See Appendix A for MALDI data.
x- Ray Crystallography
Diffraction intensities for As2LcCl4 were collected at 173 K on a Bruker Apex
diffractometer using MoKa radiation A= 0.71073 A. Crystals of As2(LbhCh crack at low
temperatures, so X-ray diffraction data for this compound was collected at room
temperature, 293 K. Space groups were determined based on systematic absences
(AS2LCCI4) and intensity statistics (As2(LbhCh). Absorption cOlTections were applied by
SADABS. Structures were solved by direct methods and standard Fourier techniques and
refined on F2 using full matrix least-squares procedures. Non-H atoms were refined with
anisotropic thermal parameters. H atoms in As2LcC14 were found on the F-map and
refined with isotropic thermal parameters. H atoms in As2(Lb)2Ch were refined in
calculated positions in a rigid group model. All calculations were performed by the
114
Bruker SHELXTL package. Single crystal X-ray diffraction studies were performed on a
Bruker SMART APEX diffractometer.
Bridge to Chapter V
In Chapter N, the dynamic nature of the self-assembly process was examined for
As2L2Cb macrocycles. Chapter V involves the same theme of dynamic self-assembly,
but focuses on a new reaction (transmetallation) and a new structure type (E2L3
cryptands). In Chapter V, a series of E2L3 (E = P, As, Sb, Bi) cryptands are presented and
their structures are compared in the solid state and in solution. While Sb2L3 and Bi2L3
were prepared by self-assembly, As2L3 and P2L3 were prepared by a transmetallation
reaction from Sb2L3. This is a rare example of transmetallation used in a supramolecular
context and it allows for the preparation of a previously inaccessible structure type (P2L3).
115
CHAPTER V
"SUPRAMOLECULAR TRANSMETALLAnON" LEADS TO AN UNUSUAL SELF-
ASSEMBLED P2L3CRYPTAND
This chapter presents a series of E2L3 (E =P, As, Sb, Bi) cryptands and the
transmetallation reaction that allowed access to our first P-containing assembly. This co-
authored work was previously published (Angewandte Chemie, International Edition
2010,1248-1251, ©WILEY-VCH Verlag GmbH & CO).l All X-ray crystallography was
carried out by Dr. Lev N. Zakharov. Professor Darren W. Johnson provided intellectual
and editorial contributions. I carried out all synthesis, crystal growth, NMR experiments,
and wrote the manuscript.
Introduction
Transmetallation is common in biochernical,2 inorganic3 and organometallic
synthesis,4 but has been largely overlooked by supramolecular chemists as a synthetic
technique for preparing discrete assemblies.s The self-assembly of complex, multi-
component metal-organic supramolecules6 occurs by the breaking and reforming of
reversible metal-ligand bonds7 and in some cases through dynamic covalent chernistry.8
These dynamic bonds also allow for the reshuffling of components within "fully-formed"
116
complexes, as revealed by ligand exchange studies.9 The introduction or removal of
guest molecules can cause rearrangement to higher or lower-order structures, which also
necessitates the breaking and reforming of bonds. 10 Transmetallation, which can occur
upon the addition of a second type of metal, is a less common display of the dynamic
nature of these assemblies.9c,I I,a Here, we report a "transmetallation" reaction of an
antimony-containing cryptand with arsenic and, remarkably, phosphorus to provide a
previously unattainable P2L3 cryptand. In this reaction, P-S bonds behave reversibly like
typical metal-ligand bonds within supramolecular assemblies suggesting a potentially
new motif for dynamic covalent chemistry.
Results and Discussion
A rigid dithiolligand, 1,4-bis(mercaptomethyl)naphthalene (H2L),12 was treated
with a pnictogen trichloride (ECh, E =As, Sb, Bi) and base resulting in self-assembly to
the corresponding cryptands, E2L3 (Scheme 1). While our group has previously prepared
As_13 and Sb14-containing cryptands by a similar synthetic route, this is one ofthe first
known examples of a Bi-containing supramolecular complex. IS X-ray quality crystals
were grown by layering chloroform solutions of each cryptand with acetonitrile (Figure
1). The structure of each cryptand is very similar, with apparent C3h symmetry and only
slight variations in ligand position. In each case, the pnictogen atoms are positioned
a The term "transmetallation" is typically used in an organometallic context, but references 9c and lId refer
to metal-exchange processes in metal-ligand complexes as transmetallation reactions.
117
base
E
E
3
Scheme 1. The self-assembly of E2L3 (E = As, Sb, Bi) cryptands.
Figure 1. Stick representations of X-ray crystal structures of As2L3 (a), Sb2L3 (b), and
BhL3 (c). Arsenic atoms are shown in purple, antimony in teal, bismuth in blue, sulfur in
yellow, carbon in gray and hydrogen in white.
within the cavity, with the lone pairs of electrons on the two atoms pointing toward each
other. The E.. ·E distance decreases from AszL3 (5.11 A) to Sb2L3 (4.83 A) to BhL3 (4.68
A), and the difference is compensated for in the increasing E-S bond distances and S-E-S
angles. In each case, the pnictogen atoms are also involved in attractive E···1t
interactions,16 as evidenced by E",Caryl contacts of less than the sum of the van der Waals
118
radii.b In solution, these cryptands display similar, but distinct, IH NMR resonances with
splitting (ABq for the methylene protons) which suggests that the ligands are "locked"
into place as they are seen in the crystal structure, rather than flipping back and forth
quickly (Figure 2).
(~) CHCI, TMSa
3
H,O
d e
a)
T····· "; "I
a TMS
CHCI, H,o
d e
b c
b)
a
. H,o TMSCHCI, CH,CN
d e
c)
Figure 2. IH NMR spectra in CDC!] for AS2L3 (a), Sb2L3(b), and BhL3(c) taken on 300
MHz spectrometer with TMS as an internal reference.
b The two closest E···Caryl contacts are 3.30 and 3.58 A for As, 3.34 and 3.58 A for Sb, and 3.36 and 3.55 A
for Bi.
119
To compare the stability of the complexes, transmetallation reactions were carried
out and monitored by IH NMR spectroscopy. Crystals of SbzL3were dissolved in CDCb
and two equivalents of AsCb were added (Scheme 2). Within 30 minutes, all the SbzL3
was consumed and a white solid precipitated out of solution which was likely a
coordination polymer incorporating both Sb and As. NMR spectroscopy identified two of
the initial soluble reaction products (Figure 3). The first is the previously reported
AszLzClz macrocycle,IZ which is converted to AszL3as the precipitate redissolves and
more ligand becomes available for reaction. This suggests that AszLzCh is an
intermediate in the self-assembly of AszL3. The second species, a heterometallic AsSbL3
cryptand,C is relatively short lived as the Sb atom is quickly replaced with As. After five
days, the only species left in solution are AszL3 and trace AszLzCh.
Similarly, BizL3 was treated with AsCb and SbCb. In each case, a reaction
occurred immediately resulting in a white precipitate. Over time, AszLzCh and SbzLzCh
were formed and identified by NMR spectroscopy, but the precipitate never completely
Sb ~ As ........CI As2 AsCI3 + coordination.. ..CDCI3 ~ ~ polymerSb S As.......CI
3 2
Scheme 2. Transmetallation of Sb2L3to AS2L3.
C A procedure for preparing heterometallic AsSbL3 independently is reported in Chapter VI.
120
redissolved and the reaction was not driven to completion as in the case of Sb2L3~
As2L3. A control reaction was carried out in which an excess of SbCh was added to
As2L3, but no reaction occurred even after several days at elevated temperatures. Given
that self-assembly reactions such as these are typically under thermodynamic
o
o 0
a) o o
•
• •
I)
I I I I I
8.5
I
8.0
I I I
7.5
1 I I
7.0
I I I
6.5
I I '
6.0
I I I
5.5
I I I
5.0
I I I
4.5 4.0
I I I
ppm
Figure 3. IH NMR spectra for the reaction of Sb2L3 (a) with AsCh after 10 min (b), 32
min (c), 1 hr 25 min (d), 7 hr (e), and 5 days (f). Sb2L3 is marked 0, AsSbL3 D, AS2L2Ch
_, and As2L3 •.
121
control, it seems that AszL3 is more stable than SbzL3 which is more stable than BhL3.
While the energies of E(III)-S bonds have not been reported, they are likely the driving
force for this transmetallation. The presumed byproduct of transmetallation is ECh
(where E is the metal that was removed) and E(III)-CI bonds decrease in strength moving
from As-CI to Sb-CI to Bi-Cl. 17
The success of this transmetallation reaction led us to believe that this route might
allow access to P-containing supramolecular complexes, which we have been unable to
prepare by any other route. SbzL3 was dissolved in CDCh, PBr3 was added to the NMR
tube, and a white solid precipitated out of solution. While this precipitate did not
completely redissolve, several new resonances appeared in the 1H NMR spectrum after
~bHd H·S_____.pHe """ """ H.1 ~ ~s..---p CHCI, a
CH,CN
H,o
a)
b c
CH2C1.
I
d e
j
I I I I I I j I II I j j I I I f I I I I I I I I I I I I i f I I I i I I I i I I I I I t I I II I I I I I iIi I i I I I I I I I f I I I I I I i I Ii' I I I I I I I I I I I I I I I II I
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
b)
1-'
·)00
I I --,
-200 ppm
Figure 4. IH (a) and 3lp (b) NMR spectra ofPzL3in CDChtaken on 600 MHz
spectrometer and referenced to CHCh and external H3P04, respectively.
b) c)
122
Figure 5. Representations of X-ray crystal structure of P2L3 as stick figure, side view (a),
with van der Waals surface (b), and stick figure, top view (c). Phosphorus atoms are
shown in orange.
two days which correspond to P2L3 (Figure 4). Crystals of this cryptand were grown by
layering this solution with acetonitrile (Figure 5). The X-ray structure reveals that the
phosphorus atoms are sitting slightly within the cavity with their lone pairs of electrons
pointing in, filling the same position as the metals Sb and Bi and the metalloid As. While
no favorable p···x interactions are expected, the P···Caryl close contacts (3.25 and 3.54 A)
are less than the sum of the van der Waals radii (3.6 A). The geometry of the ligand is
well suited for this bis(trithiophosphite): all of the ligands are in a preferred gauche
conformationl8 and the S-P-S angle (96.5°) is only slightly smaller than that for other
reported trithiophosphites.19 With a p...p distance of 5.49 A, P2L3 has a small, empty
cavity.d,20 Attempts to fill that cavity with BH3 or Au+ 21 have thus far resulted in no
reaction and P2L3 is surprisingly air-stable for a trithiophosphite. This suggests that P's
d Cavities were measured using solvent (0.7 A) surfaces inWebLab ViewerPro 4.0, December 1, 2000
release. The cavity volume was estimated as the difference between the volume of the P2L3 cryptand filled
with a proton and the P2L3cryptand with a void cavity. This was found to be 15 A3.
123
lone pairs are not inverting in solution, but are locked into their endohedral positions as
observed in the crystal structure, in effect protecting the phosphorus atoms from further
reaction or decomposition. Currently, we are working to expand the size of the cavity
and use similar cryptands as trans-directing phosphine ligands.
Conclusion
We have shown in a supramolecular context that thiolate ligands prefer As over
Sb over Bi. Surprisingly, an Sb-containing cryptand can be "transmetallated" with P,
resulting in a previously inaccessible P2L3 cryptand in which P acts like the "metal" in a
metal-ligand self-assembly reaction. All of the E2L3 cryptands have a propeller twist due
to intramolecular edge-to-face aromatic interactions, yet are achiral due to an internal
plane of symmetry (C3h point group). Heterometallic analogs would provide interesting
examples of chiral supramolecular assemblies, and in the case of P-containing cryptands,
these chiral assemblies could act as trans-directing ligands for a metal guest. The facile
transmetallation of these stable, yet labile, supramolecular main group assemblies
suggests that transmetallation is another synthetic tool for supramolecular chemists
seeking to prepare otherwise inaccessible assemblies. Such hosts offer applications in
molecular machines, lIb catalysis, and sensing. lla Furthermore, the As- and P-based
assemblies are unusually stable compared to mononuclear analogs. If the Bi-containing
cryptands display similar stability, are applications as materials precursors, catalysts and
radiopharmaceuticals22 possible?
124
Experimental Section
General Procedures
NMR spectra were obtained on a Varian INOVA 300-MHz spectrometer in
CDC!) at 25°C and referenced to the residual solvent peak unless otherwise noted. 3lp
NMR was referenced to external H3P04 (0 ppm). Commercially available reagents were
used as received.
Synthetic Procedures
BhL3. HzL (40.3 mg, 0.182 mmol) and BiCh (36.4 mg, 0.115 mmol) were
dissolved in MeOH (10 mL) and THF (40 mL) and stirred at 25°C under Nz. DIPEA
(301 ilL, 1.82 mmol) was added and the solution turned bright yellow. After 6 hr, the
solution was washed with HzO and 2 M NaOH, dried with brine and MgS04, and then
filtered. The yellow filtrate was layered with CH3CN. After two weeks, the solvent was
decanted yielding small orange needles (4.42 mg, 5.69 ,umol, 10% crystalline yield). IH
NMR: () 8.45 (m, 6H, CH), 7.71 (m, 6H, CH), 6.14 (s, 6H, CH), 5.56 (d, 6H, CHz, J =
13.0 Hz), 4.21 (d, 6H, CHz, J =13.0 Hz). Crystallographic Data for BizL3:
C3sH33BizNS6, M = 1113.97,0.14 x 0.10 x 0.06 mm, T = 173(2) K, hexagonal, space
group P631m, a = b = 11.5547(3) A, c = 16.1081(10) A, V = 1862.48(13) A3, Z = 2, Dc =
1.986 Mg/m3,,u = 9.801 mm-1, F(OOO) = 1060, 20max = 54.00°,13673 reflections, 1412
independent reflections [Rint = 0.0355], Rl = 0.0242, wR2 = 0.0613 and GOF = 1.026 for
1412 reflections (67 parameters) with I> 2cr(l), R1 = 0.0291, wR2 = 0.0640 and GOF =
1.026 for all reflections, maximin residual electron density +1.061/-0.349 eA3.
125
Sb2L3. H2L (0.237 g, 1.08 mmol) and SbCh (0.164 g, 0.720 mmol) were
dissolved in CHCh (125 mL) and stirred at 50°C under N2. Diisopropylethylamine
(DIPEA, 1.78 mL, 10.8 mmol) was added. After 1.5 hr, the solution was cooled to 25°C,
washed with 2 M HCI and H20, dried with MgS04, and concentrated in vacuo to yield a
white powder. This powder was redissolved in CHCl3 (30 mL), filtered, and layered with
CH3CN. After one week, the solution was decanted to yield colorless needles (0.167 g,
0.186 mmol, 52% crystalline yield). IH NMR: 08.43 (m, 6H, CH), 7.67 (m, 6H, CH),
5.99 (s, 6H, CH), 4.40 (d, 6H, CH2, J =12.7 Hz), 3.94 (d, 6H, CH2, J =12.7 Hz).
Crystallographic Data for Sb2L3: C3sH33NSb2S6, M =939.51, 0.18 x 0.12 x 0.08 mm, T =
173(2) K, hexagonal, space group P63/m, a = b = 11.5114(5) A, c = 16.1142(10) A, V =
1849.25(16) A3, Z = 2, Dc = 1.687 Mg/m3,,u = 1.829 mm-1, F(OOO) =932, 20max =
54.00°, 20890 reflections, 1403 independent reflections [Rint =0.0321], R1 =0.0228,
wR2 = 0.0600 and GOP = 1.073 for 1403 reflections (67 parameters) with I> 2cr(l), R1 =
0.0234, wR2 =0.0605 and GOP =1.073 for all reflections, max/min residual electron
density +0.763/-0.205 eA3.
AS2L3. Sb2L3·CH3CN (24.9 mg, 26.5 ,umol) was dissolved in CDCh (9 mL) and
treated with AsCh (4.52 ~L, 53.0 ,umol). An aliquot was transferred to an NMR tube and
monitored until it reached -99% conversion to As2L3. After one week, this aliquot was
returned to the bulk solution and layered with pentane. After two weeks, the solution was
decanted, yielding colorless needles of As2L3·CH3CN (9.49 mg, 11.2 ,umol, 42%
crystalline yield). X-ray quality crystals were grown by layering a solution of As2L 3 with
pentane. IH NMR: 08.41 (m, 6H, CH), 7.66 (m, 6H, CH), 5.75 (s, 6H, CH), 4.21 (d,6H,
126
CHz, J = 13.0 Hz), 3.96 (d, 6H, CHz, J = 13.0 Hz); I3C NMR (500 MHz): 8 133.4 (C),
131.7 (C), 126.2 (CH), 125.9 (CH), 125.3 (CH), 33.6 (CHz). Crystallographic Data for
AszL3: C3sH3zAszCI6S6, M = 1043.54,0.21 x 0.14 x 0.08 mm, T = 173 K, cubic, space
group P213,a=b=c= 16.3746(3) A., V=4390.48(14)A3,Z=4, D c = 1.579 Mg/m3,,u
=2.201 mm-1, F(OOO) =2096, 2()rnax =54.000 , 49649 reflections, 3216 independent
reflections [R int =0.0526], R1 =0.0355, wR2 =0.0949 and OaF =1.064 for 3216
reflections (197 parameters) with I> 2cr(l), R1 =0.0380, wR2 =0.0971 and OaF =1.064
for all reflections, the Flack parameter is 0.017(12), max/min residual electron density
+1.028/-0.584 eA3.
PZL3. SbzL3 (51.7 mg, 57.6,umol) was dissolved in dry 1,1,2,2-tetrach1oroethane
(20 mL) and stirred at 80 °C under Nz. The solution was treated with PBr3 (12.0 J!L, 127
,umol). After 3 days, the solution was concentrated in vacuo to 12 mL, then filtered and
layered with CH3CN. After two weeks, the solution was decanted, yielding X-ray quality
colorless needles ofPzL3in very low yield. I H NMR (600 MHz): 88.38 (m, 6H, CH),
7.65 (m, 6H, CH), 5.66 (s, 6H, CH), 4.15 (d, 3H, CHz, J =12.8 Hz), 4.11 (d, 3H, CHz, J
=13.3 Hz), 3.94 (d, 3H, CHz, J =13.3 Hz), 3.92 (d, 3H, CHz, J =12.8 Hz); 31p NMR
(600 MHz): 888.4. Crystallographic Data for PZL3: C3sH33NPzS6, M =757.95,0.07 x
0.04 x 0.02 mm, T =173(2) K, hexagonal, space group P63/m, a =b =11.2442(18) A, c =
16.219(6) A, V= 1775.8(7) A3, Z= 2, D c = 1.418 Mg/m3,,u = 0.506 mm-1, F(OOO) =
788, 2()rnax =54.000 , 5011 reflections, 1334 independent reflections [Rint =0.0935], R1 =
0.0561, wR2 =0.1121 and OaF =0.996 for 1334 reflections (87 parameters) with I>
127
2cr(f), R1 =0.0879, wR2 =0.1257 and GOF =0.996 for all reflections, max/min residual
electron density +0.467/-0.396 eA3.
X-Ray Crystallography
Diffraction intensities for AszL3, SbzL3, BjzL3, and PZL3 were collected at 173(2)
K on a Bruker Apex CCD diffractometer using MoKa radiation A = 0.71073 A. Space
groups were determined based on systematic absences. Absorption corrections were
applied by SADABS.23 Structures were solved by direct methods and Fourier techniques
and refined on F Z using full matrix least-squares procedures. All non-H atoms were
refined with anisotropic thermal parameters. All H atoms in AszL3, SbzL3, and BizL3
were refined in calculated positions in a rigid group model. H atoms in PZL3 were found
from the F-map and refined with isotropic thermal parameters. In the crystal structures of
SbzL 3, BjzL3, and PZL 3 there is a solvent molecule, CH3CN, disordered over two
positions related by a mirror plane which was treated by SQUEEZE?4 Corrections of the
X-ray data by SQUEEZE (41, 38 and 44 electron/cell, respectively for SbzL 3, BjzL3, and
PZL3) are close to the required values of 44 electrons/cell for two molecules in the full
unit cells. All calculations were performed by the Bruker SHELXTL (v. 6.10) package.z5
CCDC 753593 - 753596 contain the supplementary crystallographic data for this chapter.
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
128
Bridge to Chapter VI
Chapter V presented a series of EzL3 (E := P, As, Sb, Bi) cryptands and a new
supramolecular transmetallation. Chapter VI expands upon this work by examining these
cryptands in further detail. Trends in the solid-state and solution structures are further
analyzed. The structure of an asymmetric conformer of the cryptand, observed only in
solution, is elucidated. Furthermore, three new heterometallic cryptands (PSbL3, AsSbL3,
and AsBiL3) are prepared and their solid-state and solution structures analyzed.
129
CHAPTER VI
SELF-ASSEMBLED E2L3 CRYPTANDS (E =P, As, Sb, Bi): TRANSMETALLATION,
HOMO- AND HETEROMETALLIC ASSEMBLIES, AND CONFORMATIONAL
ISOMERISM
Chapter VI gives a deeper look into the E2L3 (E =P, As, Sb, Bi) cryptands
presented in Chapter V. Their solid-state structures are further compared and their
conformational isomerism in solution is described. Additionally, the synthesis and
characterization of three heterometallic EE'L3 cryptands are presented. This co-authored
manuscript has been submitted as an article to Inorganic Chemistry.) Dr. Timothy G.
Carter carried out liquid chromatography mass spectrometry experiments. Dr. Justin L.
Crossland carried out one self-sorting NMR experiment and performed electrospray mass
spectrometry characterization of the heterometallic cryptands. All X-ray crystallography
was carried out by Dr. Lev N. Zakharov. Professor Darren W. Johnson provided
intellectual and editorial contributions. I carried out the synthesis, crystal growth, and
NMR experiments on all cryptands and wrote the manuscript.
Introduction
The Group 15 elements range in structure, property, and application as one
130
descends from the nonmetals nitrogen and phosphorus--essential to life-to the toxic
metalloids arsenic and antimony, to the metal bismuth, the heaviest of all stable elements
offering emerging applications in therapeutics and materials science.2 While they are
often overlooked in favor of the transition metals for supramolecular design, the main
group elements, Group 15 in particular, can be used to prepare a variety of
supramolecular structure types by metal-directed self-assembly.3-11 When bound by
thiolates in the E(Ill) oxidation state, P, As, Sb, and Bi each have a trigonal pyramidal
geometry and a stereochemically active lone pair of electrons. Previously, our group has
shown that each of these elements can be positioned interchangeably within self-
assembled E2L3 cryptands. 12 Here, we expand upon this work by presenting their
dynamic solution behavior, "transmetallation" chemistry, and three new examples of
chiral, heterometallic EEL3 cryptands.
Heterometallic assemblies are relatively rare and most offer ligands with unique
binding sites specific for each type of metal based on that metal's preferred coordination
number, geometry, charge, hard/soft binding site, or electronic discrimination13-22 or are
prepared by stepwise synthesis.23 However, the Group 15 elements within the cryptands
reported here are bound by the same coordination sphere of three thiolates revealing a
surprising lack of selectivity, implying that self-sorting may be at play. This series of
homo- and heterometallic cryptands allows for the direct comparison of preferred bond
angles and distances for E-S bonds within a confined supramolecular system.
Furthermore, this series of cryptands exemplifies the dynamic nature of main group
"metal"-ligand self-assembly through the synthesis, transmetallation and solution
131
behavior of the cryptands, including the surprising observation of a stable, asymmetric
conformation of the E2L3cryptands.
These self-assembled main group complexes are reminiscent of organic
cyclophanes (or heterophanes), where an -S-E-S- group substitutes for a heteroatom or a-
C X C ' 0 A L d lla Ilf 12 11 . 'I b' 1 h 24- - - umt. ur S2 3 cryptan s ' , are structura y SUill ar to lCYC op anes,
specifically the 1t-prismands, and our recently reported AS~2 complexllj is remarkably
similar to tetrathia[3.3,3.3]cyclophane.25 However, our assemblies differ from their
organic analogues by synthesis from a self-assembly reaction rather than a stepwise
synthesis, resulting in typically high yields. Additionally, organic prismands lack the
conformational isomerism and transmetallation properties exhibited by the main group
congeners. This new generation of metallacyclophanes and metallacycles could allow
access to new structure types and dynamic host-guest interactions,26
Results and Discussion
Symmetric and Asymmetric £2L3 Cryptands
Previously, our laboratory reported a series of E2L3 cryptands (where E =P, As,
Sb, Bi) that were prepared by self-assembly reactions (Scheme 1).12 When H2L was
mixed with AsCh, SbCh, or BiCh in chloroform and the HCI byproduct was removed
with base, E2L3 was formed. Sb2L3 and BhL3 were prepared in the presence of excess
diisopropylethylamine (DIPEA), while AszL 3 was prepared in the presence of KOB. A
--- ---------------------
132
transmetallationa reaction could also be used to prepare As2L3, and "transmetallation"
was the only effective route to form P2L3 (Scheme 2). Transmetallation occurred when
~ As2L 3, the reaction was shown to be quantitative by IH NMR spectroscopy.
3~H
~SH base
3
E =As, Sb, Bi
E
E
Scheme 1. Self-assembly of E2L3 cryptands. DIPEA was used as the base for E =Sb or
Bi, while KOH was used for E =As.
2 AsCI3
or
2 PBr3
Scheme 2. Transmetallation of Sb2L 3•
a Transmetallation is used to describe the replacement of one Group 15 element with another, even when the
replacement is not a metal as in the case of As (metalloid) and P (non-metal). This language is consistent
with our previous communication12 on the topic.
133
Solid-State Structures. We previously communicated the supramolecular
transmetallation reaction that allowed for the synthesis of these cryptands (Chapter V).12
This chapter provides a thorough structural analysis (solid-state and solution) of these
systems in the context of three additional new heterometallic assemblies described in
subsequent sections and describes a surprising conformational isomerism for these
cryptands in solution. X-ray quality crystals of the complexes were grown by the slow
solution of cryptand. The structures for these symmetric cryptands are remarkably similar
(Figure 1); the only significant differences are in the position ofthe pnictogen atoms, the
Figure 1. Stick and space-fIlling representations of the X-ray crystal structures of
symmetric cryptands P2L3 (a, e), As2L3(b, f), Sb2L3 (c, g) and BhL3 (d, h). Phosphorus
is shown in orange, arsenic in purple, antimony in teal, bismuth in blue, sulfur in yellow,
carbon in gray and hydrogen in white.
134
E-S bond distances, and S-E-S bond angles (Table 1). With increasing atomic mass
comes an increase in E-S bond length and a decrease in the E···E distance. These
differences are compensated for by the decreasing S-E-S angle, allowing the ligands to
maintain almost identical positions in each cryptand (Figure 2). This trend is expected as
the extent of s-character in the E-S bonds decreases going down the group. Searching the
Cambridge Structural Database (CSD) for pnictogens bonded to three sulfur atoms in
unconstrained systems reveals that this supramolecular coordination is not greatly
affecting the bonding geometry of the pnictogens. In each of the E2L3 structures, the E-S
distance is slightly shorter than, but within 0.1 Aof the CSD average. The S-E-S bond
angles in the E2L3 structures are slightly larger than the CSD average, but within a couple
degrees (and not out of the normal range).
Table 1. Select Distances and Bond Angles for E2L3 Cryptands.
PZL3 AszL 3 SbzL3 BizL3
E···E (A) 5.491 5.108 4.827 4.683
E-S (A) 2.1182(12) 2.2514(10) 2.4206(5) 2.5157(10)
CSD averaxe 2.144 2.298 2.470 2.592
E-S ( ~)
S-E-S (0) 96.52(5) 94.00(4) 91.456(18) 90.84(3)
CSD average 95.24 91.35 91.09 90.71
S-E-S (0)
E",Caryl (A) 3.251 3.300 3.343 3.358
3.544 3.577 3.584 3.548
135
Figure 2. Overlayed stick-representations of the X-ray crystal structures of the
symmetric cryptands P2L3 (orange) and BhL3 (blue) from side (a) and top-down (b)
views.
Six E"'n interactions stabilize each of the AS2L3, Sb2L3, and BhL3 cryptands. The
E"'n interaction is an attractive interaction involving dispersion forces and the donation
of n-electrons from the aryl ring into a 0'* orbital on E.27-30 In P2L3, the six shortest
P,,,Caryl contacts are also shorter than the sum of the van der Waals radii (3.5 A), but no
attractive P···n interactions are known or expected.b,31 Each symmetric E2L3cryptand
possesses crystallographic C3h symmetry, except AS2L3, which is slightly offset and has
C3 crystallographic symmetry. This could be a result of the As.. ·n interactions causing
the ligands to twist more to allow the metals to sit deeper within the cavity, or it could be
a consequence of crystal packing. The E'''n interaction is known to be stronger for the
larger pnictogens, typically resulting in a decrease in the E",Caryl distance (Figure 3).30
b f]6-arene complexation to phosphenium cations is known, but very rare?! The CSD was searched for p ...n;
contacts of less than the sum of the van der Waals radii for P and C, turning up 20 hits. However, no
correlation between contact distance and angle was observed. See Appendix B for further detail.
a)
"-=~~....j
..
136
Figure 3. Stick representations of crystal structures of AsC!) (a),3Z SbC!) (b),33 and BiC!)
(C)34 cocrystallized with hexamethylbenzene, reported by Schmidbaur and co-workers.
The dashed lines represent the short E"'n interactions (distances to ring centroids are
shown in each case).
However, the opposite trend is observed here. In these supramolecular cryptands, the
shortest E",Caryl distance increases from AszL3to SbzL3 to BizL3. This is not an
indication of a weaker Eo··n interaction, but is likely a consequence of the growing radius
of E, the consequently longer E-S bonds, and the constricted position of the metals within
the cryptand cavity.
Solution Structures. In solution each of the EzL3cryptands appears to be present
in two different conformations. The first is a symmetric conformer similar to that in the
solid state, in which each of the three ligands are equivalent and the complex has overall
C3h symmetry. Figure 4 shows the IH NMR spectra for each of the cryptands. The
exterior aryl protons Hb and He are in very similar positions in each cryptand and are not
affected by the identity of E, as shown by the almost identical resonance shifts for each
cryptand. The resonance for interior proton Ha differs slightly depending on the
pnictogen, shifting downfield from PZL3to BizL3. The methylene protons, Hd and He, are
significantly more affected by the identity of E. In PZL3, the resonance for each of these
137
protons is split into a doublet of doublets due to splitting by the other methylene proton
and the nearby phosphorus nucleus. In each of As2L3, Sb2L3, and BhL3, these methylene
resonances appear as a single pair of doublets and are significantly shifted based on the
identity of E. Similarly to proton Ha, the signals for Hd and He in BhL3 are shifted the
farthest downfie1d.
DCI]
a
b c d e
a)
*
CP2C)4 a
d e
b c ~~
a
d e
CDC).1
b C
CDC).1 a
d c
Figure 4. IH NMR spectra for P2L3 (a), As2L3 (b), Sb2L3 (c) and BhL3 (d). The signals
from the symmetric cryptands are labeled, while those for the asymmetric cryptands are
unlabeled (See Appendix B for complete labeling scheme). * denotes C2H2Cl4 in the
spectrum.
138
A glaring feature of these 1H NMR spectra is the presence of a second, less-
symmetric species in solution. The NMR samples were prepared by dissolving crystals of
each symmetric cryptand. Initially, only the symmetric cryptand is observed. However,
over the course of a half hour a conformational change establishes a new equilibrium
between the symmetric E2L 3 cryptand and an asymmetric species, ~L3-asym. gCOSY
and NOESY NMR (Appendix B) were used to identify this asymmetric species as a
cryptand in which one ligand has "flipped" (Figure 5a), perturbing the C3 symmetry of the
complex and resulting in a conformation with only Cs symmetry. While less than 5% of
a) 6{rs~
~
symmetric E2L3
Figure 5. Cartoon representations of symmetric E2L 3 (left) and E2L 3-asym (right) in
which the ligands are represented by arrows (a). In the symmetric cryptand all of the
ligands point counterclockwise. Ln the asymmetric cryptand, two ligands point
counterclockwise (black) and the one "flipped" ligand points clockwise (red). The DFT-
calculated structure of BhL3-asym in space-filling (b) and stick (c) representations. The
"flipped" ligand is shown in red. The blue arrows indicate the protons that were
correlated by their NOEs in solution (See Appendix B for more information).
139
the As2L3cryptand is in this asymmetric form, it comprises 47% of the Sb2L3 and 60% of
the BhL3 samples based on 1H NMR integrals. To confirm that the observed species was
not actually a higher order assembly, liquid chromatography mass spectrometry was
carried out on a sample of Sb2L3. As expected, two species with different retention
times, yet the same mass-to-charge ratio, were present in solution (Figure 6, Appendix B).
The relative amount of each did not match the ratio observed by IH NMR spectroscopy,
but that could be a result of solvent effects or conformational change occurring over the
course of the experiment.
a) §i
Max: 3304
b) i Max: 3649
3500
3000
3000
2500
"" 2500 iii
2000 ~ ~i 2000 §1500
1500
1000 " "1000 iii ~~ Ii!
500 500
0 0
890 895 900 905 910 m/z 890 895 900 905 910 mlz
C) mAU
50
40
30
20
10
0
-1
-2
26 min
Figure 6. Liquid chromatography mass spectrometry data for the two conformers of
[Sb2L3+Hr (a,b). LCMS trace showing two peaks with the same m/z (c). The isotope
distribution verifies that these are both +1 charge states of a Sb2~ cryptand.
140
DFf calculations were carried out to help visualize the likely structure of E2L3-
asym. First, to judge the ability of the chosen DFf method (with a 6-31+G* basis set for
all atoms and with the B3LYP functional),35.c,36 the structures of the symmetric P2L3,
AS2L3, Sb2L3and BhL3 cryptands were calculated. These were found to match the
crystal structures very closely (see overlays in Appendix B). The only minor difference is
that in the DFf-calculated structures, the metals and ligands are not pulled quite as tightly
into the cavity. However, it has been established that this functional is not well suited for
describing the E..·1t interaction, which is likely a general limitation of DFf since
dispersion forces account for at least some of this attractive interaction.29,3o However, we
have found DFf to be very useful in qualitatively predicting the overall structures of
Group 15-containing assemblies.35
determined and it was found that in each case a stable structure was converged upon in
which one ligand has "flipped" (Figure 5b-c for BhL3-asym). In each case, the
symmetric cryptand was found to be more stable than the asymmetric cryptand by 4-6
for exact energies). These energy differences are much larger than those observed by IH
NMR spectroscopy, likely due to solvation effects and a limitation of DFf in predicting
E.. ·1t interactions, but the general trend fits: the energy difference is smaller for the
c Models were minimized using Spartan '08.36 The choice of functional and basis sets was based on those
used in Ref. 35.
141
heavier pnictogens. However, these calculations do not show that BizL3-asym is lower in
energy than its symmetric counterpart even though we observe that it is 0.24 kcal/mol
lower by IH NMR spectroscopy.
It is not immediately clear why the asymmetric cryptands are relatively more
stable when compared to their symmetric counterparts for the heavier pnictogens. The
simplest explanation is that it is a sterlc effect of the larger elements.d The larger
pnictogens require more space within the cavity, and the "flipping" of one ligand provides
that accommodation. The average of the six shortest E",Caryl contacts in the DFf
calculated model of Sb2L 3-asym (3.53 A) was found to be slightly longer than that for the
crystal structure of Sb2L3 (3.46 A), suggesting that the "flipping" does indeed open up
more space. While we cannot confirm the accuracy of the models without a crystal
structure of the asymmetric cryptand (which remains elusive), we can compare them to
what is observed in solution. IH NMR spectroscopy shows that the proton resonances for
BizL3-asym and Sb2L 3-asym follow the same pattern but are significantly shifted based on
proximity to the pnictogens. The similarity of these structures is corroborated by
overlaying the DFf-calculated structures (See Appendix B).
Another possible explanation for the trend in the relative stability of the two
conformations of cryptand is that the asymmetric conformation allows for stronger E···1t
interactions, and the strength of the E.. ·1t interaction increases down the group (Figure 3)
(this would also explain the poor prediction of the conformational energy differences by
d The van der Waals radii are 1.8 A for P, 1.85 A for As, 2.0 A for Sb, and 2.0 A for Bi.37
142
DFf). Consequently, BhL3-asym is stabilized more than Sb2L3-asym and AS2L3-asym
compared to their symmetric counterparts. In the symmetric cryptands, each pnictogen
atom is involved in three E.. ·1t interactions, as evidenced by the short E.. ,Caryl contacts.
Although the shortest E",Caryl contacts for the "flipped" ligand are not as short as they are
within the symmetric cryptand, the position of the ligand is thought to result in a stronger
E.. ·1t interaction. The "flipped" ligand is positioned such that it is sitting deep into the
cryptand cavity with three carbon atoms close to the pnictogen (within the sum of the van
der Waals radii) allowing for an 113-interaction (as compared to the 112-interaction
observed in the symmetric cryptand). Additionally, the S-E",Caryl angle is larger in the
asymmetric cryptands. This angle is 1600 for Sb2L3-asym and 1550 in the symmetric
cryptand. The larger angle allowed by the flipping of the ligand may result in a stronger
Sb···1t interaction. However, our laboratory has previously published a structural survey
that shows that the average angle for non-constrained interactions is 1550 for Sb.3o The
position of this ligand deep within the cryptand can also be observed in solution, as
evidenced by the upfield-shifted resonance for He on this ligand (-6.8 ppm).
Mechanism of Ligand Flipping. Semi-empirical AMI calculations were carried
out to see if it was energetically feasible for a ligand to "flip" without breaking any bonds.
Based on these calculations, and a look at the space-filling models, it is clear that this is
not the route to interconversion between E2L3 and E2L 3-asym. The cavity is far too
sterically congested to allow even the short end of a naphthalene ring to pass through it.
Rather, it seems far more likely that the mechanism to interconversion is through the
breaking and reforming of an E-S bond. While that bond is broken, the ligand can rotate
143
freely without steric considerations. The strength of an As-S bond is estimated to be -81
kcal/mol;e nonetheless, we have shown that these' bonds are labile enough to allow for
self-assembly and transmetallation. I Ih,IZ
Heterometallic EE'L3 Cryptands
Further synthesis was carried out to determine whether or not this self-assembly
process would result in self-sorting.J9-43 If self-sorting were to occur, it could be either
"narcissistic,,44 (molecules display a high affinity for themselves), resulting in
homometallic cryptands exclusively,or "social,,44-46 (molecules display a high affinity for
others), resulting in heterometallic cryptands exclusively. Ifno self-sorting were
occurring, a statistical 1:2:1 mixture ofhomo:hetero:homo cryptands would be expected
to form. To test these possibilities, HzL was treated with AsCh, DIPEA and either SbCh
or BiCh. Surprisingly, rather than a statistical mixture of cryptands, NMR spectroscopy
on the crude reaction mixtures revealed that the heterometallic AsSbL3and AsBiL3
cryptands were the dominant products of the reactions (>80% in each case), with the
remainder of the product being homometallic cryptand. This result completely ruled out
narcissistic self-sorting and implied that social self-sorting could be occurring, at least
kinetically.
To follow up, the synthesis of AsSbL3 was carried out in CDCh and monitored by
I H NMR. This experiment showed that after 15 minutes AsSbL3, ASzL3, and SbzL3were
e Bond strength approximated from As-S bond strengths in AsxSy polyhedra.38
144
all present, but within two hours, AsSbL3was the major product, implying social self-
sorting. However, the reaction also produced a white precipitate which could not be
identified, but was presumably a mixture of DIPEA-salts and coordination polymer
containing ligand, As, and Sb. Over the next three days, reaction continued to occur
between the soluble and insoluble components and the product ratio changed until it
contained a -1:2 ratio of AsSbL3to As2L3. There was no soluble Sb2L3present,
implying that most of the Sb was tied up in the insoluble coordination polymer. While
definitive conclusions cannot be drawn from this experiment, it does imply that initially
social self-sorting results in the kinetic AsSbL3 and coordination polymer products, but, if
given the opportunity, these will rearrange over time to give the thermodynamically stable
As2L3.12 The precipitate in this above experiment is vital to the self-sorting observed:
further NMR-scale experimentation showed that over time dissolved crystals of AsSbL3
will not rearrange to give As2L3 and Sb2L3 and dissolved crystals of AS2L3 and Sb2L3
will not rearrange to give AsSbL3.
A heterometallic PSbL3cryptand was also prepared, but was isolated from a
transmetallation reaction involving the treatment of Sb2L3 with PBr3 that did not go to
completion. X-ray quality crystals of each of AsSbL3, AsBiL3, and PSbL3 were grown
by layering a chloroform solution of the complex with acetonitrile or pentane (Figure 7).
Within each crystal, E and E' are disordered over both positions, so all of the E···E', E-S
and S-E(El-S distances and angles are averaged for the two sides of the complex (Table
2). Still, the averaged distances and angles fit into the trend observed in the
homometallic E2L3complexes. In each case, the E..·E' and E-S distances and S-E(El-S
145
angles fall between the values for the two homometallic complexes, but are closer to what
is observed for the heavier EzL3 complex. This suggests that the larger metals have more
of an effect on the geometry than the smaller metals. Like their homometallic analogues,
each of the EEL3 cryptands exhibits six close E",Caryl contacts in the solid state,
suggesting stabilization of the cryptands through E···1[ interactions.
e)
Figure 7. Stick representations of the X-ray crystal structures of AsSbL3 (a, b), AsBiL3
(c, d), and PSbL3 (e, f). Phosphorus is shown in orange, arsenic in purple, antimony in
teal, bismuth in blue, sulfur in yellow, carbon in grey and hydrogen in white.
Table 2. Select Distances and Bond Angles for EEL3Cryptands.
AsSbL3 AsBiL3 PSbL3
E···E' (A) 4.944 4.685 4.960
E(E')-S (A) 2.3537(7) 2.4499(19) 2.3212(7)
2.376(2)
S-E(E')-S (0) 92.10(2) 89.96(7) 91.26(2)
91.42(8)
E(El .. ·Cary/ (A) 3.302 3.278,3.391 3.263
3.553 3.314,3.570 3.524
146
In solution, the EEL3 cryptands are C3-symmetric, just as they are in the solid
state (Figure 8). Unlike their homometallic counterparts, no asymmetric cryptand is
observed. This could be a result of ligand strain caused by the size difference in the
metals, or there could be too little asymmetric cryptand to observe by NMR spectroscopy.
Because of the lack of O'h-symmetry in the complex, the splitting for the asymmetric (and
chiral) heterometallic cryptand would be quite complex and at a low concentration they
might not appear in the spectra. For the symmetric heterometallic cryptand, the 1H NMR
resonances for Hb and Hb , and He and He' are relatively unchanged from their
homometallic analogues, but the resonance for Ha and Ha , is split into an ARq. This is due
CDCl3
a. a'
b, b' c, c'
~LJ~---J.Jal..'--.Ja,,-- d.----"d.L
C, c'
b) ) ......b._. '--'--+ -J-.*"''-'-~ '''''-'''''''--''fV'''-~
C. c'
, dee'
I....... _ •••R. ......,
r~r--r-r--r-T-r--r--T-...,--r-T I I I , , -r-r-r-r I , I I I I iii 1 j , I I I I r i , i • • , ! ~ , i ! f ! !
8:S 8:0 is 7:0 6~5 6~0 5~5 5~0 4:5 4:0 ppm
Figure 8. IH NMR spectra ofEE'L3heterometallic cryptands: PSbL3 (a), AsSbL3 (b),
and AsBiL3 (c). * denotes Sb2L3cryptand impurity.
147
to the lack of (Jh symmetry in the heterometallic cryptands, making Ha and Ha ,
inequivalent (and diastereotopic due to chirality of assembly). Additionally, the
methylene protons at each end of the cryptand appear as separate sets of doublets (or two
doublets of doublets for the P end of PSbL3). Each of these resonances is shifted only
slightly from where they appear for the homometallic complexes suggesting that in
solution, as in the solid state, the geometries around the metals are very similar to what
they are for the homometallic complexes.
The heterometallic EEL3 cryptands are chiral, due to a right-handed or left-
handed twist of the ligands around the chirality axis of the two metals. This chirality is
different from that in most supramolecular helicates, where both (identical) metals
experience the same handedness of the ligands connecting them.47 Here, the metals
experience different handedness, but if the two metals were swapped, one would be left
with the enantiomer of the original molecule. While spontaneous resolution of one
enantiomer was not obtained upon crystallization, it may be possible to separate the
enantiomers on a chiral HPLC column. These cryptands are too small to fit guest
molecules, but larger P-containing cryptands may be able to serve as host molecules with
potential applications in chiral catalysis. We are exploring their use as a new class of
trans-directing phosphine ligands.
Conclusion
A series of homometallic (P2L3, As2L3, Sb2L3, BhL3) and heterometallic (PSbL3,
AsSbL3, AsBiL3) cryptands were prepared directly from H2L and EC!] or by
148
transmetallation of Sb2L3, showing that P, As, Sb, and Bi can be used almost
interchangeably in "metal"-directed self-assembly. Within this supramolecular
framework, the geometries of P, As, Sb, and Bi with thiolate ligands can be directly
compared, giving insight into the bonding preferences of these pnictogens. As expected,
the E-S bonds lengthen and the S-E-S bond angles contract down the group.
Surprisingly, in solution the homometallic C3h-symmetric E2L3cryptands rearrange into
asymmetric conformers (E2L 3-asym). Heterometallic cryptands were prepared in higher
than a statistical ratio, implying a self-sorting mechanism. PSbL3 is a rare example of a
chiral trans-directing phosphine and AsBiL3is a rare example of a chiral bismuth
compound with axial chirality at each pnictogen. This work exemplifies the utility of
Group 15 elements as "metals" in metal-directed supramolecular self-assembly.
Experimental Section
General Procedures
IH NMR spectra were measured using Yarian INOYA-300 and 500 spectrometers
and 13C NMR spectra were collected on a Varian INOYA-500 spectrometer in CDCh.
Spectra were referenced using the residual solvent resonances as internal standards and
reported in ppm. Mass spectrometry data were collected by directly injecting a CHCh
solution of cryptand into the spray chamber. Single crystal X-ray diffraction studies were
performed on a Broker SMART APEX diffractometer. Commercially available reagents
were used as received. The reported yields below are for isolated crystals. Caution:
Arsenic and antimony compounds are hazardous and should be handled with care! (This
149
accounts for the small scale of the reactions reported herein.) The preparation of 1,4-
bis(mercaptomethy1)naphtha1ene (H2L),48 P2L3and As2L3 via transmetallation, and Sb2L3
and BizL3 were previously reported.12
Synthetic Procedures
AsSbL30 AsCh (8.16 !J,L, 95.6 !J,mol), SbCh (21.8 mg, 95.6 !J,mol), and
diisopropylethylamine (DIPEA) (474 !J,L, 2.87 mmol) were dissolved in CHCh (50 mL)
under N2 at 50°C. H2L (70.0 mg, 320 !J,mol) was added and the solution was stirred for 3
hours. After cooling the reaction mixture to 25°C, it was washed with H20 (20 mL) and
2 M NaOH (20 mL) and dried with brine (20 mL) and MgS04. The solution was layered
with CH3CN resulting in clear, colorless needles after 1 day (7.22 mg, 8.09 !J,mol, 8%
crystalline yield). The crystals were dissolved in CDCh and the IH NMR spectrum
revealed that the product is 87% AsSbL3·CH3CN and 13% Sb2L3·CH3CN. IH NMR (300
MHz, CDCh): 88.43 (m, 6H, CH), 7.68 (m, 6H, CH), 5.87 (ABq, 6H, CH, J = 7.0 Hz),
4.37 (d, 3H, CH2 , J =13.0 Hz), 4.24 (d, 3H, CH2, J =13.0 Hz), 3.99 (d, 3H, CH2, J =
13.0 Hz), 3.91 (d, 3H, CH2, J =13.0 Hz). 13C{IH} NMR (125 MHz, CDCh): 8 =136.3,
133.6,132.0,131.6,126.43,126.37,126.35,125.9,125.2, 124.4,33.8,32.3 ppm. APCI-
MS: [H{AsSbL3}t calcd 850.9, found 851.0.
AsBiL30 AsCh (11.8 !J,L, 138 !J,mo1) and BiCh (43.5 mg, 138 !J,mo1) were
dissolved in dry MeOH (10 mL) and THF (40 mL) and placed under N2. DIPEA (684
!J,L, 4.14 mmol) was added, followed by H2L (94.9 mg, 430 ~mol) and the solution was
stirred at 25°C overnight. CHCh (30 mL) was added, then the mixture was washed with
150
H20 (20 mL) and 2 M NaOH (20 mL) and dried with brine (20 mL) and MgS04• The
solution was concentrated to yield a bright yellow solid which was suspended in CHC!)
(10 mL), filtered, and layered with pentane to yield pale yellow needles of
AsBiL3·2CHC!) after a day (12 mg, 10.2 J.lmol, 7% crystalline yield). IH NMR (300
MHz, CDC!): 0 8.45 (m, 6H, CH), 7.68 (m, 6H, CH), 6.02 (d, 3H, CH, J = 7.0 Hz), 5.80
(d, 3H, CH, J =7.0 Hz), 5.61 (d, 3H, CH2, J =12.3 Hz), 4.23 (d, 3H, CH2, J =12.8 Hz),
4.13 (d, 3H, CH2, J = 12.3 Hz), 3.98 (d, 3H, CH2, J = 12.8 Hz). l3C {IHl NMR (125
MHz, CDC1): 0 =139.1, 133.8, 132.2, 131.5, 126.7, 126.6, 126.5, 125.9, 125.3, 123.2,
33.9,31.9 ppm. APCI-MS: [H{AsBiL31t calcd 939.0, found 939.1.
PSbL30 Clear, colorless X-ray quality needles of PSbL3·CH3CN were isolated
from the previously reported12 synthesis ofP2L3 from Sb2L3·CH3CN with PBr3. These
were dissolved in CDC!) for further analysis. IH NMR (500 MHz, CDC!): 0 8.43 (m,
6H, CH), 7.67 (m, 6H, CH), 5.94 (d, 3H, CH, J =6.8 Hz), 5.70 (d, 3H, CH, J =7.2 Hz),
4.37 (d, 3H, CH2, J =12.4 Hz), 4.17 (d, 1.5H, CH2, J =13.0 Hz), 4.15 (d, 1.5H, CH2, J =
12.5 Hz), 3.96 (d, 1.5H, CH2, J =13.0 Hz), 3.95 (d, 1.5H, CH2, J =12.5 Hz), 3.93 (d, 3H,
CH2, J = 12.4 Hz). 31p NMR (500 MHz, CDC!): 0 86.7 (s). l3C{IHl NMR (125 MHz,
CDC!): 0 =136.1, 132.4, 132.2, 131.4, 126.4, 126.3, 126.2, 126.05, 125.8, 124.5,34.38
(d, 2Jcp =9 Hz), 32.2 ppm. APCI-MS: [H{SbPL31t calcd 807.0, found 807.0.
X-Ray Crystallography
Diffraction intensities for AsSbL3, AsBiL3 and SbPL3were collected at 173(2) K
on a Broker Apex CCD diffractometer using MoKa radiation A= 0.71073 A. Space
151
groups were determined based on systematic absences. Absorption corrections were
applied by SADABS.49 Structures were solved by direct methods and Fourier techniques
and refined on F2 using full matrix least-squares procedures. All non-H atoms were
refined with anisotropic thermal parameters. All H atoms in AsSbL3 and AsBiL3 were
refined in calculated positions in a rigid group model. H atoms in SbPL3 were found
from the F-map and refined with isotropic thermal parameters. In the crystal structures of
AsSbL3 and SbPL3 there were solvent molecules, CH3CN, disordered over two positions
related by a mirror plane. These molecules were isolated in the crystal packing and were
not involved in specific interactions with the cryptand molecules. These disordered
molecules were treated by SQUEEZE.50 Corrections ofthe X-ray data by SQUEEZE (42
and 44 electron/cell, respectively for AsSbL3 and SbPL3) were close to the required
values of 44 electronslcell for two molecules in the full unit cells. In the crystal structure
of AsBiL3 there were two solvent CHCh molecules. One of these molecules was
disordered over two positions related by a mirror plane. The disordered CHCh molecule
was refined with restrictions; the value of 1.75 A was used as a target for the C-CI
distances in the refinement. H atoms in the disordered solvent molecules were not taken
into consideration. In the structures of AsSbL3 and SbPL3 the Sb/As and SblP atoms,
respectively, shared two positions related by a mirror plane. The refinement of
occupation factors provided a ratio for these atoms: ASO.92Sbl.08 in AsSbL3 and Sbl.01PO.99
in SbPL3• In the structure of AsBiL3, the Bi and As atoms disordered over two
symmetrically independent positions. The refinement occupation factors for a model in
which the Bi and As atoms shared these two positions provided a ratio for the Bi/Sb
152
atoms of 0.565/0.435 and 0.417/0.583, respectively for the two positions, and the total
ratio was ASI.D2Bio.9s. All calculations were performed by the Broker SHELXTL (v. 6.10)
package.51
Crystallographic Information Files will be available from the ACS website after
publication at pubs.acs. org.
Crystallographic Data for AsSbL3·CH3CN. C3sH33Aso.92NS6Sbl.os, M =
896.66, 0.42 x 0.08 x 0.07 mm, T = 173(2) K, hexagonal, space group P63/m, a = b =
11.4342(7)A,c= 16.131(2) A, v= 1826.5(3)A3,Z=2, Dc = 1.630Mglm3,,u=2.012
mm- 1, F(OOO) = 899, 2(}max = 54.00°, 18014 reflections, 1387 independent reflections [Rin!
= 0.0574], R I = 0.0318, wRz = 0.0722 and GOF = 1.108 for 1387 reflections (69
parameters) with I > 2cr(l), R I = 0.0399, wRz = 0.0761 and GOF = 1.108 for all
reflections, max/min residual electron density +0.520/-0.226 eA3.
Crystallographic Data for AsBiL3·2(CHCh). C3sH3zAsl.ozBio.9sCl6S6, M =
1177.60,0.17 x 0.14 x 0.09 mm, T = 173(2) K cubic, space group n 13, a = b = c =
16.4744(8) A, V = 4471.2(4) A3, Z = 4, Dc = 1.749 Mglm3,,u = 5.344 mm-1, F(OOO) =
2296, 2(}max = 54.00°,9348 reflections, 3177 independent reflections [Rin! = 0.0553], the
Flack parameter is 0.037(11), R I = 0.0449, wRz = 0.1023 and GOF = 1.016 for 3177
reflections (164 parameters) with I > 2cr(l), R I = 0.0530, wRz = 0.1053 and GOF = 1.026
for all reflections, max/min residual electron density +01.089/-0.619 eA3.
Crystallographic Data for SbPL3·CH3CN. C3sH33NPS6Sb, M = 848.73, 0.32 x
0.10 x 0.09 mm, T = 173(2) K, hexagonal, space group P6J!m, a = b = 11.3830(6) A, c =
153
16.1453(18) A, v = 1811.7(2) A3, Z = 2, Dc = 1.556 Mg/m3,.u = 1.181 rom-I, F(OOO) =
860, 2()max = 54.000 , 10291 reflections, 1382 independent reflections [Riot = 0.0319], R1 =
0.0334, WR2 = 0.0810 and GOF = 1.114 for 1382 reflections (89 parameters) with I>
2cr(/), R1 = 0.0405, WR2 = 0.0849 and GOF = 1.114 for all reflections, max/min residual
electron density +0.726/-0.211 eA3.
Bridge to Chapter VII
Chapters V and VI analyzed the solid-state and solution structures of several
Group 15-containing cryptands. Chapter VII will put this chapter into the context of the
entire dissertation by tying together the conclusions from all of the previous chapters. It
will also give a brief outlook on future directions for the project.
154
CHAPTER VII
CONCLUSIONS AND FUTURE OUTLOOK
Introduction
A supramolecular approach to toxic ion chelation can give unique insight into the
chemistry of that ion. As a worldwide contaminant of human drinking water supplies,
arsenic is an important target for chelator design. This dissertation described a
supramolecular design strategy for the coordination of arsenic with thiolate ligands. Over
the course of this research, much was revealed much about the bonding preferences,
kinetics and reactivity of the As(IIl) ion.
Specifically, Chapters II and III showed that the As···1t interaction is strong
enough to influence the diastereoselectivity of a self-assembly reaction and affect the
preferred bonding geometry of the products. In Chapter IV, As(III)-thiolate bonds were
revealed to be kinetically labile on a timescale that allows for effective, albeit slow, self-
assembly. The relatively leisurely rate of the self-assembly of AS2~Chmacrocycles
allowed for the characterization of reaction intermediates and oligomeric kinetic
mistakes, both of which elude observation and characterization in most transition metal-
directed self-assembly reactions. Finally, in Chapters V and VI, the reactivity of arsenic,
155
along with phosphorus, antimony, and bismuth, was exemplified through a
supramolecular transmetallation reaction. Overall, this dissertation has provided insight
into the chemistry of the As(III)-thiolate bond, but there is still more to be learned. Here,
I will describe several potential future directions.
Potential Future Directions
Transmetallation Reactions
The work described in Chapters V and VI of this dissertation reveal the reactivity
of the Group 15 ions, E(III), with thiolate ligands. Transmetallation was found to occur
between cryptand congeners establishing the reactivity trends: BhL3~ Sb2L3~ AS2L3
and Sb2L3 ~ P2L3. It is still unclear as to whether As2L3will react with PBr3 to form
P2L3 or if As(III)-thiolate bonds are a thermodynamic sink and no reaction will occur. In
fact, P2L3may react with AsCh to give As2L3. Establishment of this reactivity is
important from a basic science perspective.
Transmetallation reactions between these cryptands and other metal ions may give
access to new assembly stoichiometries. Mercury, lead, zinc, platinum, palladium, gold,
cadmium, and tin are all reasonable targets. Additionally, the "transmetallation" with the
non-metal phosphorus and the metalloid arsenic suggest that other non-metals may
participate equally well in "metal"-directed self-assembly. Some suggestions are
selenium, nitrogen, and boron. The differences in preferred bonding geometries of these
ions could result in the formation of higher-order assemblies than the E2L3 cryptands
reported here.
156
Guest Inclusion
One goal of supramolecular chemistry is to study molecules in isolated
environments, such as within host cavities. To date, all of the assemblies prepared by our
laboratory have been too small to allow for complete encapsulation of a guest molecule.
Several macrocycles have shown partial guest encapsulation and guest identity has been
shown to affect the structure of the host (Chapter ill). However, complete encapsulation
wili necessitate the design of larger assemblies or the use of smaller guests.
Lewis basicity decreases down Group 15 as the lone pair of electrons becomes
increasingly diffuse and inaccessible. Consequently, complexes containing the heavier
elements make for worse ligands toward Lewis acidic ions. However, phosphines are
commonly used as ligands for transition metals and the previously discussed
transmetallation reaction has allowed for incorporation of P(ill) into our assemblies.
Still, the cavity of the PZL3 assembly is too small to fit most guests. Some targets that
may be complementary in size are H+, Au+, Cu+, BH3, or Ga+. Preliminary screening
suggests no reaction between PZL3 and H+, Cu+, or BH3, but Au+ and Ga+ show some
reaction. Still, preparation of P(ill)-containing cryptands with larger cavities may be
necessary.
Self-Sorting
The high-yielding preparation of heterometallic cryptands presented in Chapter VI
suggests that social self-sorting between metal ions may be occurring during self-
assembly. If this is case, then this would be one of only a handful of examples of social
157
self-sorting and unique in that the metal ions, rather than the ligands, are being selected
for. By following the reaction of HzL, AsC!), SbC!), and base by IH NMR, Dr. Justin L.
Crossland was able to get some preliminary indication that social self-sorting may be
kinetic, but the loss of reactants to an uncharacterized coordination polymer made it
impossible to draw any final conclusions. It would be very interesting to monitor this
experiment under conditions that favor discrete species formation over polymerization
(lower concentration and higher temperatures) and follow the product distribution.
158
APPENDIX A
ADDITIONAL NMR SPECTROSCOPY AND MALDI MASS SPECTROMETRY
DATA FOR THE SELF-ASSEMBLY OF AszLzCh MACROCYClES
This appendix contains the IH NMR spectra and MALDI Mass Spectrometry data
for the self-assembly of AszLbzCh macrocyc1e from Chapter IV. This co-authored
material was previously published as Supporting Information (Chemical Comunications
2009, 5606-5608, © Royal Society of Chemistry). 1 Dr. Timothy G. Carter performed all
MALDI mass spectrometry experiments and I performed all NMR spectroscopy
experiments.
159
a
liH,L'
l b
tit' ~2b I"'"b 3bl ~2b~
L SHH2LbJl CI~%c I"'"
~
SH
d 1
b
CI4-M%e 1""'/ I"'"~ ~
SH SH
2b
f CI~Xes
I"'"
9
~S,ASCI2
3b
CI
:i~~h I"'" I"'"~ ~Ass....... , .......s
CI
4b
i 1 1J
I I I I I I I I I I I I I I I I I I
4.6 4.4 4.2 4.0 3.8 ppm
Figure 1. CH2region of IH NMR spectra of reaction ofH2Lb with AsCh after 0 (a), 4
(b), 75 (c), 147 (d), 1559 (e), 2666 (t), 3995 (g), and 8395 (h) minutes. Dissolved crystals
of As2L b2Cb (4b) (i).
160
395.94
TC__022609..A7 (0.221) Is (1.00.1.00) C12H17AsCI2S2NaH2
lOQ. ~.94
I
I
I
396."
I
I
397.94
398.94
"~%
SH
1b + 2H + Na
TOF MS lD+
4.53e12
TOF MS LD+
163
396.92
I
:1
G"---.-----,------',----',~--'r---...L,_--_'r----'r__--~-­
TC_022609_A7 27 (0.544)
1m..
;1
I:
II[i 39691
II 1\11i
i
.,1 ! JI 399.93
L ....""""'fi.,t.'l<fl"......."""""f/!!J.......<..!tt."-.:;l:JJ...__~!"1!......&L~........>&1.~2I>.I6clJL' ~~o(C'!""""-<loll.<l!A:"4..~~""""''''''''~C!,'t'''"'''....,0- ~
~ ~ _ m m m m ~ ~1
Figure 2. MALDI mass spectrometry data for lb. Predicted data shown on top and actual
data shown on the bottom.
TC_022609_A7 (0.544) Is (1.00,1.00) C24H34AsGIS4NaH4
100- 58~.07
589.06
~S~%STOF~~~~,I"" I""h hSH SH
2b + 4H + Na
586.07
TC_022609_A7 27 (0.544)
100-
TO'F MSLO+
81
Figure 3. MALDI mass spectrometry data for 2b• Predicted data shown on top and actual
data shown on the bottom.
161
Te_o22BOe_A? (0.221) Is (1.00,1.00) C12Hl6As2CI4S2Na
100
636.78
538.77
;
TOF MS LD+
3.58812
.""
540.77
I
539.78 542.77
i
o ,
TC_022600_A7 27 (0.544)
100· 5i'·
TOF MS LD+
213
I,I
II
III I 53~.80 54'(" ~
J JJt""J'.....,I \r;' '\ ~....53~3~~534~~5r::35:':"1oi~53a~JL:.5~37:J.i~53I!=B~~5'!...39:J:!!~54~0~'--'54~' ,::J,,~54~2C!o':"~54~3~~544~M54~5:':;'~546~1!:!:. mlz
Figure 4. MALDI mass spectrometry data for 3b• Predicted data shown on top and actual
data shown on the bottom.
CI
~S-1.s»:S TOF~~;~"2I "" I""h hs......t'---s
CI
4b + Na
,,90
693.91
I
692.91
691.9'
TC_022609_A7 (0.544) Is (1.00,1.00) C24H32Ae.2CI2S4Na
100. ,,91
I
I
I
IO\-,--_--~------.J_----'-_-----'-,--___',.--...J,_--_'_r_--_'_r_--..,_--
TQF MSLD+
63
694.90
690.91
I
it
'Iij
Ii
"
69689I _
\':-"--'--'~c-'-'-'~':-'.::.L-':--":,.-L-lJ:'-:,-'...L:-.L.:..-"'-_-=-:+-'_c.'-'-:,-'-_'-'-:-,J::--'-'-'::"""::-'--'-1.L:T:-'-'--'-'L.5i:z
TC_022609...A7 27 (0,544)
100·
.""
162
CI§S--1%STOF~~~2I"" I""# #
CI2M,S SH
Sb + 2H + Na
730.90
I
732.90
I
731.90 I
J.........__~__---'-~--7-'2~~.90---l.,------'-!.~__I~,---'-r-------'-~-
TC_022609_A7 IG.S44) Is (1.00.1.00) C24H33A92:C13S4NpH2
100·
.~.
TOFMS LD+
101
734.88
732.88
I
TC_022609_A7 27 (0.544)
100
728.87
I
~I,
1\
!I
j I
Ii
) 1 ! l
II '~\I ~ ~ ! i u, I ~ . /', ~L if
I} \'1 " "";\<."'I.wll#i,,.) 'v!VI' ,~, . 'w,;,I~"y,W \~IY/'\i. m/z
rn m ~ n1 m rn ~ 7U
Figure 6. MALDI mass spectrometry data for Sb. Predicted data shown on top and actual
data shown on the bottom.
TC_022609_A7 (0.020) Is (1.00,1.00) C24H32As3CISS4Na
100·
870.74
,
872.73
i
TOF MS lD+
102
TC_022609_A7 27 (0.544)
100·
•
, . " ~
~ ~ ~ 8m ~1 ~2 m ~ ill ~ m m aro ~ M1 ~
Figure 7. MALDI mass spectrometry data for 6b• Predicted data shown on top and actual
data shown on the bottom.
163
TC_022609_A7 (0.020lI8 (1.00,1.00) C36H50As2CI2S6NaH4
100 92103 923.02
OL--,--_-,--__--i--_----+__--1-_----+__-+--_----i'_____~I'-----_,__-
TOF MS LD+
20
924.98
TC_022009_A7 27 (0.544)
100
G !. . ~
919 000 ~1 m m ~ ~ ~ m ~
Figure 8. MALDI mass spectrometry data for 7b. Predicted data shown on top and actual
data shown on the bottom.
TC_022609_A7 (0,544) Is (1.00,1.00) C36H48As3C14S6NaH2
100-
1062.00
1064.86
CI
;cgS7I\%S §S'AsCI2TOF~~,~I"'" I "'" I"'"b b b
'i-" SH s/ts's
i CI
! eb +2H+Na
1063.86
TC_.022609_A7 27 (0.544)
100
1062.79
TOF MS LD+
22
TC_022609_A8 (0.363) Is (1.00.1,00) C36H49A&4C+6S6Na
100 1207.70 1209.70 §8-=~\%8 §8''A CI TOFMSlO+~ S 2 2.13912I"" ,"" I"".4- .4- .4-
CI,As'8 8",/,"'8
1211.70 g" + Na CI
I
121?70 1213.69
164
TC_022009_A818 (0.383)
100 1206.71 1208,66
TOFMSlO+
11
12'02 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 12'13 1214 12'15 1216 1217 1218' mJz
Figure 10. MALDI mass spectrometry data for 9b• Predicted data shown on top and
actual data shown on the bottom.
165
APPENDIXB
SUPPLEMENTARY DATA FOR THE CHARACTERIZATION OF GROUP 15-
CONTAINING CRYPTANDS
This appendix contains the co-authored supplementary data from Chapter VI and
has been submitted for publication in Inorganic Chemistry.l Dr. Timothy G. Carter
performed the electrospray mass spectrometry experiment on Sb2L3 and Sb2L3-asym. Dr.
Justin L. Crossland performed all other mass spectrometry characterization and I3C NMR
spectroscopy. Dr. Lev N. Zakharov carried out all X-ray diffraction experiments.
Professor Darren W. Johnson provided intellectual and editorial contributions. I carried
out all lH NMR, DFT calculations, searches of the Cambridge Structural Database,
synthesis, and crystal growth.
Cambridge Structural Database (CSD) Searches
Several comprehensive searches of the Cambridge Structural Database (CSD)
were carried out to establish structural parameters for Group 15 complexes.
166
CSD Search for E-S complexes
A CSD search for complexes containing Group 15 elements with three thiolate
bonds was carried out (Chart 1). The data from this search was used to establish the CSD
average E-S distances and S-E-S angles reported in Chapter VI. Refcodes for structures
used in determining these averages are reported in Table 1. Searches were performed
using ConQuest version 1.10 with CSD database version 5.29 updates (Jan 2008). The
following filters were applied to each search: not disordered, no errors, and no powder
structures. The substructures E(SCh (E =P, As, Sb, Bi) were searched for (Chart 1).
The E atoms were constrained to only 3 bonds. Only structures with three separate
ligands were analyzed; macrocyclic structures were discarded due to ring strain. Each E-
S bond distance and S-E-S bond angle was measured and the results were averaged.
C
I
c.....s,p.....S
I
s.....c
Chart 1. E(SCh structures.
Table 1. Refcodes From the Cambridge Structural Database Included in the Structural
Survey Used to Determine Average E-S Distances and S-E-S Angles.
P As Sb Bi
CUMLIF ASMTBZ02 DEDLUT CIBKAZ XIHNIL OKOSAI
DOYXAQ ASXANT IBAYAM CIBKAZOI XIHNIL YUKRUR
ETCBPS ASXANTOI JACMUW CIDWIV YUSFUN ZAHDUH
JUFROR BOZFIF JACNAD CUYKIQ ZAZYII '7TT'kKC' It. n
I
~UIV.l~l""\.D
SEJRUU BOZFIFOI NEJRAW SQNLSBlO ZAZYOO ZUMSAB
SEJRUUOI BOZFIF02 QIFKIZ TIDGOC ZUMSAB
SEJRUU02 BOZFIF02 QIFLAS TIDHAP WMSAB
TCBMPH CATJOW UUCAT TIDHAP ZUMSEF
TCBMPH CUBVIE ZAHDIV XAVYEY ZUMSEF
167
CSD Search for P···n Contacts
The second CSD search carried out was to establish if there was a directional
preference for close contacts between phosphorus and aryl rings. The refcodes for the
structures used are reported in Table 2. No directional preference was found, suggesting
that there is no favorable interaction between phosphorus and aryl rings. The search was
performed using ConQuest version 1.10 with CSD database version 5.29 updates (Jan
2008). The following filters were applied to each search: not disordered, no errors, and
no powder structures. The searches screened for C6-arene rings and neutral, three-
coordinate phosphorus with intermolecular contacts that were shorter than the sum of the
van der Waals radii (1.70 Afor aryl C + 1.80 Afor P =3.50 A). Structures were
excluded if the phosphorus atom was bonded to another phosphorus or metal, charged, or
part of a cluster. After excluding one structure, there were 20 hits. No correlation was
found between the bond angle and distance.
Table 2. Refcodes From the Cambridge Structural Database Included in the Structural
Survey.
Phosphorus
BAVRIZ CEWGm IQIMEA WOPJOA
BILVIB CIGJOR JOBFUB YEQDEE
BUFZIL FAGLII NETNEF ZEWWAZ
BUSLEG HUMRAI PAMWIJ GIHTOH
CAYLAP ICULIC WOJMOX SIHVEL
168
NMR Experiments
Several IH NMR experiments were carried out to established the solution
structures of E2L3 cryptands. By dissolving crystals of the cryptands in chloroform and
waiting until the samples had reached equilibrium, it was observed that two species were
present in solution: the symmetric E2L3 cryptand and E2L3-asym (Figure 1).
a)
_.. ~j\._. ):l ._'_~)il.__,...........
b C
la
. I
_. ~__. L.. A .._. ~,
C DCI 'a
2 2 4
3c
d e
I,~ ~
----, ,...-! '--_..-
d e
b c
CDCI,
In
d e
b
C) I
2~:. Jb.
2a
I 4c
. , .....•.•.'\..._ .
CDCI, u
d e
b c 4
1
0 ! 20 . Ja2d J~'I 4d 4e 2c I]. 3c
d) 2b! 31> 2J4~ .I I, I 4c '.'. .1. 11 ji!,I.. II II II II
-..-JiL-l'-.-1~!-::L-'L_.JJ\ ,'"-----''-''...." \ J.J,---.J,,__P-....-..J''-''~
i", T--', t "r' T r -T" !----r-"r· f--- T"-'- '["--"; . r"T--- c- ",-- To- r -T "j .~- T "'T"'T"1--"r"-T-' -- r"T"'r-"i"'T"-r -"j
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 't.J 4.0 ppm
Figure 1. Fully labeled IH NMR spectra for P2L3 (a), As2L3 (b), Sb2L3 (c) and BbL3 (d).
The resonances for the symmetric cryptand are labeled with letters and the resonances
corresponding to the asymmetric cryptand are labeled with numbers and letters. *
denotes C2H2C14 in the spectrum.
169
In order to identify which protons belonged to which ligand in the Sb2L3
cryptands, g-COSY (Figure 2) and NOESY (Figures 3-7) experiments were carried out.
'\oY......m·(lXI:l
IlofriJ ~~J)( ! l'l!:l.l ~
(lp<.r~U" 'J'f"')'
Fil/':O:llS'}9 'm'I.- 3I1B....-cOS1
lP+O"'''..\Of) ·""",I""',.'''''''r9'''l....11'
,.L
ilfJ.,o.'kI.yl-l'oX1 •...".
N'lI·rN'(.l.li3lh
w~t:~. ~'V~OH!
lr>W..J'Iot<X!JOIIJ
{.:rpol·,\..... "
1;11...... ' •.." ..".1,
(Jo5'.,lfN~ UL$'iS!·\ltt;)J,l4lM.h
IJAT'\FWrJ:.%I!«,
~",br110.(l64~
r.t O-\IA l;'Wl(lSW.u
5-'.",,!>o'l1Off'9=
nl..... 21)'..il~JQ.:S
fc-u!!lt'roo-lllm:n.6:tM:
-'
~~_..-=-:
F1
Ippm)
1
,. ...
:i!! Ii:
10
F2lppm)
""l a D I1Tf'TI'f"T'r~•....,-,r~'I"l"f'T'rrnrrr".,.".,-r''l''''''''''f"'"r"''''T'"''TJ~
M 8A ~ M 7~ U 7ft 1.2 7D U ~
"\j , '-'.
I 1 'I' I I'I4A .oj ..i
f\
) \", f'
~v
la'I a
0 Q OJ
"
GBQ
a 0 (iJ
I i
4,6 4.5
",ppm
l.8
»~
M·
'.1
'.J
".3 ..
'.4
U
i
..,]
'.7
1
'.9 ,. '.7
iii
ItO •
., .
Ii I 1\1\ ;\ IIj\ / r.,11 ;'"
F1
, {ppm), I:lI,.
'-.
Q
1Jl.,.
" a
7.4-'
.. •1,6 _." 11-eI
,..
f]{ppm) F7lpprrol
Figure 2. gCOSY spectra for Sb2L3 in CDC!): full spectrum (top), CH region (bottom
left), CH2 region (bottom right). See Figure lc for labeling scheme.
4d
4a
a)
I I I I , , I j , , , I • i j t I ...........,..-,-,-ro-.-r;r-r->~-,---,--r+-tll-.-...,.-, , I I I I I I I ' , j , I ' , i 'T'""' , , j If, i , I
11 10 3 1 1 -0 -1 ppm
4c
2d
2a
b)
~,,~'~,~,-,-,-'-1~,~,~,~,'-1,-,r-,r-,t"ln,n,n,--.-,-,---,-~--,-,-+-rifh-~~,-,.-~, I ' , , , I ' , , ii' • , ' I j ii, !
11 10 9 8 7 1 -{) -1 ppm
2c
3c
I,
3b
c)
"".,.,."""__.....~...il~__.....''''''"....-......_''''·,j·,, -,..__....... ".....L...... .....,...."_,__....,........·......."' ........4..._.
170
11 10 9
3d
-0 -1 ppm
Figure 3. ID NOESY spectra for Sb2L3 in CDC!] with irradiation of the following
protons: 4e (a), 2e (b), and 3d (c). See Figure Ie for labeling scheme.
171
e
b
a) L 4b 4e--.---------~------- --- -J---~----__r------~ J -----...------------------.-------------.
I, • Ii' I , ,...,-, , , I j iii I I I i j I
11 10
4d
d
~1 ppm
2e
b)
2b
I
-011 10
-"'1-,-,.,..,,..,~,I""''''''~'-'''I~,.~,~,'''I'''~''''''-,..,--r-r-c,..,,~~,,_1j-,-1,-~~""-r-r..,.,,_,__r_r_r~~,...,~~
·1 ppm
2d
3e
c) 2b 2c
11 10 -0 ·1 ppm
3a
Figure 4. ID NOESY spectra for Sb2L3 in CDC!) with irradiation of the following
protons: d and 4d (a), 2d (b), and 3a (c). See Figure Ie for labeling scheme.
172
a) b c _L._
1011
......~,.....,-,-,-~,.,-,...,..,...".....,.....-.......-.-\I....,...,-,-,.-r"T-rr.,-,-.,.,...,,.,.,.-r-r-r-r..........-.-,-....,...,-,-,--r-.--r-r,.....-,-..,.-,-,
-1 ppm
a
4b
b) 3b
61011
.......,-,-...--r-r~,-r"r-r-T-,--r...-.-rlcf,..,--.---r...-.,--,-,,,"""T, , I I , I I ( j iii l I i j I I i r , , I ' • , I Iii i I I
4 3 I -0 -1 ppm
4c
4e
4a
c)
r
11 10 -I ppm
2a
Figure 5. ID NOESY spectra for Sb2L3 in CDCb with irradiation of the following
protons: a (a), 4c (b), and 2a (c). See Figure Ie for labeling scheme.
4e
2a
a)
, I ' J , I I
11 10 7 -0 -1 ppm
4a
4d
3b 4c
b)
T
11 10 6 4b 7 -0 ·1 ppm
3c
b
C) a d
,
11 10 -0 ·1 ppm
C
3d
3c
d)
173
ii' I • , Ii' t ,
11 10 9
3b
-1 ppm
Figure 6. ID NOESY spectra for Sb2L3 in CDC!) with irradiation of the following
protons: 4a (a), 4b and 3c (b), C (c), and 3b (d). See Figure lc for labeling scheme.
In order to identify which protons were part of which ligand in BhL3, g-COSY
(Figures 7) and NOESY (Figures 8 and 9) experiments were carried out.
174
'.<o<.NWO~'Ul
1",,>, I'S_~(' ,"-""'1>:.
Of-..."'!]"""
l.jo,-:f'lJ'8 ••,,, l19J ,,..:{;~Y
f~NA ~") ~>dnr'~,""<'<Ml.",!.:I
"'1'1.>....:•• 1(••)"'- ---.-c::::
::~~""'~~~~i,7 F2
AlW,&...,'i-)J:"lIt ~ tppm)
4'q,,·.~~." ' 1,;;¥m;;!?:Mi:J~""-::._"",=-====:?;e"
"\" " ..."h-il(}[~·'_~
n(>Al!\rf<...\.fS,U:,
!l<1 ...,..I~j"':~l>_
fl ",. " .......,. -'U.~
IV_t ...._\(l.,-",.t> ....,
.
.
.
.
•
----~===3::;q .
-===::2 .' .'
Fl (ppm)
I'~
'PI"")"t:::: 6.!\
~,(,
~/,}
-=--;
~-- 1f,
I ill!
s:::: ,.
l\ fl JlL
• 0
D
D
D
D (I aIII
Q D
• D
='
o
a
o
•
o
Ii
00
.00
..
D
•
"o
Oa
Figure 7. gCOSY spectra for BhL3 in CDCh: full spectrum (top), CH region (bottom
left), CH2 region (bottom right), See Figure Ic for labeling scheme.
175
3c
, I • , • i I I • I , I I , I • Iii, , I if. i I
11 10 9 8 7
a) 2b 2c
I I
r I
, , ii' t , , I ' , I I I ' • , I I I j j , j I , , I Ii. I , I
4 3 1 1 -n -I ppm
3a
4b
b) 3b
3c
11 10 -0 -I ppm
4c
2c
ppm-1-0
-r--rr-r-~~.....,-r--r""-'-"- --r-~'~"I r,~,~,~,.1~,~,~"I ~I·"'· i , I I I j I I I j I • I j I I I Ii, I I I '''''''''''''''T'"l
11 10 9 8
2a
Figure 8. ID NOESY spectra for BhL3 in CDCb with irradiation of the following
protons: 3a (a), 4e (b), and 2a (e). See Figure Id for labeling scheme.
a) 2a 4e
176
• I • i j , I • , f I I I
11 10 9
, , t j Ii, ( , I ' , , I I • i , I I I , I , I •• ) , I I , I , I f I I , I i j j , I
-0 -1 ppm
4a
3b
b) l 4c
11 10 -0 -1 ppm
3c
3a
c)
11 10
2b
2c
2d
,1
I
• I ' • I I I ' , I j I ' j I , I If, i I I I I • I j , I • I i j j , I I I j I I Ii, i I
7 6 5 4 3 1 -0 -1 ppm
Figure 9. ID NOESY spectra for BhL3 in CDCh with irradiation of the following
protons: 4a (a), 3c (b), and 2b (c). See Figure Id for labeling scheme.
177
Phosphorus NMR
Routine characterization ofPSbL3 included 31p NMR (Figure 10).
400 300 200 100 0 -200 ppm
Figure 10. 31p NMR spectrum for PSbL3, externally referenced to H3P04 (0 ppm).
Density Functional Theory Calculations
Density Functional Theory (DFT) calculations were carried out on the symmetric
(Figures 11 and 12) and asymmetric cryptand structures (Figure 13). The energies
derived from these calculations are reported in Table 3.
Figure 11. Overlayed stick-representations of the X-ray crystal structures (blue) and
DFT-calculated structures (red) of P2L3 (a,b), As2L3 (c,d), Sb2L3 (e,f) and BhL3 (g,h).
178
a)
Figure 12. Overlayed stick-representations of the DFf-calculated structures of SbzL3
(teal) and BhL3 (blue) from side (a) and top (b).
Figure 13. DFf-calculated structures ofpzL3-asym (a,e), AszL 3-asym (b,t), SbzL 3-asym
(c,g) and BizL3-asym (d,h).
Table 3. Energies Derived From DFT-Calculations and IH NMR Spectroscopy
Experiments for Symmetric and Asymmetric EzL3 Cryptands.
DFf Calculations H NMR Experiments
Cryptand Energy sym Energyasym Energy dif. (L10) Eq. Eq. Ratio L10calc
(kcaVmol) (kcaVmol) (kcal/mol) svm asym (kcal/mol)
P2L3 -2799891.361 -2799884.752 -6.6083 1 0 NA NA
As2L3 -2379204.541 -2379199.236 -5.30559 60 3 0.5 0.148588
Sb2L 3 -2378314.07 -2378310.028 -4.04242 0.53 0.47 0.89 0.005959
BhL3 -2378372.83 -2378368.762 -4.06814 2 3 1.5 -0.02011
179
Mass Spectrometry Experiments
Liquid Chromatography Mass Spectrometry experiments were carried out on the
Sb2L3 cryptand to show that two species were present in solution with the same mass-to
charge ratio (Figure 14). Routine Electrospray Mass Spectrometry was carried out on all
of the heterometallic cryptands (Figures 15-17).
0 0
a) 3500 en b) .,;en enIX) Mr1>::: 1104
'"
t"'CiX: 3649
3500
3000
3000
2500
0
0 2500 §
2000 0 § 0
...: ...:
en 2000 enIX) ~ IX) 0
1500 00
1500 en
1000 0 c~
0
oj N
en 1000 ~~
'"
'"0
500
en
500
0 0
890 895 900 905 910 915 mlz 890 895 900 905 910 915 m/z
C) d)
mAU mAU50
200
175
40
150
30 125
100
20
75
50
10
25
0 0
250 300 350 400 nm 250 300 350 400 nm
Figure 14. Liquid chromatography mass spectrometry data for [Sb2L 3+Ht showing that
symmetric and asymmetric cryptands have identical masses (a,b) and UV/vis spectra
(c,d).
60
40
APel, Pos, Scan, 50
Max; 11981
I
I
I I 0
1 0 .0lol;i~~I II",
ro I: 1111 J84'riO-~~-~-~~8'~~0"-+i,~+I--,i--+l,-~-86ri0~-~-~-~-8T~0-~~-~;
Figure 15. LCMS spectrometry data for [AsSbL3+Ht.
·MSD3 SPC, time=0.922:0.933 of JUSTINIASBIL3.D APCI, Pos, Scan, 50
180
Max: 164'74
60
q
0 ::;:d
'"40 .,.Cl
20
.Ill'O....L.,--------I I i930 935 940 945
Figure 16. LCMS spectrometry data for [AsBiL3+Ht.
Max: 45432
I ;MSD3 SPC, lime=I.034:1.058 of JUSTINISBPL3.D ~CI. Pos. scan, 50
I 100 ~ g
I
, 80
I 60
I ~ ~ r
I · ~
l_. 0 790 800 81~0_CD-----._~8=20 =8~0~d
Figure 17. LCMS spectrometry data for [PSbL3+Ht.
X-Ray Crystallography
The X-ray crystal structures of all heterometallic cryptands were determined
(Figure 18).
181
CJ/".lX\
./ , ; J J '.
~}" / /.\( "-./' ,",(t! Ilf "\ I J t
. ."V "t /'" r" /' -.....,/
....• I 0 -·-I·l .
.(J,/I~/
Figure 18. ORTEP representations (30% ellipsoids) of the X-ray crystal structures of
PSbL3 (a), AsSbL3 (b), and AsBhL3(c).
182
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Appendix A
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Commun. 2009,5606-5608.
AppendixB
(1) Cangelosi, V. M.; Carter, T. G.; Crossland, J. L.; Zakharov, L. N.; Johnson, D. W.
submitted to Inorg. Chem.