NEW INSIGHTS INTO THE ROLES OF METALS IN NITRIC OXIDE DELIVERY
A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry
By
Marie M. Melzer, B.S.
University of North Carolina at Charlotte
Washington , DC April 29, 2009
NEW INSIGHTS INTO THE ROLES OF METALS IN NITRIC OXIDE DELIVERY Marie M. Melzer, B.S.
Thesis Advisor: Timothy H. Warren, Ph.D.
Abstract
The biochemistry of organic nitroso compounds (E-NO, E = RS, RO, R2N, R) is connected to that of nitric oxide. These organic derivatives can serve either as sources of
NO in vivo or produce similar effects as NO such as vasodilation. In contrast to free NO, these organic derivatives are stable towards dioxygen. Release of NO from many organonitroso compounds requires a reducing equivalent, implicating redox active metalloenzymes. Thus in many cases the “stored” NO in its carrier molecules has to go through certain release-and-capture cycles to execute its various biological functions.
The transport of NO in biological systems is via S-nitrosothiols, part of sulfur-containing proteins.
Employing monovalent nickel and copper beta-diketiminates and tris(pyrazolyl)- borates as models for these metal ions in metalloenzymes, we find that the E-NO bonds of O-nitroso (RO-NO), N-nitroso compounds (R2N-NO), and S-nitroso (RS-NO) are readily cleaved to form well defined metal complexes [Ni](II)-E. In the case of the most biologically relevant Cu complexes, we observe an important contrast to all previously studied systems in which [Cu](II)-E species are reductively cleaved by NO to give the organonitroso compounds E-NO. The NO released in the nickel system binds with an extra equivalent of Ni(I) to form [Ni]-NO. For copper chemistry the fate of the NO
ii depends on the ligand system used. Copper beta-diketiminate products are decomposed
and copper tris(pyrazolyl)borate nitrosyls [Cu](NO) are observed.
Copper(I) N-heterocylic carbene complexes are less electron-rich and do not activate the S-NO bond. Rather, we have shown that copper can have a role in the formation of the S-NO bond through trans-s-nitrosation as well as nitrosonium addition to the copper(I) thiolate [Cu]-SR. This work has provided of insight into the biochemistry of
NO and the role of metals in E-NO bond cleavage and formation.
iii Acknowledgments
My experience in graduate school has been one of intense learning and growth. Not only have I gained a wide array of scientific skills, I walk away with analytical and problem solving skills that can only come through many years of scientific research.
There are many people who have walked alongside me through this journey. I am forever thankful and in debt to their support (and too often patience!).
It was an honor and privilege to work for Professor Timothy Warren the past five years. Not only is he a brilliant scientist, gifted teacher, and probably the most patient man I have ever met, he genuinely cares about the well-being and success of each of his students on a personal level. As a person who values family, I could not have asked to work for a more supportive boss when it came to time with family. Over the past five years, I have had several family commitments and emergencies, and Tim always gave me his full support in dealing with these issues. I aspire to be the kind of leader and mentor that Tim was to me.
I would like to thank the members of my committee, Professor Bahram Moasser,
Professor Steven Metallo, and Professor Toshiko Ichiye for their assistance and dedication to my Ph.D. journey. Your thoughts, comments, questions, and suggestions during my Phase 2A and Phase 2B were most appreciated and helpful in my graduate school experience. I would especially like to thank Bahram for his assistance with my kinetic questions.Kim Yearick Spangler, Dr. Yosra Badiei, and Matthew Varonka were my daily sanity throughout these past five years. The company of good friends and laughter helped me not to take life and chemistry too seriously. I could not have made iv this journey without you there and I will miss each of you tremendously. To Stefan
Wiese, thank you for being a patient glovebox mate with my mess and vials everywhere.
You were truly someone enjoyable to work alongside. To my undergraduate student
Ashley Bartell and Project SEED student Corwin Ward, thank you for your enthusiasm
and assistance on the nitrosamine project.
I appreciate assistance from Professor K. Travis Holman (X-ray structures) and Dr.
Ercheng Li (VT 1H and 15N high field NMR studies). The office staff: Kay Bayne, Inez
Traylor and Travis Hall have made the business side of graduate school much more amenable.
Finally, I would like to thank my family, Mom, Dad, Suzi and Rich Melzer, my sisters Jessica, Jocelyn, Allie, Gabrielle, and Miriam, my brother Chuck, my sister in- laws Sarah and Joanna, my brother in-law Tom, my nephews Brent and Michael, and my precious nieces Chloe and Montana. The experience of graduate school is not one walked alone. I appreciate everything that you have done for me along the way to encourage me to reach my goals.
Last, but most importantly, I would like to thank my husband Jonathan Melzer for his unconditional love and friendship. You are the most important thing in my life and I could not have made it without you. Thank you for being there for me when I was sad and frustrated, thank you for your support during the busy final months of completion, and thank you for making me feel like the most loved woman in the world. I hope to have many more life experiences with you by my side.
v Respective Contributions
Dr. Susanne Meyer from Professor Karsten Meyer’s research at the University of
Erlangen-Nürnberg performed in depth EPR analyses and simulation studies for several
II I compounds, [Me2NN]Cu (ON-Me2NN)2Cu (1), [Me2NN]Cu-NPh2 (2), [Me2NN]Cu-
15 NPh2 (2'), [Me2NN]Cu-I (3) (Figures 2.8, 2.13, and 2.14).
vi Table of Contents
Title……………………………………………………………..…………………………i
Abstract…………………………………..……….………………………………....…...ii
Acknowledgements……………………………………………..…………………….....iv
Respective Contributions…………………………………………….…………………vi
Table of Contents……………...………………………………..……………………....vii
General Introduction Organonitroso Compounds: N-nitrosoamines, O-nitrosoalcohols,
S-nitrosothiols; Biological Activities, Chemical Properties, and Interactions with
Metals…………………………………………………………………………...…………1
Abstract….………...... …………….....……………..…..……1
Introduction…...... …………….....……………….....……1
I.1.a. N-Nitrosamines (R2NNOs) - biological applications..…...……..…...... ….... 3
I.1.b. N-Nitrosamines – syntheses….………………….....…………..…...... ……4
I.1.c. N-Nitrosamines - chemical properties….……………………....…….…..…5
I.2.a. O-Nitrosoalcohols (RONOs) - biological applications….…...……..…..…...6
I.2.b. O-Nitrosoalcohols – syntheses….…………….…….....……...... …..……...8
I.2.c. O-Nitrosoalcohols – chemical properties….………..….……...……..……..8
I.3.a. S-Nitrosothiols (RSNOs) - biological applications……………...... …..…...11
I.3.b. S-Nitrosothiols – syntheses….…...…………...... ……………...…..……...13
I.3.c. S-Nitrosothiols - chemical properties….….…………….....………..……..13
I.4.a. N-nitrosamines - complexes with metals….…...…….…...……...…..…….19
vii I.4.b. O-Nitrosoalcohols and S-Nitrosothiols - complexes with metals……...…..21
Chapter 1 Reductive Cleavage of O-, S-, N-Organonitroso Compounds by Nickel(I) β-
Dketiminates...…………………………………………………………………………...30
Abstract………………….……….…………………………………….……...... …..30
Introduction………………..…………………………………..……….……...... 30
Results and Discussion……………...……………………………….……………...33
1.1. Reaction of [Me3NN]Ni(2,4-lutidine) with CyONO or AdSNO…..…...... 33
1.2. Reaction of [Me3NN]Ni(2,4-lutidine) with Ph2NNO……………...…..……34
1.3. Independent synthesis of [Me3NN]Ni-NPh2 and reactivity with 2,4-
lutidine………………..…………………………………..……….……...... 35
1.4. Electronic properties of [Me3NN]Ni-NPh2. …………...……………...... 40
1.5. Mechanistic considerations…………………………………….……...... 44
Summary…………………………………………………………………...….……..46
Experimental Procedures…………………………………………………..………...53
References…………………………………………………………………...…...... 66
Chapter 2 A Three Coordinate Copper(II)-Amide from Reductive Cleavage of a
Nitrosamine……………….……………...………………………………………………69
Abstract..………………………………………………………….……………...... 69
Introduction………………..…………………………………..……….……...... 69
Results and Discussion……………...……………………………….……………...74
II I 2.1. Synthesis and characterization of [Me2NN]Cu (ON-Me2NN)2Cu ...... …...74
2.2. Isolation of [Me2NN]Cu-NPh2 from reaction mixture………………...... 78 viii 2.3. Independent synthesis of [Me2NN]Cu-NPh2..………………...... …………..79
2.4. Electronic properties of [Me2NN]Cu-NPh2.……...…………...... …………..86
2.5. Reaction of {[Me2AI]Cu}2 + Ph2NNO..……...…………...... ……………….88
t 2.6. Reaction of {[Me2AI]Cu}2 + xs BuONO..……...…………...... ……………89
2.7. Electronic differences between {[Me2NN]Cu}2 and {[Me2AI]Cu}2….…….92
Summary…………………………………………………………………...….……..94
Experimental Procedures…………………………………………………..………...97
References…………………………………………………………………...…...... 114
Chapter 3 Release of NO from S-nitrosothiols and Organic Nitrites at a β-Diketiminato
Copper(I) Complex ………….……………...……………………………………….....118
Abstract..………………………………………………………….……………...... 118
Introduction..………………………………………………………………..…...... 118
Results and Discussion……………...……………………………….………….....125
t 3.1. Reaction of BuONO with {[Me2NN]Cu}2. …..…………….…………...... 125
t 3.2. Reaction of BuONO with {[Me2NN]Cu}2, flushed with N2(gas)…………127
3.3. Reaction of Ph3CSNO with {[Me2NN]Cu}2……………………………….131
3.4. Reaction of Ph3CSNO with {[Me2NN]Cu}2, flushed with N2(gas)……….132
3.5. Isolation of decomposition products in reaction of Ph3CSNO with
{[Me2NN]Cu}2………………………………………………………………….134
3.6. Mechanistic considerations - comparison with related nickel(I) system…..139
Summary…………………………………………………………………...….……141
Experimental Procedures…………………………………………………..…….....142 ix References…………………………………………………………………...…...... 153
Chapter 4 Reaction of S-nitrosothiols and Nitric Oxide with Tris(pyrazolyl)borate
CopperComplexes…….…….……………...…………………………………………...157
Abstract..………………………………………………………….……………...... 157
Introduction………………..…………………………………..……….……...... 157
Results and Discussion……………...……………………………….………….....166
4.1. Synthesis and stability of TpiPrCuII-SR complexes…………….………...... 166
iPr2 I 4.2. Reactivity of Tp Cu + RSSR in the presence of O2…………………...... 171
4.3. Reactivity of TpiPrCuII-SR complexes with S-nitrosothiols………………..174
iPr II 4.4. Reactivity of Tp Cu -SR complexes with NOgas…………………………178
iPr I 4.5.Tp Cu reactivity with Ph3SNO……………………………………………181
iPr 4.6. Tp Cu(NO) reactivity with C6F5SNO………………………………….....183
4.7. Synthesis of Tp(CF3)2Cu complexes and initial reactivity studies………...... 185
Summary…………………………………………………………………...….……189
Experimental Procedures…………………………………………………..…….....190
References..………………………………………………………………...…...... 206
Chapter 5 S-Nitrosothiol and Nitrosonium Reactivity at Two Coordinate Copper(I)
Thiolates …...…………………………………………………………………………...211
Abstract..………………………………………………………….……………...... 211
Introduction………………..…………………………………..……….……...... 211
x Results and Discussion……………...……………………………….………….....220
5.1. Synthesis and characterization of copper(I) thiolates IPrCu(SR)……….....220
5.2. Trans-s-nitrosation reactions between IPrCu(StBu) and BnSNO……….....226
5.3. Trans-s-nitrosation reactions between IPrCuStBu and tBuSNO…………...229
5.4. Trans-s-nitrosation reactions between IPrCuSBn and BnSNO……………230
5.5. Variable temperature NMR spectroscopy exploring degenerate exchange
tBu tBu between IPrCuSCH2Ar and ArCH2SNO…………………………………..232
+ 5.6. Reactivity of copper-thiolates IPrCu(SR) with NOgas and NO ……………240
5.7. Reactivity of the one coordinate copper cation {IPrCu}+ with RSNOs…...246
Summary…………………………………………………………………...….……251
Experimental Procedures…………………………………………………..…….....253
References..………………………………………………………………...…...... 273
Appendix Synthesis of Copper β-Diketiminate and Anilidoimine Complexes……...... 277
Introduction………………..…………………………………..……….……...... 277
Preparation of compounds……………...……………………………….…………279
A.1. General experimental procedure for β -diketimine ligands (L1H-L3H)…...279
A.2. General experimental procedure for β -diketimine ligand L4H……………281
A.3. General experimental procedure for anilineimine ligands (L5H-L7H)...…282
A.4. General experimental procedure for anilineimine ligand L8H……………283
A.5. General experimental procedures to prepare lithium salts of β -diketimate
ligands (L3-L4) and anilidoimine ligands (L7-L8)……………………………..284
xi A.6. General procedure for the synthesis of LCu(MeCN) complexes L3Cu –
L8Cu……………………………………………………………………………287
I A.7. General procedure for [Cu ]2 complexes {L1Cu}2, {L2Cu}2, {L5Cu}2... ..289
References..………………………………………………………………...…...... 291
xii General Introduction
Organonitroso Compounds:
N-nitrosoamines, O-nitrosoalcohols, S-nitrosothiols.
Biological Activities, Chemical Properties, and Interactions with Metals
Abstract
N-nitrosamines, O-nitrosoalcohols, and S-nitrosothiols are three classes of related nitric oxide donors. The biological activities, syntheses, chemical properties as well as interactions with metals are reviewed for this important class compounds closely connected to nitric oxide itself.
Introduction
Nitric oxide, a simple diatomic gas, has much richer biological chemistry than initially expected. Just over twenty yeas ago this diatomic radical was thought to be simply a toxic gas—one of the constituents of acid rain, smog, and tobacco smoke. By
uterine relaxation cytostasis neurotransmission
gastrointestinal antiplatelet motility NO action
vasorelaxation immune function bronchodilation Figure I.1. Bioeffector functions of NO.
1 1988, however, it became widely accepted that nitric oxide was the important signaling
molecule in smooth muscle relaxation induction, thus serving as a potent vasodilator.1-4
Following this discovery, interest in the biology of nitric oxide grew at an extremely rapid pace which led to the identification of a rich collection of roles for this stable, simple inorganic radical. NO has been connected with immune function, hypertension, male impotence, septic shock, insulin-dependent diabetes mellitus, macrophage mediated destruction of oncogenic cells, and various nervous system activities (Figure I.1).5
The NO produced from the oxidation of L-arginine to L-citruline by various isoforms of nitric oxide synthase (NOS) has a lifetime of only 3-5 s in the blood.6 NO reacts with oxygen and oxygen containing enzymes to produce nitrates and nitrites
(Scheme I.1). Thus, a stable source for NO delivery is needed in the absence of nitric oxide synthase.
L-Arginine N-hydroxy-arginine L-Citrulline
Scheme I.1. Synthesis of NOgas in vivo from L-arginine to L-citrulline in the presence of O2, nitric oxide synthase (NOS), and NADPH.
2 The biochemistry of organic nitroso compounds (E-NO, E = RS, RO, R2N, R)
(Figure I.2) is connected to that of nitric oxide. These organic derivatives can serve either as sources of NO in vivo or produce similar effects as NO such as vasodilation. In contrast to free NO, these organic derivatives do not readily react with dioxygen.
Figure I.2. Family of organonitroso compounds.
I.1.a. N-Nitrosamines (R2NNOs) - biological applications.
N-nitrosamines with α-C-H atoms are generally considered to be carcinogenic.7,8
The established mechanism for carcinogensis is α-hydroxylation catalyzed by a variety of oxidzases and oxygenases such as cytochrome P450 and related enzymes. Decomposition
+ of the α-hydroxy- N-nitroso compounds produces powerful alkylating agents RN2 which
9 + can lead to DNA damage (Scheme I.2a). Spontaneous formation of the RN2 alkylating agent by R2NNO in vivo can also occur (Scheme I.2b). The release of NO by N-nitroso compounds in vivo can occur by denaturization and is carried out by the same cytochrome P450-related enzyme which accounts for 10-20% of total nitrosamine metabolism.10 After one-electron oxidation of the α-carbon atom, a highly unstable α-
• nitro amino radical is generated, which readily releases NO (Scheme I.2c).11
3 Scheme I.2. a) DNA alkylation pathway for R2NNO by cytochrome P450. b) DNA + alkylation pathway via spontaneous generation of RN2 alkylating agent. c) Denaturization by cytochrome P450 to form an unstable α-nitroso amino radical that readily releases NO.
N-nitroso-N-methylaniline has been shown to be an inhibitor of protein tyrosine phosphatases, papain, and caspase.10 The nitrosamine nitrosates the critical cysteine residues in the active site forming an S-nitrosothiol that results in enzyme inhibition. N- nitrosoindole can cause depurination, deamination, and the formation of a novel guanine analogue, oxaninie.12
I.1.b. N-Nitrosamines – syntheses.
N-nitrosamines can be synthesized by N-nitrosation of amines. Typical nitrosating agents
t 13-16 include N2O4, ClNO, RONO (R = Bu, Bu), and acidified nitrite (Scheme I.3a). N-
4 nitrosamine formation from their lithium amide precursors has been suggested as an
alternative route to the preparation of some nitrosamines (Scheme I.3b).17
Scheme I.3. Synthetic routes to N-nitrosamines.
I.1.c. N-Nitrosamines - chemical properties.
N-nitrosamines are known to take on planar structures due to a high rotational barrier about the N-N bond. These barriers are of similar magnitude to amides R2NC(O)R
‡ but the actual magnitude depends on the structure ( Gc = 14-25 kcal/mol, Tc = 36-170
b)N-N Rotational Barriers F3C NN NN
F3C O O ~ 5 kcal/mol 25 kcal/mol N O N NN O
16.5 kcal/mol < 6 kcal/mol
Figure I.3. a) Resonance structures of R2NNO. b) Several representative structures of R2NNO compounds with different values for the rotational barrier about the N-N bond.
5 °C) (Figure I.3a).18 A rotational barrier as low as ~ 5 kcal/mol has been reported for N- nitrosohexafluorodimethylamine19 and < 6 kcal/mol for N-nitroso-N-methylaniline
(Figure I.3b).20 These two examples exhibit a lower barrier to rotation due to the electron withdrawing groups present in the molecule. Bicyclic N-nitrosamines also exhibit lower values for the barrier to rotation than found in typical aliphatic compounds.21
• N-nitrosamines are potential NO /NO+ donors through homolytic or heterolytic cleavage of the N-NO bond (Scheme I.4). Lower barriers to rotation typically correspond to a lower N-NO hemolytic bond dissociation energies. Thus, aryl and bicyclic nitrosamines have higher NO-releasing potentials than the alkylnitrosamines. Studies have shown that the homolytic cleavage of N-NO bonds to give NO radical is thermodynamically more favorable by 23-45 kcal/mol than the heterolytic cleavage which generates NO+,9,22 though this would depend on the ability to solvate the resulting
- + R2N and NO charged species.
Scheme I.4. Heterolytic and homolytic decomposition of N-nitrosamines. I.2.a. O-Nitrosoalcohols (RONOs) - biological applications.
Organic nitrites RONOs are esters between alcohols and nitrous acid, some of which have been used as clinical vasodilators for a long time (Figure I.4).18 From a study comparing organic nitrates such as nitroglycerin and organic nitrites, the enzymes 6 responsible for vascular bioconversion of organic nitrates and organic nitrites to NO are
different.23 Organic nitrites are converted enzymatically to NO in vascular smooth muscle and the primary NO-generating activity is associated with the cytosol. In contrast, organic nitrates are metabolized by an enzyme associated with the plasma membrane.
Figure I.4. Examples of organic nitrites used as vasodilators in the clinical setting.
Organic nitrites can generate NO in vivo,24 requiring a one-electron reduction
(Scheme I.5, bottom). They also undergo rapid hydrolysis to give nitrite ion and the corresponding alcohol. The nitrite ion is not an active intermediate in vascular metabolism of nitrite esters but can be reduced to NO (Scheme I.5, top).10 S- nitrosothiols can be formed from organic nitrites in vivo via an enzymatic process in the vascular smooth muscle. Cytostolic GSTs can catalyze the reaction of RONO with R΄SH
Scheme I.5. NO• generation from organic nitrites.
7 to produce R΄SNO and play a significant role in the metabolism of organic nitrites in biological membranes (Scheme I.5, middle). Xanthine oxidase (XO) can catalyse the anaerobic reduction of organic nitrites to NO• (Scheme I.5, bottom).
I.2.b. O-Nitrosoalcohols – syntheses.
O-nitrosoalcohols can be synthesized by O-nitrosation of the corresponding alcohol.
Typical nitrosating agents include HNO2 (generated in situ from HNO3/H2SO4 or
2- 13,25 acidified NO ) or ClNO (Scheme I.6a). The reaction using HNO2 is the most common. We found that for the synthesis of bulky RONOs (e.g. 1-AdONO; 1-Ad = 1- adamantyl), the reaction of the lithium alkoxide LiOR with NOBF4 led to the desired product (Scheme I.6b).
Scheme I.6. Synthetic routes to O-nitrosalcohols.
1.2.c. O-Nitrosoalcohols – chemical properties.
The IR spectra of organic nitrites generally display two N=O stretching
-1 frequencies (νNO) in the 1610 - 1685 cm range due to presence of anti and syn isomers which are nearly equal in energy. The anti isomer occurs at a higher frequency compared to the syn, but the actual values depend on the R group attached to the oxygen atom
26 (Figure I.5). The presence of electron withdrawing groups shifts νNO to higher values.
8 Figure I.5. Organic nitrite syn/anti conformational preferences along with IR values for two comparative compounds. NMR spectroscopy can be used to assign anti and syn conformations in organic nitrites
and determine gas-phase and liquid-phase thermodynamic parameters ( H°, S°, G°).
The syn conformers of the linear Cl-C4 alkyl nitrites are more stable in both gas and liquid phases. For the sterically hindered isopropyl, isobutyl, and neopentyl nitrites, however, the anti conformer predominates.27
The homolytic bond dissociation energy of the RO-NO bond is between 36-41 kcal/mol.28 Organic nitrites are both light and heat sensitive causing homolysis of the O-
Scheme I.7. Nitroso dimer formation from photolysis of a tertiary alkyl nitrite.
9 NO bond. The proceeding steps differ in photolysis and thermolysis. The shape of the
compound also plays a role in the final product formation. The thermal decomposition of
alkyl nitrites usually yields predominantly the alcohol and carbonyl analogs. Photolysis,
however can lead to several different products. Tertiary organic nitrites form a nitroso
dimmer via an alkoxy radical rearrangement (Scheme I.7). Straight chained nitrites can
undergo δ-H-abstraction (Barton rearrangement)29-31 to form nitroso-alcohol products
(Scheme I.8). Cyclic nitrites can ring open to form linear nitroso aldehyde dimers32 or form rearranged nitroso-alcohol cyclic products.33
Scheme I.8. Formation of a C-nitroso alcohol product from photochemical induced δ-H atom abstraction of an organic nitrite.
10 1.3.a. S-Nitrosothiols (RSNOs) - biological applications.
S-nitrosothiols are biological metabolites of NO and were previously less well- known than their oxygen counterparts due to their general thermal and chemical instability. Special interest in S-nitrosothiols, however, was invigorated around 1990 when it was found that it is an endogenous carrier of NO involved in a range of physiological functions.34 RSNOs have been proposed to be NO storage, transfer, and delivery vehicles. Many NO related biological functions such as anti-platelet aggregation, vasodilation, and pre-eclampsia35 have been directly associated with RSNOs, either in the release of NO or as the RSNO itself.36
S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CySNO) are examples of endogenous RSNOs and are found in plasma at 0.02 - 0.2 and 0.2-0.3 M, respectively
Figure I.6. Examples of S-nitrosothiols with in vivo human plasma concentrations given for endogenous RSNOs. 11 (Figure I.6).37-39 Protein S-nitrosothiols that contain a primary cysteine residue such as S- nitrosoalbumin are significantly more stable than small S-nitrosothiol molecules.36 The exact reasons for this extra stability as well as the processes by which NO promotes glutathione modification through transnitrosation are not fully understood.
Trans-s-nitrosation is the transfer of the NO group from one SR group to another SR' group. This process is reversible and found to be first order in both the thiol and nitrosothiol.40 This process is important in the protein regulation through the modification of cysteine by S-nitrosation. The intermediate for this reaction is proposed to be a nitroxyl disulfide [RS(NO)SR']- (Scheme I.9) from ESI-MS, DFT calculations, and 15N NMR studies.41-44
Scheme I.9. Trans-s-nitrosation reaction between RS- and RSNO procedes through a nitroxyl disulfide intermediate [RS(NO)RS]-.
Copper-zinc superoxide dismutase (CuZnSOD) has been considered as a possible
Cu-enzyme that could catalyze the S-NO cleavage in vivo.45 CuZnSOD is an abundant enzyme in cells and is the major source of copper in human red blood cells46 present at a concentration of ca. 20 µM.47 The active site contains a Cu2+ ion bound to four histidine resiudes and has been identified as an active catalyst for low molecular weight RSNO decomposition.41,48 12 1.3.b. S-Nitrosothiols – syntheses.
S-nitrosothiols are generally synthesized from the reaction of thiol RSH with various nitrosating reagents XNO such as NOCl, N2O4, NO2, N2O3, HNO2, and R'ONO
(Scheme I.10a).13 S-nitrosation from reaction of RSNO and R'ONO is quantitative in
RSNO generation. As thiols often have a pungent odor and a few lower molecular weight ones (e.g. tBuSH) have an intense odor nearly indistinguishable from EtSH contained in natural gas, we have employed the use of non-volatile thallium thiolates TlSRs with
49,50 NOBF4 for the synthesis of a range of RSNOs (Scheme 1.10b).
Scheme I.10. Synthetic routes to S-nitrosthiols.
1.3.c. S-Nitrosothiols - chemical properties.
Most S-nitrosothiols, especially primary and secondary RSNOs, are unstable towards thermal loss of NO to form the corresponding disulfides RSSR. Such primary species such as S-nitroso-N-acetylcysteine do not have long shelf-lives and are usually
Figure I.7. S-nitrosothiols exhibit partial S=N bond character due to resonance which results in anti and syn isomeric forms. 13 Figure I.8. The syn and anti isomers of S-nitrosothiols can be independently characterized by 15N NMR and UV-Vis at 183 K and 298 K, Houk et al J. Am. Chem. Soc.2000, 122, 5889-5890. characterized only spectroscopically. In contrast, several tertiary RSNOs, including that
derived from N-acetylpenicillamine (SNAP), have been isolated and crystallized (Figure
I.9).
The S-NO bond exhibits significant double bond character due to the
delocalization of a sulfur lone pair onto the nitroso group (Figure I.7). This delocalization
allows the RSNOs to exist as syn and anti isomers. The structural preference for one
conformation over the other is dependent on the aliphatic substitution. Syn is preferred
for primary and secondary groups while anti is preferred for tertiary groups. This
suggests that the syn rotamer is favored on electronic grounds and the anti rotamer
minimizes steric interactions.
Variable temperature 15N NMR was used to study the syn / anti orientation equilibria for EtSNO, iPrSNO, tBuSNO (Figure I.8).51 All spectra from these three 14 compounds exhibited one broad peak in their 15N NMR spectra at room temperature.
When the temperature was lowered to -50 °C two sharp signals were resolved and were assigned to the syn and anti orientations of the RSNO structure. The primary and secondary RSNOs showed a preference for the upfield signal (syn orientation) and the tertiary RSNO showed a preference for the downfield signal (anti orientation). There are only seven crystal structures known for RSNOs including the structure S- nitrosohemoglobin.52 The SNO group in S-nitrosohemoglobin was modeled after the
SNO group in SNAP.53 This might need to be remodeled since nitroso group is on the primary cysteine residue and primary RSNOs favor the syn orientation.
The first reported high-resolution solid-state structure of an S-nitroso derivative of a cysteine or cysteinyl-containing compound reveals the geometry about the C-S-N=O group to be in the syn orientation with a dihedral angle of 2.4(3)° (Figure I.9).54 The X- ray crystal structure of S-nitrosocaptopril, a primary RSNO, reveals the geometry about the CSNO linkage to be in the syn orientation with a dihedral angle of 0.68°.51 The X-ray
55 crystal structure of SNAP (dihedral angle = 176.3°), ONSC(Me)2NHC(O) (dihedral
56 57 angle = 178.51°), and Ph3CSNO (dihedral angle = 175.7°) (Figure I.9) all reveal the geometry about the CSNO linkage to be in the anti orientation. A sterically encumbered, bowl-shaped triarylmethyl S-nitrosothiol, Ar3CSNO (Ar = 3,5-di(3,5- dimethylphenyl)phenyl) reveals both the anti and syn ortientation 0.67:0.33 in its X-ray crystal structure (Figure I.9).58
15 CySNO (1°) TritylSNO (3°) SYN ANTI
Ar3CSNO (3°) Ar3CSNO (3°) SYN (33 %) ANTI (67%)
Figure I.9. X-ray structures for the S-nitrosothiol of L-cysteine ethyl ester hydrochloride (EtCySNO), Ph3CSNO, and Ar3CSNO reveal the geometry about the RSNO bond.
Depending on the carbon substitution at the sulfur atom, RSNOs can be green
(tertiary) or pink (primary and secondary) in color. Their UV-Vis spectra typically show three bands – two intense bands in the UV and one weak band in the visible (Figure
I.8).51,52 Absorbances at wavelengths between 225-261 nm (ε ~ 104 cm-1M-1) are
* 3 -1 -1 attributed to the π → π transition, 330-350 nm (ε ~ 10 cm M ) are attributed to n0 →
* -1 -1 * π transition, and 550-600 nm (ε ~ 20 cm M ) are attributed to the forbidden nN → π
* transition. It is this low energy, weak nN → π transition determines the compound’s color.
Thermal and photochemical decompositions of RSNOs produce both the disulfide and NO. Homolytic cleavage was found to be generally ~29 kcal/mol lower in energy
16 than the corresponding heterolytic cleavage in acetonitrile (Figure I.10).59 Most S- nitrosothiols are unstable at room temperature and will decompose to give the disulfide and NO over time. Clean first-order kinetics were obtained for the decomposition of
RSNOs in the presence of a large excess of the corresponding thiol RSH.60 Measured enthalpies of activation ∆H≠ for a series of primary, seconday, and tertiary alkyl substituted RSNOs were only slightly lower than the theoretically calculated (DFT) homolytic bond dissociation energies of 30 – 33 kcal /mol.60 The use of a large excess of thiol to obtain reproducible kinetics suggests that there may be a bimolecular component to S-nitrosothiol decomposition. This is also consistent with the greater thermal stability of S-nitrosothiols with greater steric hinderance around the S-NO bond. Nonetheless, the measured activation parameters are inconsistent with a mechanism involving simple thermolysis to effect S-NO bond cleavage in biology – it is too slow. Moreover, little selectivity would be expected from purely thermally controlled S-NO cleavage.
Figure 1.10. Homolytic cleavage of the RS-NO bond is more facile than the heterolytic cleavage of the RS-NO bond.
Photolytic decomposition of RSNOs differ in aerobic vs. anaerobic environments.
In an anaerobic environment the S-NO bond homolytically cleaves, NO is released along with the thiyl radical, similar to thermal decomposition. In an aerobic environment the thiyl radical as well as NO can react with oxygen leading to more complex reaction
17 Scheme I.11. Photochemical decomposition of GSNO or RSNO in aerobic conditions yields disulfide and NO•.
pathways. When GSNO is irradiated by light at either 340 or 545 nm in the presence of
oxygen, GSOO• radical is first generated. This GSOO• radical can further react with another GSNO to form GSSG and NO (Scheme I.11).61
Under aerobic conditions, nitric oxide can react with dioxygen to form nitrous
62 anhydride (N2O3) (Scheme I.8). This molecule is believed to be the chain carrier involved in the chain-decomposition reaction of RSNOs.63 Kinetic data show that the rate of the chain reaction is independent of the concentration of RSNO and decreases with increasing bulkiness of the alkyl group. Thus, steric effects are prominent in the propagation step.
18 I.4.a. N-Nitrosamines - complexes with metals.
The interaction of nitrosamines with heme-containing biomolecules can result in
activation and/or denitrosation of the nitrosamines.7,8 In small molecule model complexes, nitrosamines may form intact R2NNO adducts with metal centers and have been shown to crystallize in three binding modes (Figure I.11). These intact R2NNO- metal complexes are formed by either attack of the nitrosamine on the metal or attack of an amide nucleophile on a metal-nitrosyl complex. The bonding mode for A has been shown for the reaction of Ph(Me)NNO with Na2PdCl4 (Figure I.11A). Adducts with O- bonding (Figure I.11B) mode have been isolated from the reaction of Me2NNO with the
52 following metal halide complexes: PdCl2, CuCl2, NiCl2, CoCl2, CdCl2, ZnBr2, AlCl3.
Adducts with N-bonding from the N=O nitrogen atom have been isolated and
- characterized from the reaction of [IrCl5] with a variety of typically unstable primary nitrosamines (Figure I.11D).64
A B C D
Figure I.11. Bonding modes in metal—nitrosamine complexes established by single- crystal X-ray crystallography. . In the crystal structure of the complex (Me2NNO)CuCl2 the Cu atoms are bridged by two chlorine atoms and the nitrosamine binding occurs via O-binding mode to one Cu and N-bonding mode to another (Figure I.11C).65,66 N-nitrosopiperidine complexes with
19 CuCl2 in an O,N-bonding mode where half of the Cu atoms are axially bonded to two N
atoms and the other half are axially bonded to two O atoms.67
Richter-Addo studied metalloporphyrin adducts of N-nitrosamines,
68 69 70,71 (porph)M(ONNR2) (M = Fe , Ru , Os ) (Scheme I.12). The first isolable metalloporphyrin complex was isolated from the reaction of excess Et2NNO and ferric porphyrin and displays O-bonding from the Et2NNO and Fe. The average N-O and N-N distances of the Et2NNO ligands (1.273 and 1.282 Å, respectively) suggest a significant contribution from the N=N resonance structure. Ruthenium and osmium carbonyl and nitrosyl nitrosamine complexes were also prepared and isolated, characterized by crystallography and various spectroscopic methods.
1 Scheme I.12. η -O binding of Et2NNO in M = Fe, Ru, O TTP or OEPs compounds.
20 I.4.b. O-Nitrosoalcohols and S-Nitrosothiols - complexes with metals.
Organic nitrites have long been used as nitrosating agents in coordination
chemistry in order to form metal-NO complexes as they are synthetically useful sources
+ of NO . Metal [M](RONO) complexes are less common than [M](R2NNO) complexes.
+ The reaction of alcohols with [IrCl3(NO)L2] leads to the formation of isolable
72 IrCl3(RONO)L2 (Scheme I.13a). Another example of an isolable M(RONO) complex
2+ 72 comes from the reaction of alkoxide ions with [Ru(bpy)2Cl(NO)] (Scheme I.13b).
Thus far, there is only one crystallographically characterized complex. In this X-ray structure, the organic nitrite is chelated to the Pd center through a metal-carbon bond
(Scheme I.13c).73
Alkyl nitrites and S-nitrosothiols both exhibit net trans addition of the RO-NO and RS-NO bonds to Ru and Os metalloporphyrins to give the corresponding
(por)M(NO)(SR) complexes.74,75 Mechanistic studies supported initial S-binding of the
RSNO to the metalloporphyrin center which then results in S-N bond cleavage to release
Scheme I.13. a) Reaction of ROH with [Ir](NO) leads to [Ir](RONO) b) Reaction of ROH with [Ru](NO) leads to [Ru](RONO) c) a [Pd](RONO) complex. 21 the stable NO radical which could then react with the 17-electron (por)M(CO)(SR)
intermediate to generate the observed nitrosyl product (Scheme I.13).76,77 The reaction of
S-nitroso-N-acetyl-L-cysteine methyl ester (RSNO) with ferrous (TPP)Fe(THF)2 only led to the generation of the known five-coordinate (TPP)Fe(NO) in almost quantitative
74 + yield, while the reaction of ferric [(TPP)Fe(THF2)] with isoamyl nitrite (RONO) resulted in the formation of the cationic nitrosyl alcohol complex [(TPP)Fe(NO)(HO-- i + 74 C5H11)] .
The first metal bound S-nitrosothiol was isolated from the reaction of benzylthiol
78 with the iridium nitrosyl K[IrCl5NO] (Scheme I.14). Benzyl-S-nitrosothiol is very unstable and readily dissociates to benzyl disulfide, BnSSBn and NO in air within 2 hr and 72 h anaerobically. When the benzyl-S-nitrosothiol is coordinated to the Ir center through the nitrogen, however, it is stable in acteonitrile and water over periods of weeks.
This work was further extended to include variety of coordinated nitrosothiols consisting of cysteine derivatives, mercaptosuccinic acid, benzyl thiol, and phenyl thiol.79 There were two structures possible in the case of the benzyl and phenyl-S-nitrosothiol, one
+ where all of the Cl atoms from the [Ir(Cl5)NO] remain coordinated to the Ir (Scheme
Scheme I.14. Reaction of RSH with [Ir](NO) to yield [Ir](N(O)SR). a) all other ligands are Cl- b) one Cl- is displaced by MeCN.
22 I.14A) and a second where one labile Cl- dissociates and is replaced by a coordinated
MeCN (Scheme I.14B). In the case of cysteine derivative thiols and mercaptosuccinic acid complexes form in A only.
Aim of Project
Understanding the mechanism by which E-NO compounds deliver NO is crucial for the effective treatment of diseases associated with disrupted regulation of NO and the future of NO delivery drugs. We have concentrated our efforts in understanding the reactivity of R2NNO, RONO, and RSNO with Ni and Cu model complexes. In particular, the copper chemistry is of high biological relevance due to its numerous roles in NO metabolism prescribed to copper ions and enzymes. Through the use of well defined model complexes, we aim to outline factors responsible for the cleavage and formation of
N-NO, O-NO, and S-NO bonds in this family of organonitroso compounds E-NO.
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29 Chapter 1
Reductive Cleavage of O-, S-, and N-Organonitroso Compounds by
Ni(I) β-Diketiminates
Abstract
An electron-rich nickel(I) β-diketiminate cleaves the E-NO bond of O-, S-, and N- organonitroso species to give the nickel-nitrosyl [Me3NN]Ni-NO along with dimeric nickel(II)-alkoxide or thiolate complexes {[Me3NN]Ni}2(µ-E)2 or the mononuclear nickel(II)-amide [Me3NN]Ni-NPh2. This diamagnetic, three coordinate amide exhibits temperature dependent NMR spectra due to a low lying triplet state.
Introduction
Stamler and others recognized S-nitrosothiols (RSNOs) in the early 1990s to serve as potent sources of NO in vivo.1-3 In contrast to O- and N-nitroso derivatives, S- nitrosothiols can thermally expel NO with concomitant formation of the corresponding disulfide (Scheme 1.1) due to the relative weakness of the RS-NO bond (31-32 kcal/mol)4 and strength of RS-SR bond (65-66 kcal/mol).5 This leads to relatively short lifetimes for
RSNOs, though they circulate at ca. 0.2 µM in human plasma.6,7
Organic nitrites (RONOs) and N-nitrosamines (R2NNOs) are much more thermally stable than S-nitrosothiols and typically require a reducing equivalent or photolysis8 to release NO (Scheme 1.1). This reflects their higher E-NO homolytic
t 9 10 dissociation energies (e.g. BuO-NO = 40.9(8) and Ph2N-NO = 87.7 kcal/mol ). As release of NO from many organonitroso compounds requires a reducing equivalent, it
30 Scheme 1.1. NO formation from O-, S-, and N-organonitroso compounds.
suggests a role for metalloenzymes in their metabolism. Each of these three classes of
organonitroso substances is known to interact with heme-containing biomolecules11-14 and copper ions are implicated in the catalytic decomposition of S-nitrosothiols.15
While N-nitroso compounds typically form intact E-NO adducts with metal complexes, O-nitroso and S-nitroso compounds commonly undergo E-NO bond cleavage serving as nitrosating agents in metal-nitrosyl synthesis.11 For instance, metalloporphyrin
16 17 18,19 adducts of N-nitrosamines (porph)M(ONNR2) (M = Fe , Ru , Os ) are known while
RONOs and RSNOs react to give a net trans-addition to form trans-(porph)M(NO)(E) (E
= OR or SR) species (Schemes I.9 and 1.2).20-26
Mechanistic studies of NO transfer from the stable S-nitrosothiol Ph3CSNO to a
a) b)
Scheme 1.2. a) Contribution of the dipolar resonance form of diethyl nitrosamine in its binding to ferric porphyrins. b) Trans addition of RENO compounds to porphyrin. 31 Co(II) porphyrin suggests that Co-NO bond formation proceeds via concerted homolytic
14 S-NO bond cleavage (Scheme 1.3). In the case of nickel, polymeric [(RS)Ni(NO)]x
27 species have been obtained upon the reaction of Ni(CO)4 with RSNOs.
Scheme 1.3. A cleavage of the Ph3CS-NO bond to form a [Co](NO) complex. S-NO bond cleavage is first thought to go through an N-bound RSNO-Co complex. . Employing the β-diketiminate framework, Pooja Kapoor in the Warren group has found that related C-nitroso compounds such as 3,5-dimethylnitrosobenzene react with
8 I 6 two equivalents of the d [Me2NN]Co (η -toluene) to undergo a four-electron reductive
a)
b)
6 Scheme 1.4. a) Activation of the ArN=O bond by 2 equiv. [Me2NN]Co(η -toluene). b) Synthesis of [NN]Ni(NO). . 32 III 28 cleavage of the ArN=O bond to give {[Me2NN]Co }2(µ-NAr)(µ-O) (Scheme 1.4a).
9 I Since the addition of NOgas to related d β-diketiminato Ni complexes results in the formation of stable [β-diketiminato]Ni(NO) species (Scheme 1.4b),29 the reducing ability of the [β-diketiminato]NiI fragment coupled with its low-coordination number was tested for clean 1-electron reactions with organonitroso compounds.
Results and Discussion
1.1. Reaction of [Me3NN]Ni(2,4-lutidine) with CyONO and AdSNO.
Careful addition of 1.0 equiv CyONO or AdSNO to 2.0 equiv [Me3NN]Ni(2,4- lutidine) (1) in toluene at room temperature results in the formation of green solutions.
Green crystals also immediately precipitate from the solution with CyONO whereas purple crystals form after standing at room temperature overnight with AdSNO. X-ray characterization of each solid substance identifies them as {[Me3NN]Ni}2(µ-OCy)2 (2)
(83% yield) and {[Me3NN]Ni}2(µ-SAd)2 (3) (88% yield), respectively (Scheme 1.5).
1 When these reactions are performed in benzene-d6, H NMR analysis shows that
29 [Me3NN]Ni(NO) (4) is formed in > 90% yield based on integration of its characteristic
Scheme 1.5. Activation of the E-NO bond by 2 equiv [Me3NN]Ni(2,4-lutidine) to form [Me3NN]Ni(NO) (4) and ½ equiv {[Me3NN]Ni}2( -E)2 (2 or 3). . 33 β-diketiminato backbone C-H resonance at δ 4.40 ppm against an internal standard.
Despite the steric bulk of the cyclohexyl alkoxide and adamantyl thiolate ligands, the X-ray structures of 2 and 3 consist of [Me3NN]Ni-E (E = OCy, SAd) dimers related by inversion symmetry (Figures 1.9 - 1.11). The asymmetric unit in the X-ray structure of 2 consists of two unique monomeric [Me3NN]Ni-OCy units. Both 2 and 3 show pseudo- tetrahedral coordination at nickel (twist angles between N-Ni-N / E-Ni-E planes:
81.1° and 83.0° for 2, 70.7° for 3), but have distinct Ni…Ni separations of 3.050(1) and
3.072(1) Å (for 2) and 3.559(1) Å (for 3). This is partially a result of the considerably shorter Ni-O bond distances spanning 1.955(2) - 1.994(2) Å in 2 relative to the longer Ni-
S distances of 2.318(1) and 2.303(8) Å in 3.
1.2. Reaction of [Me3NN]Ni(2,4-lutidine) with Ph2NNO.
In contrast to reactions with CyONO and AdSNO which produce very insoluble dimeric products, the reaction between 1.0 equiv Ph2NNO and 2.0 equiv [Me3NN]Ni(2,4- lutidine) (1) in benzene-d6 results in a deep blue-violet, homogeneous solution. We anticipated that [Me3NN]Ni-NPh2 (5) would form along with the nickel nitrosyl 4
1 (Scheme 1.6). H NMR analysis shows [Me3NN]Ni-NO (4) in > 90% yield along with
Scheme 1.6. Activation of the Ph2N-NO bond by 2 equiv [Me3NN]Ni(2,4-lutidine) to form [Me3NN]Ni(NO) (4) and [Me3NN]Ni-NPh2 (5).
34 broad resonances for 2,4-lutidine. Attempts at crystallization failed to produce X-ray
quality crystals of any new product.
1.3. Independent synthesis of [Me3NN]Ni-NPh2 and reactivity with 2,4-lutidine.
The Ni(II)-amide 5 can be synthesized independently by addition of LiNPh2 to
[Me3NN]NiI(2,4-lutidine) (prepared from addition of NiI2 and 2,4-lutidine to
[Me3NN]Tl) in THF (Scheme 1.7). Crystallization of the product from pentane provided the nickel-amide [Me3NN]Ni-NPh2 (5) as deep blue crystals in 59% yield. The X-ray structure of three-coordinate 5 exhibits short Ni-Namido (1.823(1) Å) and Ni-Nβ-dik
(1.826(1) and 1.833(3) Å) distances. The Namido atom is planar (sum of angles about N =
358.1(1)°) with one of the two N-aryl rings coplanar with the other twisted out of the Ni-
N-C plane by 65.9° (Figure 1.12).
Scheme 1.7. Independent synthesis of 5 via [Me3NN]NiI(2,4-lutidine) with LiNPh2.
Following the addition of Ph2NNO to 1 by UV-Vis spectroscopy in Et2O
-1 -1 demonstrates that [Me3NN]Ni-NPh2 (5) (λmax = 375 nm; ε = 6770 M cm , λ = 598 nm; ε
= 2210 M-1cm-1) is formed in the presence of 2,4-lutidine (Figure 1.1, Scheme 1.6). In
-1 -1 addition, [Me3NN]Ni(NO) (4) is observed at λmax = 445 nm (ε = 2000 M cm ).
[Me3NN]Ni-NPh2 (5) exhibits rich solution behavior. Despite the diamagnetic
30 1 nature of benzene-d6 solutions of 5 (µeff = 0.0 B.M. at RT by the Evans method), H
NMR spectra of 5 prepared from [Me3NN]Ni(I)(2,4-lutidine) invariably show broad 35 Reaction of 2 [Me3NN]Ni(2,4-lutidine) + Ph2NNO Et2O, 25 °C
2 [Me3NN]Ni(2,4-lutidine) + Ph2NNO
Pure Compound λmax(nm) Amax -1 -1 ε[Me (cm3NN]Ni(NPhM ) 2) 375 1.653 5800 399 1.535 4000 [Me3NN]Ni-NO 598 0.163 2200 [Me3NN]Ni-NPh2 + 2 2,4-lutidine Absorbance (scaled)
[Me3NN]Ni-NO + 2 2,4-lutidine
Wavelength (λ, nm)
Figure 1.1. UV-Vis studies in Et2O to confirm presence of [Me3NN]Ni-NPh2 (5) and [Me3NN]Ni(NO) (4) in reaction of [Me3NN]Ni(2,4-lutidine) and Ph2NNO.
peaks devoid of coupling information (Figure 1.2). We believe this to be due to trace
amounts of 2,4-lutidine present in samples of 5 prepared from [Me3NN]NiI(2,4-lutidine) which can lead to a rapid equilibrium between [Me3NN]Ni-NPh2 5 its 2,4-lutidine adduct
[Me3NN]Ni(NPh2)(2,4-lutidine) 6 (Figure 1.2).
To avoid the possibility of any exchange broadening in NMR spectra of 5 by 2,4- lutidine, we prepared 5 in a one-pot procedure in 53% yield under conditions excluding
Scheme 1.8. Synthesis of 5 under 2,4-lutidine free conditions. 36 µeff~ 2.8 B.M. µeff = 0.0 B.M. (predicted) (H.S.-d8)
* [Me3NN]Ni-NPh2 + 2,4-lutidine (1 equiv)
[Me3NN]Ni-NPh2 + 2,4-lutidine (0.1 equiv)
1 [Me3NN]Ni-NPh2 H NMR benzene-d6 0.01.02.03.04.05.06.07.08.09.0
1 Figure 1.2. H NMR spectra (300 MHz, benzene-d6) of [Me3NN]Ni-NPh2 with 2,4- lutidine present in the solution in varying amounts (0 eq., 0.01 eq., 1 eq.). (* indicates residual solvent peak).
this Lewis base (Scheme 1.8). Addition of incremental amounts of 2,4-lutidine up to 1
equiv per 5 results in increased broadening followed by complete disappearance of all 1H
NMR resonances attributed to 5 (Figure 1.2). Moreover, the effective magnetic moment of this solution increases to 1.3 B.M. (based on 5) when a full equivalent of 2,4-lutidine is present. The decrease in the UV-vis band of 5 at λ = 598 nm in the presence of an excess of 2,4-lutidine (Figure 1.3) also supports the formation of a Lewis base adduct.
Presumably this sterically encumbered adduct 6 would be tetrahedral with an expected
37 spin-only magnetic moment of 2.8 B.M. (Figure 1.2). A Job plot experiment was
conducted in order to unambiguously determine the stoichiometry of the 2,4-lutidine
adduct of 5. These results suggest that the 2,4-lutidine binds in a 1:1 ratio to 5 (Figure
1.4).
38 0.45
0.4
0.35
0.3
0.25
0.2 Absorbance 0.15 1. [Me NN]Ni-NPh 2. [Me3NN]Ni-NPh2 3 2 + 0.1 1 equiv. 2,4-lutidine
0.05 3. [Me NN]Ni-NPh + 10 equiv. 2,4-lutidine 0 3 2 350 400 450 500 550 600 650 700 750 800 Wavelength (λ, nm)
Figure 1.3. UV-Vis spectra in Et2O at room temperature for the solution studies of [Me3NN]Ni-NPh2 (5) with added 2,4-lutidine (0, 1, 10 equiv).
2 3 Job Plot 1.75 2 3 1.75 1.5 1.5 1.25
1 4 1.25 0.75 2 4 0.5 1 1 0.25 5
Absorbance (396 nm) 0 Absorbance 0 0.25 0.5 0.75 1 0.75 2 Mole Fraction of [Me3NN]Ni-NPh2
0.5 1
0.25 5 0 350 400 450 500 550 600 650 700 750 800 Wavelength (λ, nm)
Figure 1.4. Job plot of 2,4-lutidine with [Me3NN]Ni-NPh2 (5) to determine the stoichiometery of the binding interaction between 2,4-lutidine and 5. 39 1.4. Electronic properties of [Me3NN]Ni-NPh2.
1 Room temperature H NMR spectra of lutidine-free 5 in toluene-d8 show sharp signals expected for a diamagnetic species, but many appear at chemical shifts considerably different than in other related diamagnetic complexes such as
[Me3NN]Ni(NO) (4). For instance, the backbone C-H resonance in 5 occurs at δ 1.83 ppm whereas it appears at δ 4.40 ppm in 4. Moreover, this and many other chemical
m-H (β-diketiminate) o-Me p-Me m-NPh2 25 °C
10 °C
-10 °C
-30 °C
-50 °C
-70 °C * o-NPh2 p-NPh2 CH-backbone CH3-backbone 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 1 Figure 1.5. Variable temperature H NMR spectra of [Me3NN]Ni-NPh2 (300 MHz, toluene-d8). 40 Figure 1.6. d-orbital splitting diagram for the low spin (5 – L.S.) and high spin (5 – H.S.) states of 5. The two highest levels are the dxz and the dyz.
shifts in 5 such as the o- and p-NPh2 resonances are particularly temperature sensitive
(Figure 1.5). Upon cooling to – 70 °C, the backbone C-H resonance migrates to δ 4.39 ppm and the p-NPh2 signal moves from δ 5.67 (RT) to 7.03 ppm (Figure 1.5)
We attribute this behavior to contact shifts from a minute contribution of the high- spin state of [Me3NN]Ni-NPh2 (5 – H.S.) which increases with increasing temperature
(Figure 1.6). Both low-spin and high-spin three-coordinate β-diketiminato nickel-amides
31 32 have been isolated such as [Me3NN]Ni-N(Cp2Co)Ad) and LNi-N(TMS)2, respectively. While density functional theory (DFT) studies on [Me3NN]Ni-NPh2 suggest that the low-spin form is favored by 8 kcal/mol (Figure 1.7), the β-diketiminato central backbone as well as the o- and p-NPh2 C atoms bear significant electron density in the two “singly occupied” Kohn-Sham molecular orbitals (MOs) of 5 – H.S. (Figure
1.8).
41 [Me3NN]Ni-NPh2 S = 0 [Me3NN]Ni-NPh2 S = 1, +8.1 kcal/mol (5- L. S.) (5- H. S.) Ni-N1 1.793 Å N1-Ni-N3 121.3° Ni-N1 1.833 Å N1-Ni-N3 131.3° Ni-N2 1.790 Å N1-Ni-N3 144.6° Ni-N2 1.833 Å N1-Ni-N3 126.8° Ni-N3 1.785 Å N1-Ni-N3 94.4° Ni-N3 1.814 Å N1-Ni-N3 97.1°
Figure 1.7. DFT structures of low-spin (5 – L.S.) and high-spin (5 – H.S.) [Me3NN]Ni-NPh2. (ADF ZORA BP/TZ2P(+)). The high-spin S = 1 form is calculated to be 8.1 kcal/mol higher in electronic energy. DFT optimized distances and angles are also collected.
42 5 – H.S. HOMO-1 (spin α: -4.33 eV) 5 – H.S. HOMO (spin α: -3.72 eV)
5 – L.S. HOMO (-4.05 ev) 5 – L.S. LUMO (-3.08 eV)
Figure 1.8. Contour plots of frontier KS - molecular orbitals for 5 – H.S. (HOMO-1 and HOMO, top) and 5 – L.S. (HOMO and LUMO, bottom) and along with orbital energies.
43 1.5. Mechanistic considerations.
We propose three possible routes by which the E-NO bond of N-, O-, and S- nitroso compounds E-NO can be reductively cleaved by 2 equiv. [Me3NN]Ni(2,4- lutidine) to give [Me3NN]Ni(NO) and [Me3NN]Ni-E (or ½ {[Me3NN]Ni}2(µ-E)). While we are unsure of the exact binding mode of a putative [NiI](ENO) adduct, it is likely that the E-NO compound comes into contact with the Ni(I) center prior to E-NO bond cleavage. First, we considered the formation of [Ni](NO) which leaves the E• radical to combine with a second equiv of [Ni](2,4-lutidine) (Scheme 1.9, Mechanism A). In the second route, [Ni]-E would first form to release free NO• which is then trapped by
Mechanism A
[Me3NN]Ni(2,4 lutidine) + E NO [Me3NN]Ni(NO) + E 2,4 lutidine II [Me3NN]Ni(2,4 lutidine) + E [Me3NN]Ni (E) 2,4 lutidine Mechanism B II [Me3NN]Ni(2,4 lutidine) + E NO [Me3NN]Ni (E) + NO 2,4 lutidine
[Me3NN]Ni(2,4 lutidine) + NO [Me3NN]Ni(NO) 2,4 lutidine Mechanism C E [Me3NN]Ni(2,4 lutidine) + E NO [Me3NN]Ni 2,4 lutidine NO
[Me3NN]Ni(2,4 lutidine)
[Me3NN]Ni(NO) + II [Me3NN]Ni (E)
Scheme 1.9. Three possible mechanisms for E-NO bond cleavage by [Me3NN]Ni(2,4- lutidine).
44 [Ni](2,4-lutidine) to form [Ni](NO) (Scheme 1.9, Mechanism B). The third mechanism
features a longer lived [Ni](E-NO) intermediate that requires an additional [Ni] fragment
to activate the E-NO bond, forming a strict 1:1 ratio of [Ni](NO) and [Ni]-E (Scheme 1.9,
Mechanism C).
The reactions presented in Sections 1.1 and 1.2 feature a 2:1 [Ni] : E-NO ratio.
Subsequently, we analyzed the amount of [Ni](NO) that forms when the stoichiometery
of Ni(I) : E-NO was varied (1:2, 1:1, and 2:1) by 1H NMR using naphthalene as an internal standard for these three organonitroso compounds (E = OCy, SAd, NPh2). When
1 equiv [Me3NN]Ni(2,4-lutidine) reacts with 1 equiv of E-NO, [Me3NN]Ni(NO) forms in
>80% yield (based on the moles of Ni). This suggests that mechanism B and C are not the correct route for this reaction. Mechanism B is ruled out as in the absence of an extra equivalent of Ni(I) the [Me3NN]Ni(NO) forms first, consumes the majority of the Ni(I), and leaves behind the E• (not detected as major product). Mechansim C is ruled out because a 1 : 1 ratio of [Ni] : E-NO, we would expect both [Me3NN]Ni(NO) and
[Me3NN]Ni(E) to form in 25 % yield with the other 50% of [Ni] unreacted. This leaves mechanism A as the best option for the cleavage of the E-NO bond by Ni(I). Further support of mechanism A is shown by the reaction of 2 equiv of E-NO (E = OCy, SAd,
NPh2) with 1 equiv of Ni(I)-lutidine: [Me3NN]Ni(NO) is formed in 88-92 % yield (based on the moles of Ni).
Scheme 1.10. Further support of Mechanism A where [Ni](NO) forms preferentially over [Ni]-E. In the presence of 1 equiv of E-NO the only observed nickel containing species is the [Ni](NO). 45 Summary
I The electron-rich Ni β-diketiminate [Me3NN]Ni(2,4-lutidine) reductively cleaves the E-NO bond of O-, S-, and N-organonitroso compounds to give the nickel nitrosyl
[Me3NN]Ni(NO) and corresponding [Me3NN]Ni-E species. This behavior contrasts with
33 II 34,35 II 36 the reductive nitrosylation observed by Ford involving Cu -OR and Cu -NR2 species which react with NO to give the corresponding O- and N-organonitroso species along with CuI complexes. Such reactivity at related β-diketiminato CuI complexes will be explored in Chapters 2 and 3.
46 N2΄ O1΄ N1 Ni΄ Ni N1΄ O1 N2
Figure 1.9. X-ray structure of one of the two independent molecules of {[Me3NN]Ni}2(µ-OCy)2 found in the solid-state structure of 2 (all H atoms omitted). Selected bond distances (Å) and angles (deg): Ni1–O1 1.994(2), Ni1–O1´ 1.963(2), Ni1– N1 1.971(2), Ni1–N2 1.957(2), N1–Ni1–N2 92.70(9), O1–Ni1–O1´ 77.38(8), N2–Ni1– O1´ 116.60(9), N1–Ni1–O1´ 137.33(9), N2–Ni1–O1 118.55(9), N1–Ni1–O1 116.64(9).
47 N4΄ N3 O2΄ Ni2΄ Ni2 O2 N3΄ N4
Figure 1.10. X-ray structure of one of the two independent molecules of {[Me3NN]Ni}2(µ-OCy)2 found in the solid-state structure of 2 (all H atoms omitted). Selected bond distances (Å) and angles (deg): Ni2–O2 1.955(2), Ni2–O2´ 1.972(2), Ni2– N3 1.964(2), Ni2–N4 1.974(2), N3–Ni2–N4 92.50(10), O2–Ni2–O2´ 77.06(9), N4–Ni2– O2´ 120.25(9), N3–Ni2–O2´ 115.01(9), N4–Ni1–O1´ 137.38(9), N3–Ni2–O2 116.78(9). 48 N2΄ S1΄ N1 Ni Ni ΄ N1΄ S1 N2
Figure 1.11. X-ray structure of {[Me3NN]Ni}2(µ-SAd)2 (3) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Ni1–S1 2.318(8), Ni1–S1´ 2.303(8), Ni1– N1 1.953(2), Ni1–N2 1.950(2), N1–Ni1–N2 93.81(9), S1–Ni1–S1´ 79.26(3), N2–Ni1– S1´ 108.76(6), N1–Ni1–S1´ 144.00(7), N2–Ni1–S1 123.22(7), N1–Ni1–S1 111.79(6).
49 N1 C24 N3 C30 Ni N2
Figure 1.12. X-ray structure of [Me3NN]Ni-NPh2 (5) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Ni1–N1 1.833(2), Ni1–N2 1.826 (2), Ni1–N3 1.823(1), N3–C24 1.421(1), N3–C24 1.406(2), N1–Ni1–N2 94.28(6), N3–Ni1–N1 121.08(7), N3–Ni1–N2 144.61(7), Ni–N3–C24 113.5(2), Ni–N3–C30 126.6(2).
50 N1
Ni N3
N2 I
Figure 1.13. X-ray structure of [Me3NN]Ni(I)(2,4-lutidine)•(Et2O) (all H atoms and ether molecule in the crystal lattice omitted). Selected bond distances (Å) and angles (deg): Ni1–N1 1.953(2), Ni1–N2 1.949 (3), Ni1–N3 2.046(3), Ni1–I1 2.569(6), N2–Ni1–N1 94.86(9), I1–Ni1–N3 116.04(8).
51 Table 1.1 Crystallographic parameters for 2, 3, 5, and 7. Compd. 2 3 5 7
Formula C58H80 N4Ni2O2 C33 H44 N2NiS C35H39N3Ni C30H38I N3Ni,
C4H8O Mol. Wt. 982.68 559.47 560.40 700.36 Temp.(K) 100(2) 173(2) 173(2) 173(2) Crystal Block Block Block Plate description Crystal color Green Purple Blue Green Crystal size 0.0096 0.0392 0.0370 0.0017 (mm3) System Monoclinic Monoclinic Monoclinic Monoclinic Space group P2(1)/c P2(1)/n P2(1)/n P2(1)/n a (Å) 13.0521(12) 15.202(3) 11.144(2) 15.691(4) b (Å) 19.2644(17) 12.297(3) 16.469(4) 8.4554(19) c (Å) 20.7729(19) 15.767(4) 16.532(4) 26.077(6) α (deg) 90 90 90 90 β (deg) 95.5150(10) 92.331(3) 91.421(3) 100.823(4) γ (deg) 90 90 90 90 Volume (Å3) 5199.0(8) 2945.1(12) 3033.2(11) 3398.0(13) Z 4 4 4 4 θ range (deg) 1.44-28.00 2.10-27.00 2.18-27.00 1.59-27.00 Measd reflns 46529 24338 25619 27864 Unique reflns 12405 6429 6619 7391 GOF of F2 1.099 1.024 0.944 1.076
R1 ( I > 2σ(I)) 0.0506 0.0453 0.0350 0.0431 wR2 (all data) 0.1527 0.1180 0.0912 0.1036 Largest diff. 1.660 and - 0.971 and - 0.490and – 1.009 and - peak and hole 0.676 0.565 0.287 0.744 (e-.Å-3) 52 Experimental Procedures
General experimental details.
All experiments were carried out in a dry nitrogen atmosphere using an MBraun
glovebox and/or standard Schlenk techniques. 4A molecular sieves were activated in
vacuo at 180 ºC for 24 h. Dry toluene and dichloromethane were purchased from Aldrich
and were stored over activated 4A molecular sieves under nitrogen. Diethyl ether and
tetrahydrofuran (THF) were first sparged with nitrogen and then dried by passage through
1 activated alumina columns. Pentane was first washed with conc. HNO3/H2SO4 to remove olefins, stored over CaCl2 and then distilled before use from sodium/benzophenone. All deuterated solvents were sparged with nitrogen, dried over activated 4A molecular sieves and stored under nitrogen. 1H and 13C NMR spectra were recorded on either a Varian 300 MHz or 400 MHz spectrometer (300 or 400 and 75.4 or
100.4 MHz, respectively). All NMR spectra, including Evans method data, were recorded at room temperature unless otherwise noted and were indirectly referenced to TMS using residual solvent signals as internal standards. GC-MS spectra were recorded on a Varian
Saturn 2100T, elemental analyses were performed on a Perkin-Elmer PE2400 microanalyzer in our laboratories, and UV-Vis spectra were recorded on either an Agilent
8432 or a Cary 50 spectrophotometer.
Cyclohexanol, diphenylamine, tert-butylnitrite, 1.6 M n-butyllithium, sodium metal, and elemental iodine were obtained from Acros, anhydrous NiCl2 from Strem, and
31 2,4-lutidine from Aldrich; all were used as received. [Me3NN]Ni(2,4-lutidine),
31 37,38 Tl[Me3NN], and AdSH were synthesized according to published procedures. 53 Preparation and characterization of compounds.
CyONO. CyONO was synthesized according to the reported procedure for synthesis of
RONO (R = ethyl, tert-butyl, isopropyl) from an acidic solution of sodum nitrite.39 CyOH
(10.020 g, 0.100 mol) in 18 M H2SO4 (2.78 mL, 0.050 mol) and H2O (2.00 mL, 0.111 mol) was added dropwise to a stirring solution of NaNO2 (10.500 g, 0.152 mol) in 50 mL
H2O at 0 ºC. The solution was stirred for one hour and then allowed to separate into two
layers. 20 mL of pentane was added to the reaction mixture and the organic layer was
separated from the water layer. The organic layer was washed twice with saturated
aqueous Na2CO3 and 25 mL of brine. The organic layer was dried over Na2SO4 and filtered through silica gel to remove any remaining alcohol. The pentane was removed in
1 vacuo to yield a yellow oil, 10.45 g, 81% yield. H NMR (benzene-d6, 400 MHz, 25 °C):
5.039 (m, 1, C(1)H), 1.652 (m, 2, C(2)H), 1.494-1.440 (m, 2, C(3)H), 1.374-1.307 (m, 2,
C(2)H), 1.293-1.221 (m, 1, C(4)H), 1.145-1.043 (m, 2, C(3)H), 1.028-0.995 (m, 1,
13 C(4)H). CNMR (benzene-d6, 100.4 MHz, 25 °C): δ 77.95 (C1), 32.32 (C2), 25.32 (C4),
-1 23.84 (C3). IR (cm ): νNOsyn 1599, νNOanti 1635. Organonitrites typically exhibit two bands for vNO, with the anti (trans) conformation at higher energy than the syn (cis) conformation.11,40
41 t Ph2NNO. BuONO (30.50 g, 0.300 mol) was added to Ph2NH (5.00 g, 0.030 mol) until all of the amine dissolved. The solution was stirred for 30 minutes and the tBuOH and excess tBuONO were removed in vacuo leaving a yellow/orange solid (5.524 g, 93%
1 yield). H NMR (benzene-d6, 400 MHz, 25 °C): δ 7.248 (m, 4, m-ArH), 7.029-6.899 (m,
54 13 2, p-ArH), 6.684 (m, 2, o-ArH). CcNMR (benzene-d6): δ 143.24, 137.40, 129.65,
129.39, 129.07, 127.82, 126.61, 119.78.
AdSNO.42 tBuONO (2.09 g, 20.3 mmol) was added to the stirring solution of AdSH
(1.00 g, 5.08 mmol) in 8 mL CH3CN and at -35 ºC. The solution was allowed to stir for
15 minutes. The solvent was removed in vacuo and the residue was extracted with ether
(2 × 5 mL) and filtered. The solution was concentrated to ca. 2 mL. The solution was left to crystallize at –35 °C overnight. The mother liquor was removed and the crystals were dried in vacuo to afford at total yield of 876 mg (76 %) green crystals. The product was
1 stored in the dark at -35 ºC to avoid disulfide formation. H NMR (benzene-d6, 400 MHz,
13 1 25 °C): δ 2.300 (d, 6, C(2)H2), 1.923 (m, 3, C(3)H), 1.503 (d, 6, C(4)H2). C{ H}NMR
(benzene-d6): δ 55.51 (C1), 43.55 (C2), 36.31 (C4), 30.25 (C3).
Synthesis of {[Me3NN]Ni}2(µµµ-OCy)2 (2). CyONO (19 mg, 0.150 mmol) in 3 mL toluene was added dropwise to [Me3NN]Ni(2,4-lutidine) (150 mg, 0.301 mmol) in 5 mL toluene.
The red solution turned green immediately and a precipitate formed after the solution sat at room temperature for 30 min. X-ray characterization of the green crystals formed allows their identification as [Me3NN]Ni2(µ-OCy)2 (63 mg, 83% yield). The product is too insoluble for further spectroscopic characterization. Anal. Calcd for C58H80N4Ni2O2:
C, 70.89; H, 8.21; N, 5.70. Found: C, 70.89; H, 8.55; N, 5.70. Single crystal X-ray unit cell data (at 100 K): a = 13.052(2) Å, b = 19.264(2) Å, c = 20.773(2) Å, α = γ = 90°, β =
95.515(2)°, V = 5199.0(8) Å3; space group P2(1)/c.
Synthesis of {[Me3NN]Ni}2(µµµ-SAd)2 (3). AdSNO (30 mg, 0.150 mmol) in 3 mL toluene
55 was added dropwise to a solution of [Me3NN]Ni(2,4-lutidine) (150 mg, 0.301 mmol) in 5 mL toluene. The red solution turned purple/green immediately and a purple precipitate formed after the solution sat at room temperature overnight. The resulting solution is green. X-ray characterization of the purple crystals formed allowed their identification as
-1- -1 [Me3NN]Ni2(µ-SAd)2 isolated in 88% yield (74 mg). UV-Vis (CH2Cl2, nm (M cm )):
657 (2540), 542 (3570), 375 (9430). Anal. Calcd for C66H88N4Ni2S2: C, 70.84; H, 7.93;
N, 5.01. Found: C, 70.66; H, 7.89; N, 4.81. Single crystal X-ray unit cell data (at 173 K): a = 15.202(3) Å, b = 12.297(3) Å, c = 15.767(4) Å, α = γ = 90°, β = 92.331(3)°, V =
2945.1(12) Å3; space group P2(1)/n.
Reaction of [Me3NN]Ni(2,4-lutidine) with Ph2NNO. Ph2NNO (19 mg, 0.150 mmol) in
3 mL toluene was added dropwise to [Me3NN]Ni(2,4-lutidine) (205 mg, 0.411 mmol) in
5 mL toluene. The red solution turned blue immediately. No precipitate formed during this reaction. An independent synthesis of [Me3NN]Ni-NPh2 (5) was performed in order to confirm the fate of the “NPh2” fragment. UV-Vis data indicates formation of
[Me3NN]Ni-NPh2 and [Me3NN]Ni(NO) in the presence of 2,4-lutidine (Figure 1.1).
29 General procedure for quantification of [Me3NN]Ni(NO) from reaction of
[Me3NN]Ni(2,4-lutidine) with organonitroso (E-NO) substrates. Naphthalene (0.038 g, 0.029 mmol) was dissolved in 1 mL benzene-d6. [Me3NN]Ni(2,4-lutidine) (0.146 g,
0.030 mmol) was dissolved in 2 mL benzene-d6. These solutions were analytically transferred to a 5 mL volumetric flask and diluted to 5 mL with benzene-d6 to make 5 mL of a 60 mM stock solution of [Me3NN]Ni(2,4-lutidine).
56 Reaction of [Me3NN]Ni(2,4-lutidine) with CyONO to form [Me3NN]Ni(NO). CyONO
(0.026 g, 0.200 mmol) was added to 2 mL of benzene-d6 in to make a 100 mM stock solution. 150 µL of the 100 mM CyONO stock solution (0.015 mmol) was added dropwise to 500 µL of [Me3NN]Ni(2,4-lutidine) (60 mM, 0.030 mmol) in benzene-d6.
1 Analysis of the solution by H NMR shows the formation of [Me3NN]Ni(NO) (4) based on its characteristic β-diketiminato backbone C-H resonance at δ 4.4 ppm. The nickel nitrosyl 4 is formed in 97% yield based on the integration of its backbone C-H resonance against the naphthalene standard.
Reaction of [Me3NN]Ni(2,4-lutidine) with AdSNO to form [Me3NN]Ni(NO). AdSNO
(0.040 g, 0.200 mmol) were added to 2 mL of benzene-d6 in to make a 100 mM stock solution. 150 µL of the 100 mM AdSNO stock solution (0.015 mmol) was added dropwise to 500 µL of [Me3NN]Ni(2,4-lutidine) (60 mM, 0.030 mmol) in benzene-d6.
1 Analysis of the solution by H NMR shows the formation of [Me3NN]Ni(NO) (4) based on its characteristic β-diketiminato backbone C-H resonance at δ 4.4 ppm. The nickel nitrosyl 4 is formed in 93% yield based on the integration of its backbone C-H resonance against the naphthalene standard.
Reaction of [Me3NN]Ni(2,4-lutidine) with Ph2NNO to form [Me3NN]Ni(NO).
Ph2NNO (0.040 g, 0.200 mmol) was added to 2 mL of benzene-d6 in to make a 100 mM stock solution. 150 µL of the 100 mM Ph2NNO stock solution (0.015 mmol) wase added dropwise to 500 µL of [Me3NN]Ni(2,4-lutidine) (100mM, 0.030 mmol) in benzene-d6.
1 Analysis of the solution by H NMR shows the formation of [Me3NN]Ni(NO) (4) based
57 on its characteristic β-diketiminato backbone C-H resonance at δ 4.4 ppm. No other
diamagnetic compound was seen in the spectra other than broad signals for 2,4-lutidine.
The nickel nitrosyl 4 is formed in 90 % yield based on the integration of its backbone C-
H resonance against the naphthalene standard.
[Me3NN]Ni(I)(2,4-lutidine). A solution of [Me3NN]Tl (3.00 g, 5.58 mmol) in 100 ml
THF was added to a stirring solution of NiI2 (1.74 g, 5.58 mmol) in 60 mL THF with 3 equiv. 2,4-lutidine (1.95 mL, 16.7 mmol). After addition the solution remained dark green/black in color. The solution was allowed to stir overnight and a yellow precipitate of TlI formed. The TlI was removed by filtration over Celite. The volume of the solution was reduced to 50 mL and it was allowed to crystallize overnight at -35 °C. The mother liquor was removed and the residue was washed with cold pentane (3 × 1 mL) to yield
1.922 g of green/black crystals. The volume of the mother liquor was reduced to 15 mL and placed back in the freezer to yield a second crop of crystals (0.698 g) for a combined yield of 75 % as a mono-THF solvate. For analysis the crystals were crushed into a fine power and dried in vacuo to give an elemental analysis reading free of THF. 1H NMR
(benzene-d6, 300 MHz, 25 °C): δ 93.5 (s, 1, 2,4-lutidine-ArH), 47.5 (s, 6, p-Ar- Me), 34.8
(s, 12, Ar-o-Me2), 32.7 (s, 4, m-Ar-H), -4.2 (br s, 3, 2,4-lutidine-Me), -11.3 (br s, 3, 2,4- lutidine-Me), -46.6 (s, 6, backbone-Me), -118.1 (s, 1, 2,4-lutidine-ArH). The backbone-H and one 2,4-lutidine-ArH were not observed. µ eff (benzene-d6) = 2.38 B.M.; UV-Vis
-1 -1 (CH2Cl2, nm (M cm )) 527 (562) and 676 (507); Anal. Calcd for C30H38N3NiI: C,
57.55; H, 6.07; N, 6.71. Found: C, 57.82; H, 6.04; N, 6.65.
58 X-ray quality crystals were obtained from crystallization of [Me3NN]Ni(I)(2,4-lutidine) in ether. One molecule of ether appears in the crystal lattice.
LiNPh2. n-Butyllithium (5.0 mL, 8.0 mmol, 1.6 M solution in hexanes) was added
dropwise to a solution of Ph2NH (1.00 g, 6.911 mmol) in 8 mL toluene at -35 °C. The solution was allowed to warm to room temperature for 1 hr after which a white precipitate had formed. The mother liquor was removed and the precipitate was washed with 3 mL of cold pentane and dried in vacuo affording 1.11 g of product in 92 % yield.
Synthesis of [Me3NN]Ni-NPh2 (5) from [Me3NN]Ni(I)(2,4-lutidine). LiNPh2 (0.067 g,
0.385 mmol) in 3 mL of THF was added to a stirring solution of [Me3NN]Ni(I)(2,4- lutidine) (0.242 g, 0.385 mmol) in 5 mL of THF at -35 °C. The dark solution immediately turned royal blue and was allowed to stir for 1 hr. The volatiles were removed in vacuo and the solid was extracted with pentane (3 × 5 mL). The pentane extracts were filtered through Celite and the filtrate was concentrated to 5 mL. The solution was left to crystallize overnight at -35 °C and afforded 127 mg (59% yield) of X- ray quality crystals of 5.
X-ray diffraction of one of these crystals shows the structure to be [Me3NN]Ni-NPh2 free
1 of 2,4-lutidine. The H NMR spectrum (benzene-d6) of these crystals, however, show trace amounts of 2,4-lutidine as very broad peaks. The 2,4-lutidine cannot be completely removed from the reaction mixture and its presence causes a change in solution spectra of
[Me3NN]Ni-NPh2. (See Figures 1.2, 1.3, 1.4).
59 Synthesis of [Me3NN]Ni-NPh2 (5) from NiI2 under 2,4-lutidine free conditions. In a one pot synthesis, n-butyllithium (1.90 mL, 3.00 mmol, 1.6 M solution in hexanes) was added dropwise to a solution of [Me3NN]H (1.00 g, 3.00 mmol) in 25 mL of THF at -35
°C. The solution was allowed to warm to room temperature and stir for 1 hr. Anhydrous
NiI2 (0.936 g, 3.00 mmol) was added as to the reaction mixture which caused an immediate color change from pale yellow to dark purple/black. The reaction was allowed to stir overnight. LiNPh2 (0.524 g, 3.00 mmol) in 8 mL of THF was then added to the solution which caused an immediate color change to royal blue. The solution was allowed to stir at RT for 1.5 h. The volatiles were removed in vacuo and the solid was extracted with pentane (3 × 10 mL). The pentane extracts were filtered through Celite and the
Plot of Chemical Shift vs 1/T for [Me3NN]Ni-NPh2 (4) (toluene-d8, 300 MHz) δ (ppm)
1/T (K-1)
Figure 1.14. Plot of chemical shift (ppm) vs. 1/T for 5 in toluene-d8. This plot shows that there is not a linear relationship between the chemical shift and 1/T and therefore does not follow Curie-Weiss behavior. 60 filtrate was concentrated to 8 mL. The solution was left to crystallize overnight at -35 °C
1 and afforded 0.894 g (53% yield) of product. H NMR (toluene-d8, 25 °C) δ 7.524 (t, 4,
NPh2-m-Ar-H), 7.054 (s, 4, m-Ar-H), 6.162 (d, 4, NPh2-o-Ar-H), 5.685 (t, 2, NPh2-p-Ar-
H), ), 3.389 (s, 12, o-Ar-H), 2.651 (s, 6, p-Ar-Me), 1.829 (s, 1, backbone-H), 0.138 (s, 3,
13 backbone-Me). C NMR (toluene-d8, 25 °C) δ 146.97, 143.78, 141.71, 138.68, 137.68,
-1 - 131.72, 129.51, 121.10, 118.23, 66.75, 24.73, 19.42, 16.95. UV-Vis (Et2O, nm, (cm M ):
598 (2210), 399 (4070), 375 (5760). Anal. Calcd for C35H39N3Ni: C, 75.01; H, 7.01; N,
7.50. Found: C, 74.90; H, 7.19; N, 7.45. µ eff (benzene-d6, R.T.) = 0.0 B.M.
Solution behavior of [Me3NN]Ni-NPh2 in the presence of 2,4-lutidine. A 38 mM solution of [Me3NN]Ni-NPh2 (0.060 g, 0.113 mmol, 1.5 mL) was prepared in benzene-d6.
A 93 mM solution of 2,4-lutidine (0.010 g, 0.093 mmol, 1 mL) was prepared in benzene-
1 d6. Three H NMR spectra are collected where the final concentration of the
[Me3NN]Ni(II) fragment is 19 mM: (1) [Me3NN]Ni-NPh2 in the absence of 2,4-lutidine,
(2) [Me3NN]Ni-NPh2 + 0.01 eq 2,4-lutidine, and (3) [Me3NN]Ni-NPh2 + 1 equiv. 2,4- lutidine. (See Figure 1.2).
Table 1.2. Measured solution magnetic moment for [Me3NN]Ni-NPh2 in benzene-d6 as a function of the amount of 2,4-lutidine present in the solution.
Spectrum [Me3NN]Ni-NPh2 2,4-lutidine Benzene-d6 µeff (B.M.) (38 mM) (93 mM) 1 0.500 mL 0 mL 0.5 mL 0.0 2 0.500 mL 0.020 mL 0.480 mL 0.0 3 0.500 mL 0.204 mL 0.296 mL 1.3
61 Solution UV-Vis studies with [Me3NN]Ni-NPh2 (5) and 2,4-lutidine. [Me3NN]Ni-
NPh2 (5) (0.007 g, 0.0125 mmol) was dissolved in 2 mL of Et2O. The solution was analytically transferred to a 10.00 mL volumetric flask and diluted to 10.00 mL with Et2O to make 10.00 mL of a 1.25 mM stock solution of [Me3NN]Ni-NPh2. 2,4-lutidine (20.0
µL, 0.173 µmol) was added to a 10.00 mL volumetric flask and Et2O was added to make
10.00 mL of a 17.3 mM stock solution. Three UV-Vis spectra were collected where the final concentration of the [Me3NN]Ni(II) fragment is 0.063 mM: (1) [Me3NN]Ni-NPh2 in the absence of 2,4-lutidine, (2) [Me3NN]Ni-NPh2 + 1 eq. 2,4-lutidine, and (3)
-1 [Me3NN]Ni-NPh2 + 10 eq. 2,4-lutidine. (See Figure 1.3). Keq ~ 8000 M (calculated assuming that [Me3NN]Ni(NPh2)(2,4-lutidine) has A598 nm = 0).
Table 1.3 Experimental setup to calculate Keq for 5 + 2,4-lutidine to give 6.
Spectrum [Me3NN]Ni-NPh2 (1.25 mM) 2,4-lutidine (17.3 mM) Et2O 1 0.150 mL 0.000 mL 2.850 mL 2 0.150 mL 0.011 mL 2.839 mL 3 0.150 mL 0.110 mL 2.740 mL
62 Estimation of Keq for 2,4-lutidine binding to [Me3NN]Ni-NPh2. In the absence of 2,4- lutidine, a 0.063 mM solution of [Me3NN]Ni-NPh2 (5) exhibits an absorbance at A590 nm =
0.138. Upon addition of 1 equiv 2,4-lutidine (0.063 mM initial concentration), the absorbance A598 nm = 0.101. Assuming that the absorbance of [Me3NN]Ni(NPh2)(2,4- lutidine) at 598 nm is 0, we can assign the new concentration of [Me3NN]Ni-NPh2 (5) as
(0.101/0.138)(0.063 mM) = 0.046 mM. Given the 1:1 adduct (see Job’s plot in Figure
1.4), [2,4-lutidine] = 0.046 mM and [[Me3NN]Ni(NPh2)(2,4-lutidine)] = 0.017 mM
(0.063 – 0.046 mM). These final concentrations can be used to estimate the equilibrium constant for binding:
-5 [[Me3NN]Ni(NPh2)(2,4-lutidine)] (1.7×10 M) -1 Keq = = - 5 -5 ~ 8000 M [[Me3NN]Ni-NPh2][2,4-lutidine] (4.6×10 M)(4.6×10 M)
43 Job Plot for the binding of 2,4-lutidine to [Me3NN]Ni-NPh2 to confirm 1:1 stochiometry of adduct. A 0.400 mM stock solution of [Me3NN]Ni-NPh2 (5) in ether was prepared by diluting 3.2 mL of a 1.25 mM stock solution of 5 in ether to 10.0 mL using a volumetric flask. A 0.400 mM stock solution of 2,4-lutidine in ether was prepared by diluting 0.230 mL of a 17.3 mM stock solution of 2,4-lutidine in ether to
10.0 mL using a volumetric flask. To construct the Job plot, the mole fractions of 5 and
2,4-lutidine were varied while keeping constant the total molar concentration of these two were species at 0.400 mM. The UV-vis absorbance at 396 nm (a peak which grows as
[Me3NN]Ni(NPh2)(2,4-lutidine) (6) is formed) was plotted against the mole fraction of
63 [Me3NN]Ni-NPh2 (5) in the solution (Figure 1.4). A 1:1 stochiometery was determined for the binding of 2,4-lutidine to [Me3NN]Ni-NPh2.
Table 1.4 Experimental setup for Job plot analysis of 5 with 2,4-lutidine.
Spectrum Mole Fraction [Me3NN]Ni-NPh2 2,4-lutidine A400 nm 0.400 mM 0.400 mM 1 1.00:0.00 3.000 mL 0.000 mL 0.524 2 0.75:0.25 2.250 mL 0.750 mL 0.659 3 0.50:0.50 1.500 mL 1.500 mL 1.791 4 0.25:0.75 0.750 mL 2.250 mL 1.047 5 0.00:1.00 0.000 mL 3.000 mL 0.042
DFT calculation details
The DFT calculations employed the Becke-Perdew exchange correlation functional [1] using the Amsterdam Density Functional suite of programs (ADF 2007.01)
[2]. Slater-type orbital (STO) basis sets employed for H, C, and N atoms were of triple-ζ quality augmented with two polarization functions (ZORA/TZ2P) while an improved triple-ζ basis set with two polarization functions (ZORA/TZ2P+) was employed for the
Ni atom. Scalar relativistic effects were included by virtue of the zero order regular approximation (ZORA) [3]. The 1s electrons of C and N as well as the 1s – 2p electrons of Ni were treated as frozen core. The VWN (Vosko, Wilk, and Nusair) functional was used for LDA (local density approximation) [4]. Default convergence (∆E = 1 × 10-3
-2 -2 hartree, max. gradient = 1 × 10 hartree / Å, max. Cartesian step = 1 × 10 Å) and integration (4 significant digits) parameters were employed for geometry optimizations.
Experimental X-ray coordinates for [Me3NN]Ni-NPh2 (5) were used as the starting point for the geometry optimization of low-spin [Me3NN]Ni-NPh2 (5 – L.S.) in a 64 restricted (S = 0) calculation. The geometry optimization for high-spin [Me3NN]Ni-
NPh2 (5 – H.S.) employed the DFT optimized coordinates for 5 – L.S. as a starting point in an unrestricted (S = 1) calculation specifying 2 unpaired electrons (spin α – spin β).
ADFview [2a] was used to prepare the three-dimensional representations of the structures shown in Figure 1.7 as well as to render the frontier Kohn-Sham MOs shown in Figure
1.8.
DFT References
[1] (a) Becke, A. Phys. Rev. A 1988, 38, 3098. (b) Perdew, J. P. Phys. Rev. B 1986,
34, 7406. (c) Perdew, J. P. Phys. Rev. B 1986, 33, 8822.
[2] (a) http://www.scm.com – last accessed July 25, 2008. (b) te Velde, G.;
Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.;
Snijders, J. G.; Ziegler, T. J. Comput. Chem. 2001, 22, 931. (c) Fonseca Guerra, C.;
Snijders, J. G.; te Velde, G.; Baerends, E. J.; Acc., T. C. Theor. Chem. Acc. 1998, 99,
391.
[3] (a) Snijders, J. G.; Baerends, E. J.; Ros, P. Mol. Phys. 1979, 38, 1909. (b) Ziegler,
T.; Tschinke, V.; Baerends, E. J.; Snijders, J. G.; Ravenek, W. K. J. Phys. Chem. 1989,
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68 Chapter 2
A Three Coordinate Copper(II)-Amide from Reductive Cleavage of a
Nitrosamine
Abstract
An electron-rich copper(I) β-diketiminate cleaves the N-N bond of the nitrosamine Ph2N-
NO to give a three ligand, two copper product where the backbone C-H of the ligand is
II nitrosated along with the novel, three coordinate [Me2NN]Cu -NPh2. Spectroscopic and theoretical studies provide insight into this extremely rare example of a structurally characterized three coordinate copper(II) amide. Use of a related anilidoimine copper(I)
+ complex prevents nitrosative (NO ) attack at the backbone by Ph2NNO. The copper(I) anilidoimine is less electron rich and does not promote cleavage of the Ph2N-NO bond.
+ + This ligand is not free from NO attack; [Me2AI]NO is formed from NO attack at the amide nitrogen in the presence of excess tert-butyl nitrite. As the copper(II)-amide
[Me2NN]Cu-NPh2 reacts with NOgas to form Ph2NNO, both N-NO bond cleavage and formation are observed at a common copper center.
Introduction
Nitrosoamines were first described in the chemical literature over a hundred years ago by Geuther,1 and were occasionally used as solvents or synthetic intermediates in the preparation of hydrazines and diazoalkanes.2 It was not until 1956 that nitrosoamines such as dimethylnitrosamine were found to induce liver cancer in rats and can alkylate
69 proteins and amino acids.3-5 Thus the conversion of an amine to a nitrosamine leads to carcinogenic materials, especially when α-C-H atoms are present.6 Nitrosamines are found in common pollutants such as tobacco smoke, motivating approaches for their reduction to amines.
More recent studies show that nitrosamines have vasorelaxant activity7,8 and can be considered as a class of NO donors since the N-NO bond can be homolytically or
9 - heterolytically cleaved. The related diazeniumdiolates [R2NN2O2] formed by the pressurization of secondary amines with NO in a basic solution have been extensively employed as NO donors. Moreover, a new class N-aryl based nitrosamines have been shown to function as both NO and HNO donors.10
The interaction of nitrosamines with heme-containing biomolecules can result in activation and/or denitrosation of the nitrosamines.6,11 In small molecule model
Figure 2.1. Schematic representations of the molecular structures of a) (Me2NNO)CuCl2 in which all copper centers are identical having one N and one O binding from two adjacent nitrosamines. b) {(CH2)5NNO}-CuCl2 in which half of the copper centers exhibit N binding and the other have exhibit O binding from the nitrosamine. 70 complexes nitrosamines may form intact R2NNO adducts with metal complexes. Richter-
12 Addo studied metalloporphrin adducts of N-nitrosamines, (porph)M(ONNR2) (M = Fe ,
Ru13, Os14,15) (Scheme I.10). In non-heme complexes, two solid state structures of copper with nitrosamines show unique coordination modes of the nitrosamine ligands in an extended solid (Figure 2.1).16,17, 18
Delivery and storage of nitric oxide in vivo is often accomplished via reductive nitrosylation: reduction of an oxidizing metal center by NO with concomitant nitrosylation of a nucleophile. (Scheme 2a).19,20 Copper centers in cytochrome c oxidase and laccase,21,22 a few ferriheme proteins,23-25 as well as Cu(II)26 and Fe(III)27,28 model systems exhibit reductive nitrosylation through the use of water or an alcohol as the nucleophilic agents (NOTE: nitrosylation refers to attack by NO•, nitrosation refers to attack by NO+).
Scheme 2.1 Equilibrium of a) reductive nitrosylation (metal reduced) and b) reductive cleavage (R2N-NO bond reduced).
Reductive nitrosylation is also at the core of a small molecule copper
DAC/cyclam-based NO sensor. Reaction of NO to form a new N-NO bond with concomitant reduction to Cu(I) removes quenching present in the Cu(II) coordinated
71 Scheme 2.2. Intramolecular nitrosylation of a copper coordinated deprotonated amide by NO+ formed upon concomitant reduction of Cu2+ to Cu1+.
cyclam.29 This is the first well defined example of intramolecular nitrosylation of a deprotonated amine coupled to reduction of the metal center from Cu2+ to Cu1+. A mechanism was proposed in which the key step features attack of NO on the deprotonated amine with concerted electron transfer to the coordinated copper center.
Once the Cu2+ ion is reduced it is released from the cylcam owing to the preference of
Cu+ for tetrahedral coordination and the inability of the macrocylic cyclam ligand to
easily accommodate that geometry.
Depending on the nature of the metal center, the reverse process may be favored
(Scheme 2.1b). Copper modified zeolites have been shown to remove and trap volatile
nitrosamines in mainstream cigarette smoke due a strong interaction between the N-N=O
of the nitrosamine and the Cu in the zeolite.30,31 The exact structure and mechanism of the copper-nitrosamine interaction, however, remains unknown. We recently reported that an electron-rich nickel(I) β-diketiminate complex [Me3NN]Ni(2,4-lutidine) cleaves the E- 72 Figure 2.2. Copper(I) synthons used herein using the β-diketiminate and anilio imine ligands.
NO bond of O-, S-, and N-organonitroso species to give the nickel-nitrosyl [Me3NN]Ni-
NO along with dimeric nickel(II)-alkoxide or thiolate complexes {[Me3NN]Ni}2( -E)2
32 or the mononuclear nickel(II)-amide [Me3NN]Ni-NPh2 (see Chapter 1).
We have employed electron-rich β-diketiminate as well as anilidoimine ligands as supporting ligands to provide access to low-valent copper(I) and copper(II) complexes
(Figure 2.2 and Appendix Figure A.1) which could be used as precursors for studying the reactivity of E-NO compounds with electron-rich, well defined copper complexes. Herein we report the reactivity of diphenylnitrosamine Ph2NNO with the related copper(I) β- diketiminate {[Me2NN]Cu}2 and anilidoimine {[Me2NN]Cu}2.
73 Results and Discussion
II I 2.1. Synthesis and characterization of [Me2NN]Cu (ON-Me2NN)2Cu .
32,33 34 Addition of 2 equiv Ph2NNO to 3/2 equiv {[Me2NN]Cu}2 at -35 ºC in ether resulted in color change from light yellow to dark brown. Formation of a copper mirror indicated that this reaction followed a complex course. Crystallization of the reaction mixture from ether allowed the isolation of both dark brown and green crystals.
Single crystal X-ray characterization of the brown crystals isolated in ca. 24 %
II I yield (based on the moles of Cu) identifies them as [Me2NN]Cu (ON-Me2NN)2Cu (1)
(Figure 2.3). Formation of 1 requires reaction of 3 equiv [Me2NN]Cu (monomer in solution) with 2 equiv. Ph2NNO. Additional products of the reaction are 2 equiv Ph2NH
0 1 13 along with Cu . We confirmed the presence of Ph2NH by H and C NMR and GC/MS.
The formation of a copper mirror on the sides of the vial confirms the formation of Cu0
Scheme 2.3. Reaction of 3/2 equiv. {[Me2NN]Cu}2 with 2 equiv. Ph2NNO to form 1. The backbone of the ligand is nitrosated (NO+ for H+ exchange).
74 Ph O N N N Ph N Cu H Cu+ N N
O N N O N Cu+ N Cu+ H Ph N Ph N N NH Ph Ph
Scheme 2.4. Nitrosation of β-diketiminate backbone CH in [Me2NN]Cu by Ph2NNO.
(Scheme 2.3)
The resonance structure of the β-diketiminate ligand in which the negative charge
is localized at the backbone C-H may be helpful to explain why [Me2NN]Cu is susceptible to nitrosation at the β-diketimate backbone. The localized negative charge on
- the backbone C-H may attack Ph2N-NO to give Ph2N which may deprotonate the backbone C-H to form Ph2NH. While this mechanism is simply a proposal, it rationalizes the susceptibility of the ligand backbone to NO+ attack.
Complex 1 has two copper ions with vastly different coordination environments.
Cu1 is linear (N1-Cu1-N3= 176.61(15)º), a relatively uncommon geometry for Cu which
75 is only observed in the 1+ oxidation state (d10). The coordination environment of Cu2 is square planar completed by two O-donors resulting from the nitrosation of the former β- diketiminato backbone C-H sites in the two modified β-diiminate ligands now coordinated to the linear Cu1 center. The square planar configuration at Cu2 is consistent with assignment of the Cu(II) oxidation state for Cu2. Both the square planar configuration at Cu2 as well as the axially biased EPR spectrum of 1 in frozen toluene glass (gparallel = 2.20, gperp = 2.05 with Aparpallel(Cu) and Aperp(Cu) = 177 and 26 G ; Figure
2.13) are consistent with assignment of a Cu(II) center in 1.
76 N2 O1 N1 N5
N7 Cu1 Cu2 N6 N4 N8 N3 O2
II I Figure 2.3. X-ray structure of [Me2NN]Cu (ON-Me2NN)2Cu (1) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu1–N1 1.863(4), Cu1–N3 1.870(3), Cu2- N7 1.942(3), Cu2–N8 1.940(4), Cu2-O1 1.953(3), Cu2–O2 1.948(3), N7–Cu2–N8 95.37(14), O1–Cu2–O1 158.88(13), O2–Cu2–N8 91.82(13), N7–Cu2–O2 162.73(13), N7–Cu1–O1 92.24(14), N1–Cu1–N3 176.61(15).
77 2.2. Isolation of [Me2NN]Cu-NPh2 from {[Me2NN]Cu}2 / Ph2NNO reaction mixture.
Pentane recrystallization of the green product which forms upon the interaction of
Ph2NNO with {[Me2NN]Cu}2 allows for the isolation of the novel three coordinate copper(II)-amide [Me2NN]Cu-NPh2 (2) in 31 % yield, identified by a preliminary single- crystal X-ray diffraction from the reaction mixture which included 1. Product 2 may form
I in a more easily understood route: the Ph2N-NO bond is reductively cleaved by the Cu complex to form [Me2NN]Cu-NPh2 (2) and release NOgas (Scheme 2.5). This follows a
I similar route to our previous work with [Me3NN]Ni (2,4-lutdine) and Ph2N-NO where the
II [Me3NN]Ni -NPh2 forms along with [Me3NN]Ni(NO) (see Chapter 1). The copper chemistry differs from the nickel chemistry principally in that the copper does not form an easily isolable copper-nitrosyl [Me2NN]Cu(NO).
I Scheme 2.5. Reductive cleavage of the Ph2N-NO bond by [Me2NN]Cu to release NOgas and form [Me2NN]Cu-NPh2 (2). 78 2.3. Independent synthesis of [Me2NN]Cu-NPh2.
A higher quality X-ray structure of 2 was obtained through its independent synthesis. Reaction of {[Me2NN]Cu}2( -Cl)2 with 2 equiv. LiNPh2 gives [Me2NN]Cu-
NPh2 (2) (62 % yield) by X-ray crystallography and UV-Vis characterization. After working up the X-ray data, however, unexpected electron density (> 3 e- / Å3) was found on C2 (Figure 2.4). This residual was too large to be ignored. In a similar compound,
Tolman found residual electron density on the backbone of his ligand and modeled it as a chlorine in 10% occupancy.35 He attributed this rogue chlorine atom to the
CuCl2•0.8THF used in the reaction synthesis. We too use CuCl2•0.8THF in the synthesis of {[Me2NN]Cu}2( -Cl)2 and therefore model the residual electron density to a chlorine atom in 15% occupancy with the hydrogen atom at 85% occupancy (Figure 2.4).
Refining the data under these conditions removes the residual electron density from the backbone. There is no further disorder in the structure and an R1 value of 0.0660 results after the final refinement, suggesting otherwise good quality crystal data.
79 N1 N3 C2 Cu1 Cl N2
Figure 2.4. X-ray structure of [Me2NN]Cu-NPh2 (2) with 0.15:0.85 Cl:H on C2 (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.916(4), Cu–N2 1.888(4), Cu–N3 1.840(4), C2-Cl 1.539(6), N1–Cu–N2 97.12(16), N3–Cu–N1 122.76(16), N3–Cu–N2 139.66(17).
80 We then moved to the use of the copper(II)-iodide [Me2NN]CuI to synthesize
[Me2NN]Cu-NPh2 (2). Reaction of {[Me2NN]Cu}2 with 1 equiv. I2 gives [Me2NN]CuI (3,
36 37 % yield) as purple crystals. If any extra I2 is added to the reaction mixture, the solution turns from purple expected for 3 to rusty brown with immediate precipitation of an uncharacterized compound. While the yield from the reaction to form 3 is quite low (<
40%), further attempts to improve the yield were not successful. It could be that excess iodine in the reaction solution reacts at the backbone C-H position. For instance, Dr.
Yosra Badiei from the Warren group has observed H[Cl2NNI] in the reaction of
{[Cl2NN]Cu}2(benzene) with I2 to give the β-diketimine ligand H[Cl2NNI] free of copper with an iodine atom on the backbone C-H replacing the H atom at this position.37
Curiously, this [Cu]-I complex crystallizes as a mononuclear species [Me2NN]Cu-
I (3) [Cu-I = 2.4295(5) Å] from ether (Scheme 2.6, Figure 2.5) and a dinuclear species
… {[Me2NN]Cu}2( -I)2 (3-dinuclear) [Cu-I = 2.6128(8) and 2.6076(9) Å; Cu Cu separation 3.673(2) Å] from pentane (Scheme 2.6, Figure 2.6). Reaction of 3 with LiNPh2 in THF delivers 2 in 81 % yield as green crystals from pentane (Scheme 2.7).
Scheme 2.6. Synthesis of [Me2NN]Cu-I (3) from reaction of {[Me2NN]Cu}2 with I2, crystallized from ether. Crystallization from pentane gives {[Me2NN]Cu}2( -I)2 (3- dinuclear).
Scheme 2.7. Synthesis of [Me2NN]Cu-NPh2 (2) from [Me2NN]Cu-I (3) with LiNPh2.
81 N1 I Cu1
N1'
Figure 2.5. X-ray structure of [Me2NN]Cu-I (3) (all H atoms omitted) crystallized from ether. Selected bond distances (Å) and angles (deg): Cu–N1 1.8767(17), Cu–I 2.4295(5), N1–Cu–N1´ 97.07(10), N1–Cu–I 131.46(5).
82 N2' N1 I Cu1' Cu1 I' N1' N2
Figure 2.6. X-ray structure of {[Me2NN]Cu}2( -I)2 (3-dinuclear) (all H atoms omitted) crystallized from pentane. Selected bond distances (Å) and angles (deg): Cu–N1 1.930(4), Cu–N2 1.926(4), Cu–I 2.6128(8) Cu–I´ 2.6076(9), N2–Cu–N1 96.20(16), Cu– I–Cu´ 89.42(3), N2–Cu–I 137.40(11) N2–Cu–I´ 100.86(11), N1–Cu–I 99.45(11), N1– Cu–I´ 141.95(11), I–Cu–I´ 90.58(3).
83 The X-ray crystal structure of 2 shows a short Cu-Namide distance of 1.841(6) Å with Cu-Nβ-dik distances of 1.914(6) and 1.885(6) Å (Figure 2.7). Both the Cu atom and
Namido atoms are planar (sum of angles 359.7(3) and 357.2(5)°, respectively). One of the two N-aryl rings is coplanar with N center while the other is twisted out of the Cu-N-C plane by ca. 65°. The metal-nitrogen distances are longer in the copper(II)-amide system
(Cu-Namide distance of 1.841(6) and Cu-Nβ-dik distances of 1.914(6) and 1.885(6) Å) than
32 in the related β-dikeiminato nickel(II)-amide [Me3NN]Ni-NPh2 (Ni-Namide distance of
1.823(1) and Ni-Nβ-dik distances of 1.826(1) and 1.833(3) Å).
[Me2NN]Cu-NPh2 (2) represents a rare example of a crystallographically characterized three-coordinate copper(II)-amide. Peters has recently reported the
2 t structure of the diphosphinoborate κ -[Ph2B(CH2PBu 2)]Cu-N(p-tolyl)2 which exhibits a
Cu-N bond distance of 1.906(2) Å.38 Based on several spectroscopic measurements, this species was best described as a Cu(I) coordinated aminyl radical. Employing chelating ligands, X-ray structures of two square planar copper(II) amides with electron-deficient sulfonyl amido substituents39,40 as well as distorted tetrahedral phosphine-amide species41 have been reported. In copper(I) chemistry, Gunnoe described the structures of three and
t t 42 two coordinate amides such as ( Bu2PCH2CH2PBu 2)Cu-NHPh and the N-heterocyclic carbene-based IPrCu-NHPh.43
84 N1 N3 Cu1
N2
Figure 2.7. X-ray structure of [Me2NN]Cu-NPh2 (2) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.914(6), Cu–N2 1.885(6), Cu–N3 1.841(6), N1–Cu–N2 97.0(3), N3–Cu–N1 122.4(3), N3–Cu–N2 140.2(3).
85 2.4. Electronic properties of [Me2NN]Cu-NPh2.
The electronic spectrum of 2 in ether exhibits four bands in the visible to near IR at 426 nm (530 M-1cm-1), 532 nm (280 M-1cm-1), 774 nm (1200 cm-1M-1), and 908 nm
(1200 cm-1M-). Monitoring by UV-vis spectroscopy, toluene solutions of 2 (1.20 mM) have a half-life of approximately 7 hr at RT, turning colorless after a day. GC/MS studies reveal that Ph2NH is the primary organic product of decomposition.
Simulation of the X-band EPR spectrum of 2 in frozen toluene glass (Figure 2.8) indicates a rhombic signal (g1 = 2.145, g2 = 2.048, g3 = 2.010) with A1(Cu) = 100 G.
The hyperfine to Cu is modestly depressed relative to that found in other three-
i 44 coordinate β-diketiminato halide species such as [ Pr2NN]CuCl as well as [Me2NN]CuI
(3) (A1(Cu) = 120 and 139 G (Figure 2.14), respectively) though similar to that found in
i Tolman’s three coordinate phenoxide [ Pr2NN]CuOAr (Ar = p-MeOC6H4); A1(Cu) = 90
G).45 We have unfortunately been unable to simulate reliable A(N) values for the amido
15 N atom, including the use of Li NPh2 the synthesis of 2. The EPR spectrum of 2 is
2 t distinct from Peter’s Cu(I) aminyl complex κ -[Ph2B(CH2PBu 2)]Cu-N(p-tolyl)2 which exhibits g-values (2.030, 2.008, 2.008) close to that of the free electron with a
38 significantly depressed A1(Cu) of ca. 60 G.
Nonetheless, DFT analysis of 2 points to appreciable radical character on the amido N atom as a result of the 3-electron / 2-center π-interaction between the Cu d- orbital most destabilized by σ-interactions with the β-diketiminate ligand (dyz) and the
2 9 II filled lone pair of an sp -hybridized amido N atom (pz) (Figures 2.8 and 2.9). The d Cu center of the β-diketiminato fragment possesses one electron in this dyz orbital which 86 g-values N R 2.32.42.5 2.12.2 2.0 1.9 z R N Cu N
y x * N R R N Cu N
N R
N Cu N R 260 280 300 320 340 Magnetic field / mT Figure 2.8. Cu-amido 2-center, 3-electron π-orbital interactions (left) and X-band EPR spectrum and simulation for [Me2NN]Cu-NPh2 (2) (frozen toluene glass, 30 K, 8.982 GHz). Simulation provides g1 = 2.145, g2 = 2.048, g3 = 2.010 with A1(Cu) = 100 G and A2(Cu) ≈ A3(Cu) ≈ 0 G. Simulation employed Aiso(N) = 14.5 G for three equivalent N atoms. Data were collected and simulated by Dr. Susanne Mossin of Prof. Karsten Meyer’s research group at the University of Erlangen, Germany (right) interacts with the sp2-hybridized amido lone pair to singly populate the Cu-N π* orbital which represents the SOMO of 2. The DFT spin densities at Cu and N are 0.30 and 0.27 e-, respectively, with significant delocalization of unpaired electron density over the two aryl rings (Figure 2.9, right). This analysis indicates a rather covalent Cu-amido π- interaction in 2 consistent with the modest value of A(Cu) observed in the EPR spectrum of 2. This bonding description is qualitatively similar to that in related copper(II)- thiolates in which the thiolate S atom bears significant spin density.44,46,47
The presence of electron-spin at the amido N atom suggests the possibility of N- centered reactivity with other radical species such as NO. We observe the immediate formation of Ph2NNO when 1 equiv NOgas is added to isolated [Me2NN]Cu-NPh2. While 87 [Me2NN]Cu-NPh2 (2) Cu-N1 1.930 Å N1-Cu-N3 132.3° Cu-N2 1.935 Å N2-Cu-N3 130.2° Cu-N3 1.880 Å N1-Cu-N2 97.4°
Figure 2.9. DFT structure (left) and contour plot of SOMO (right) for [Me2NN]CuNPh2 along with selected bond distances and angles. DFT electron spin densities predicted: Cu - - - 0.30 e ; Namide 0.27 e ; Nβ-dik 0.06, 0.08 e .
we were unable to quantify the Ph2NNO formed since it can be consumed by any
I II I [Me2NN]Cu species formed in solution to give [Me2NN]Cu (ON-Me2NN)2Cu (1), this system nonetheless demonstrates both the reductive cleavage of Ph2N-NO as well as the reductive nitrosylation of the corresponding Cu(II)-amide 2.
2.5. Reaction of {[Me2AI]Cu}2 with Ph2NNO.
In order to discourage nitrosation of the β-diketiminate backbone which ultimately results in the formation of 1, we turned our we turned our attention to anilidoimine ligands48 because the backbone of the ligand is “protected” from nitrosation due to the incorporation of an aryl ring. Combination of 2 equiv. Ph2NNO and
88 {[Me2AI]Cu}2 in benzene-d6 led to broadening of the [Me2AI]Cu(arene) which suggests some interaction between the [Me2AI]Cu and Ph2NNO moieties (Scheme 2.8).
Importantly, ligand nitrosation does not take place.
Scheme 2.8. Interaction of Ph2NNO with ½ equiv. {[Me2AI]Cu}2 in arene solvents.
t 2.6. Reaction of {[Me2AI]Cu}2 with excess BuONO.
Even though ligand nitrosation does not take place in the reaction between ½ equiv. {[Me2AI]Cu}2 and Ph2NNO, this anilidoimine ligand is still susceptible to nitrosation with more powerful NO+ sources such as organonitrites. In the presence of
Scheme 2.9. Nitrosation of the anilioimine {[Me2AI]Cu}2 from the reaction of excess t BuONO to give [Me2AI]NO (4).
89 t + excess BuONO, {[Me2AI]Cu}2 is attacked by NO at the amido nitrogen to lose its copper ion and give [Me2AI]NO (4) which was isolated by crystallization from ether
(Figure 2.10, Scheme 2.9). The negative charge on the backbone is not completely delocalized and the amido nitrogen bears a significant amount of that charge, thus making it susceptible to NO+ attack. All attempts at synthesizing 4 in the absence of copper were unsuccessful.
90 N1 O1 N3
N2
Figure 2.10. X-ray structure of [Me2AI](NO) (4) (all H atoms omitted). Selected bond distances (Å) and angles (deg): N1–N3 1.356(2), N3–O1 1.226 (2), N1–N3–O1 114.12(10).
91 2.7. Electronic differences between {[Me2NN]Cu}2 and {[Me2AI]Cu}2.
It is interesting to note that the copper(I) β-diketiminate [Me2NN]Cu activates the nitrosamine towards N-NO cleavage while the related anilidoimine complex [Me2AI]Cu does not under analogous conditions. Comparison of the IR spectra of analogous 2,6- dimethylphenylisocyanide complexes [Me2NN]Cu(CNAr) (5) and [Me2AI]Cu(CNAr) (6) indicates stronger backbonding from a more electron-rich copper center in the the β-
-1 diketiminato complex (νCN = 2124 and 2131 cm , respectively) (Figures 2.11 and 2.12).
This extra electron-richness may contribute to its reactivity in the reductive cleavage of the Ph2N-NO bond. In this context, the clean reaction between 2 equiv. [Me3NN]Ni(2,4- lut) and Ph2NNO to give [Me3NN]Ni-NPh2 and [Me2NN]Ni(NO) is likely due to the significantly more rich NiI metal center coupled with the formation of a stable {NiNO}10 species.
Figure 2.11. The IR v(C≡N) stretching frequencies are dependent on the electronic nature of the β-diketiminate-like ligand and indicate that the β-diketiminate is more electron rich.
92 N1 Cu1 C22 N3 N2
Figure 2.12. X-ray structure of [Me2NN]Cu(NCAr) (5) (Ar = 2,6 dimethylbenzene) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.926(2), Cu– N2 1.940(2), Cu–C22 1.815(2), C22–N3 1.156(3), C23–N3 1.404(3), N1–Cu–N2 98.03(8), N1–Cu–C22 133.78(9), N2–Cu–C22 127.82(8), Cu–C22–N3 174.8(2), C22– N3–C23 174.4(2).
93 Summary
This model system allows for the observation of both cleavage and formation of
an N-NO bond at a common copper center. While the β-diketiminate ligand is not a
completely innocent spectator, it provides a framework to allow for the isolation of the novel three coordinate copper(II)-amide [Me2NN]Cu-NPh2. Electronic effects are important in determining the ability to release NO from the R2NNO substrate. This may be of particular relevance in the biologically important generation of NO at copper sites from S-nitrosothiols RSNOs such as S-nitrosoglutathione which serve as a circulating reservoirs of NO.49
94 Table 2.1. Crystallographic parameters for 1, 2, 2', and 3-mononuclear.
Compd. 1 2 2' 3
Formula C63H73Cu2N8O2, C33H35CuN3 C33H34.85Cl0.15 C21H25Cu I N2
C4H10O CuN3 Mol. Wt. 1175.49 537.18 542.35 495.87 Temp.(K) 173(2) 100(2) 100(2) 100(2) Crystal Block Block Plate Block description Crystal color Brown Green Green Purple Crystal size 0.0410 0.0108 0.0217 0.0010 (mm3) System Triclinic Monoclinic Monoclinic Orthorhombic Space group P-1 C2/c C2/c Pbcn a (Å) 11.4757(7) 17.384(4) 17.348(5) 8.3269(8) b (Å) 14.7928(9) 15.302(4) 15.293(4) 13.9138(14) c (Å) 19.6284(11) 20.982(5) 21.153(6) 18.1184(18) α (deg) 82.2820(10) 90 90 90 β (deg) 79.1630(10) 96.118(3) 96.041(4) 90 γ (deg) 74.2790(10) 90 90 90 Volume (Å3) 3138.0(3) 5550(2) 5581(3) 2099.2(4) Z 2 4 4 4 θ range (deg) 1.06-25.00 1.78-25.00 1.78-27.00 2.25-28.00 Measd reflns 28645 17768 23267 17703 Unique reflns 11036 4882 6088 2525 GOF of F2 0.981 1.107 0.990 1.058
R1 ( I > 2σ(I)) 0.0556 0.0854 0.0660 0.0304 wR2 (all data) 0.1548 0.2439 0.1742 0.0858 Largest diff. 0.524 and 1.270 and 0.621 and 1.168 and - peak and hole -0.706 -0.603 -0.627 0.897 (e-.Å-3) 95 Table 2.1. Crystallographic parameters for 3-dinuclear, 4, and 5.
Compd. 3-dinuclear 4 5
Formula C42H50Cu2I2N4 C23H23N3O C30H34CuN3 Mol. Wt. 991.76 358.45 500.14 Temp.(K) 100(2) 100(2) 173(2) Crystal Plate Block Plate description Crystal color Purple Yellow Green Crystal size 0.0700 0.0882 0.0082 (mm3) System Monoclinic Triclinic Monoclinic Space group P2(1)/n P-1 P2(1)/n a (Å) 12.802(5) 8.3787(3) 12.9345(13) b (Å) 8.998(3) 8.4058(3) 11.3086(11) c (Å) 17.664(5) 13.8050(5) 19.1873(18) α (deg) 90 78.8960(10) 90 β (deg) 103.511(3) 83.9890(10) 106.4630(10) γ (deg) 90 89.4670(10) 90 Volume (Å3) 1978.6(12) 948.78(6) 2691.5(5) Z 2 2 4 θ range (deg) 1.78-28.00 1.51-27.00 1.64-26.00 Measd reflns 17452 10922 20975 Unique reflns 4694 4099 5282 GOF of F2 1.045 1.075 1.063
R1 ( I > 2σ(I)) 0.0413 0.0363 0.0379 wR2 (all data) 0.1040 0.0976 0.1067 Largest diff. 1.288 and 0.282 and 0.521 and peak and hole -0.981 -0.211 -0.238 (e-.Å-3)
96 Experimental procedures
General experimental details.
All experiments were carried out in a dry nitrogen atmosphere using an MBraun
glovebox and/or standard Schlenk techniques. 4A molecular sieves were activated in
vacuo at 180 ºC for 24 h. Dry toluene and dichloromethane were purchased from Aldrich
and were stored over activated 4A molecular sieves under nitrogen. Diethyl ether and
tetrahydrofuran (THF) were first sparged with nitrogen and then dried by passage through
1 activated alumina columns. Pentane was first washed with conc. HNO3/H2SO4 to remove olefins, stored over CaCl2 and then distilled before use from sodium/benzophenone. All deuterated solvents were sparged with nitrogen, dried over activated 4A molecular sieves and stored under nitrogen. 1H and 13C NMR spectra were recorded on either a Varian 300 MHz or 400 MHz spectrometer (300 or 400 and 75.4 or
100.4 MHz, respectively). All NMR spectra, including Evans method data, were recorded at room temperature unless otherwise noted and were indirectly referenced to TMS using residual solvent signals as internal standards. GC-MS spectra were recorded on a Varian
Saturn 2100T, elemental analyses were performed on a Perkin-Elmer PE2400 microanalyzer in our laboratories, and VU-Vis spectra were recorded on either an Agilent
8432 or a Cary 50 spectrophotometer.
EPR measurements were performed by Dr. Susanne Mossin in Prof. Karsten
Meyer’s research group at the University of Erlangen, Germany. Measurements were made on samples in solution in quartz tubes with Young valves. Anisotropic simulation was performed using the program ESRSIM written by Høgni Weihe, University of 97 Copenhagen, Denmark. Solution EPR spectra were recorded on a JEOL continuous wave
spectrometer JES-FA200 equipped with an X-band Gunn oscillator bridge, a cylindrical
mode cavity, and a helium cryostat. The g-value in the solution spectrum was calibrated using the second and fourth line of the Mn2+ hyperfine spectrum from an external Mn marker. The marker consists of Mn2+ thermally dispersed in MgO placed on the tip of a probe which is inserted slightly into the cavity. The cavity was tuned with both sample and probe inserted. The Mn marker is provided with the JEOL JES-FA200 spectrometer.
Diphenyamine, iodine, and tert-butylnitrite were obtained from Acros and were
50 51 52 33 used as received. Copper tert-butoxide , CuCl2•THF0.8 {[Me2AI]Cu)2 , and Ph2NNO were synthesized according to published procedures.
Preparation of compounds.
{[Me2NN]Cu}2. {[Me2NN]Cu}2 was synthesized with modifications to the literature
34 procedure. [Me2NN]H (2.00 g, 6.536 mmol) in 10 mL of toluene was adding to a stirring solution of copper(I) tert-butoxide (1.071 g, 7.843) in 25 mL of toluene. The solution was allowed to stir for 2 hr, filtered over Celite, and the volatiles were removed in vacuo to yield brown oil. The brown oil was washed with pentane (3 × 8 mL) to afford
1 2.25 g (92 %) of {[Me2NN]Cu}2 as a yellow powder. H NMR (benzene-d6, 400 MHz, 25
°C): δ 7.100 (d, 4, m-ArH), 6.993 (t, 2, p-ArH), 4.776 (s, 1, CHbackbone), 2.016 (s, 12, o-
ArMe2), 1.643 (s, 6, Mebackbone).
98 Reaction of {[Me2NN]Cu}2 with Ph2NNO. At room temperature Ph2NNO (0.125 g,
0.633 mmol) in 3 mL Et2O was added to a slurry of {[Me2NN]Cu}2 (0.350 g, 0.475 mmol) in 5 mL Et2O. The solution immediately turned dark green/brown. The solution was allowed to stir for two hours and 35 mg of copper metal plated on the outside of the vial during the course of the reaction (58 % based on total moles of Cu) removed in vacuo. The dried solid was stirred with 5 mL of pentane for 5 minutes causing the solution to turn dark green. The insoluble components were allowed to settle and the solution is filtered through Celite. This pentane washing procedure was repeated two more times. The filtrates were combined and concentrated to 3 mL and allowed to crystallize overnight at -35 °C. X-ray quality crystals form (0.160 g) and were identified as [Me2NN]Cu-NPh2 (2) (0.160 g, 0.298 mmol, 31% yield based on moles of Cu) crystallized The pentane insoluble solids were then washed with Et2O (3 × 5 mL) causing the solution to turn reddish brown. The washings were combined, filtered through Celite, and concentrated to 3 mL. The solution was allowed to crystallize overnight at -35 °C. X- ray quality crystals formed (0.082 g, 16 % yield, based on moles of Cu) and were
II I -1 -1 identified as [Me2NN]Cu (ON-Me2NN)2Cu 1. UV-Vis (Et2O, 25 °C, nm(cm M ))
341(110000). Anal. Calcd for C63H73Cu2N8O2: C, 68.70; H, 6.68; N, 10.17. Found: C,
68.88; H, 6.65; N, 10.41.
99 Independent synthetic routes to [Me2NN]Cu-NPh2 (2).
We synthesized 2 via two different Cu(II) starting material routes. We initially used {[Me2NN]Cu}2( -Cl)2, but discovered that the backbone C-H of the ligand is subject to attack by a Cl atom. Use of [Me2NN]Cu-I prevents halogenation of the ancillary ligand and allows for synthesis of pure [Me2NN]Cu-NPh2 (2).
{[Me2NN]Cu}2(µ-Cl)2. This compound was synthesized according to the published
53 compound {[Me2NN]lCu}2( -Cl)2 (methine C-H on backbone replaced with Cl) with some minor changes. In a one pot synthesis, n-butyllithium (2.00 mL, 3.27 mmol, 1.6 M solution in hexanes) was added dropwise to a solution of [Me2NN]H (1.00 g, 3.27 mmol) in 25 mL of THF at -35 °C. The solution was allowed to warm to room temperature and
II I Figure 2.11. Beer’s Law plot for [Me2NN]Cu (ON-Me2NN)2Cu (1) in Et2O. 100 stir for 1 hr. The solution of [Me2NN]Li in THF was added to a slurry of CuCl2•THF0.8
(0.627 g, 3.27 mmol) in 10 mL of THF causing the formation of a dark green solution.
The reaction mixture was allowed to stir for 4 hr and the solvent was removed in vacuo.
The green residue was extracted with CH2Cl2 (3 × 5 mL) yielding a purple solution that was filtered through a pad of Celite. The volume of solvent was reduced to 2 mL, pentane
(2 mL) was added, and the solution was stored at 20 °C overnight, causing the deposition of dark crystals, 0.987 g (75 % yield). No other characterization was performed on this species and it was directly used as described below.
[Me2NN]Ni-NPh2 (2) using {[Me2NN]Cu}2(µ-Cl)2. A solution of Ph2NLi (0.200 g, 1.143 mmol) in 3 mL of THF was added to a stiring solution of [Me2NN]Cu2(µ-Cl)2 (0.461 g,
0.572 mmol) in 4 mL THF. The brown solution immediately turned dark green and the solution was allowed to stir for 1 hr. The solvent was removed in vacuo and the solids were extracted 3 times with 5 mL of pentane. The solution was filtered over Celite, concentrated to 4 mL, and allowed to crystallize overnight at -35 °C. The mother liquor was removed and the residue was washed with a few mL of cold pentane to yield 0.255 g of green crystals. The volume of the mother liquor was reduced to 2 mL and placed back in the freezer to yield a second crop of crystals (0.124 g) for a combined yield of 62%.
Crystals of X-ray quality were grown from this reaction mixture and allowed for the identification of this compound to be the same as from the reaction of {[Me2NN]Cu}2 with Ph2NNO.
101 X-ray of [Me2NN]Cu-NPh2 (2) from {[Me2NN]Cu}2(µµµ-Cl)2. After working up the X- ray data, unexpected electron density (> 3 e- / Å3) was found on the β-diketiminate backbone methine C atom. This number was too large to be considered residual. In a similar compound, Tolman found residual electron density on the backbone of his ligand and modeled it as a chlorine in 10% occupancy.35 He attributed this rogue chlorine atom to the CuCl2•0.8THF used in the reaction synthesis. We too, use CuCl2•0.8THF in synthesizing [Me2NN]Cu2( -Cl)2 and model the residual electron density to a chlorine atom in 15% occupancy with the hydrogen atom at 85% occupancy. The C(2)-Cl(1) has a bond distance of 1.539(6). Refining the data under these conditions removes the residual electron density from the backbone. There is no further disorder in the structure and an
R1 value of 0.0660 results after the final refinement, suggesting good quality crystal data.
We then moved to [Me2NN]Cu-I to synthesize [Me2NN]Cu-NPh2.
Synthesis of [Me2NN]Cu-I (3). At room temperature I2 (0.070 g, 0.276 mmol) in 3 mL
Et2O was added to a slurry of {[Me2NN]Cu}2 (0.200 g, 0.271 mmol) in 5 mL Et2O. The solution immediately turned dark purple. The reaction is allowed to stir for 1 hr. The ether was removed in vacuo and the solids were extracted pentane (3 × 5 mL). The solution was filtered over Celite, concentrated to 3 mL, and allowed to crystallize overnight at -35 °C. The mother liquor was removed and the residue was washed with a few mL of cold pentane to yield 0.096 g of purple crystals (37% yield). UV-Vis (Et2O, 25
°C, nm(cm-1M-1)) 280(6600), 328(27000) 425(1200), 515(3500), 592(2400), 646(2200),
102 755(1300). Anal. Calcd for C21H25Cu1N2I1: C, 50.86; H, 5.08; N, 5.65. Found: C, 50.40;
H, 4.87; N, 5.51.
Distinct X-ray structures of [Me2NN]CuI (3) from pentane and ether.
Single crystal X-ray diffraction of [Me2NN]CuI (3) from pentane and ether gave different structures corresponding to dinuclear and mononuclear forms of this β-diketiminato copper(II) iodide. {[Me2NN]Cu}2( -I)2 (3 – dinuclear) crystallized from pentane (unit cell data: space group P2(1)/c, a = 12.802(5) Å, b = 8.998(3) Å, c = 17.664(5) Å, α= β=
3 90°, γ = 103.511(3)°, V = 1978.60(12) Å ) whereas the three coordinate [Me2NN]CuI (3
– mononuclear) crystallized from ether (unit cell data: space group Pbcn, a = 8.235(1) Å, b = 13.9138(14) Å, c = 18.1184(18) Å, , α= β= γ = 90°, V = 2099.2(4) Å3).
- Synthesis of [Me2NN]Ni-NPh2 (2) using [Me2NN]Cu-I (3) (Cl free conditions). A solution of Ph2NLi (0.200 g, 1.143 mmol) in 3 mL of THF was added to a stiring solution of [Me2NN]Cu-I (0.566 g, 1.143 mmol) in 4 mL THF. The purple solution immediately
turned dark green and the solution was allowed to stir for 1 hr. The solvent was removed
in vacuo and the solids were extracted with pentane (3 × 5 mL). The solution was filtered
over Celite, concentrated to 4 mL, and allowed to crystallize overnight at -35 °C. The
mother liquor was removed and the residue was washed with a few mL of cold pentane to
yield 0.495 g of green crystals (81 % yield). Crystals of X-ray quality were grown from
this reaction mixture and allowed for the identification of this compound to be the same
-1 - as from the reaction of {[Me2NN]Cu}2 with Ph2NNO. UV-Vis (Et2O, 25 °C, nm(cm M
103 1 )) 426(530), 532(280), 774(1200), 908(1200). Calcd for C33H35Cu1N3: C, 73.78; H, 6.57;
N, 7.82. Found: C, 73.46; H, 6.79; N, 7.75.
15 54,55 Ph2 NH. This compound was synthesized using the room-temperature palladium
56 catalyzed amination of Ar-Br compounds with Pd(dba)2 with slight modifications. In
15 the dry box, bromobenzene (565 L, 5.375 mmol), Ph NH2 (500 mg, 0.532 mmol),
Pd(dba)3 (0.044 g, 0.054 mmol), tri-tert-butylphosphine (10 L, 0.041 mmol), and potassium tert-butoxide (0.908 g, 8.110 mmol) were weighed directly into a screw cap vial. A stir bar was added followed by 10 mL of toluene to a give a purple mixture. The vial was removed from the dry box, and the mixture was stirred at room temperature for 1 hr. After 1 hr, the reaction mixture was adsorbed onto silica gel and chromatographed to
15 5% ethyl acetate/hexanes to give 0.823 g (91 % yield) of pure Ph2 NH2 as a gray solid.
15 GC/MS was taken on the solid to show complete consumption of Ph NH2 and pure
15 Ph2 NH2; GC/MS (CI-MS: m/z = 171(M + 1)) with a negligible amount of Ph3N.
104 Figure 2.12. Beer’s Law plot for [Me2NN]Cu-NPh2 (2) in Et2O.
15 Li NPh2. n-Butyllithium (2.75 mL, 4.400 mmol, 1.6 M solution in hexanes) was added
15 dropwise to a solution of Ph2 NH (0.500 g, 2.911 mmol) in 8 mL toluene at -35 °C. The solution was allowed to warm to room temperature for 1 hr after which a white precipitate had formed. The mother liquor was removed and the precipitate was washed with 3 mL of cold pentane and dried in vacuo affording 0.456 g of product in 89 % yield.
15 15 [Me2NN]Cu- NPh2. A solution of Ph2 NLi (0.200 g, 1.136 mmol) in 3 mL of THF was added to a stiring solution of [Me2NN]Cu-I (0.563 g, 1.136 mmol) in 4 mL THF. The purple solution immediately turned dark green and the solution was allowed to stir for 1 hr. The solvent was removed in vacuo and the solids were extracted 3 times with 5 mL of
105 pentane. The solution was filtered over Celite, concentrated to 4 mL, and allowed to
crystallize overnight at -35 °C. The mother liquor was removed and the residue was washed with a few mL of cold pentane to yield 0.435 g of green crystals (71 % yield).
Characterization by UV-Vis reveals this compound to be spectroscopically identical to
-1 -1 [Me2NN]Cu-NPh2. UV-Vis (Et2O, 25 °C, nm(cm M )) 426(530), 532(280), 774(1200),
908(1200).
Reaction of [Me2NN]Cu-NPh2 with 1 equiv NOgas. A solution of [Me2NN]Cu-NPh2
(0.040 g, 0.072 mmol) in 600 L of benenze-d6 was added to a NMR tube and capped with a rubber septa. The sealed NMR tube was brought outside the glovebox and NOgas
(1.75 mL, 0.072 mmol) was added. A 1H and 13C NMR were immediately taken on the sample to show the formation of Ph2NNO along with some [Me2NN]H and other
1 paramagnetic peaks. NMR data for Ph2NNO: H NMR (benzene-d6, 400 MHz, 25 °C): δ
7.199 (d, 2, o-ArH), 6.924-6.857 (m, 6, ArH), 6.666 (d, 2, o΄ -ArH). 13C{1H}NMR
(benzene-d6): δ 143.22, 137.35, 129.65, 129.39, 129.06, 127.82, 126.59, 119.72. No attempt was made to quantify the amount of Ph2NNO produced from the reaction since
II the copper in the solution will react with the nitrosamine and form [Me2NN]Cu (ON-
I Me2NN)2Cu . Thus the longer the reaction of NOgas with [Me2NN]Cu-NPh2 is allowed to stand, the more Ph2NNO will be consumed by copper.
Reaction of {[Me2AI]Cu}2 with Ph2NNO. At -35 °C, Ph2CNNO (0.020 g, 0.102 mmol) in 400 L of benzene-d6 is added drop wise to a stirring solution of {[Me2AI]Cu}2 (0.040 g, 0.051 mmol) in 600 L benzene-d6. The solution immediately turns from 106 orange/yellow to light brown. Analysis of the reaction mixture by both 1H and UV-Vis shows that the Ph2NNO ligand is labile and that the Cu(I) does not reductively cleave the
1 Ph2N-NO bond. The H NMR spectra (Figure 2.13a) shows broadening of the peaks attributed to {[Me2AI]Cu}2 suggesting that the nitrosamine exchanges with the
{[Me2AI]Cu}2 on the NMR timescale. At ~500 nm a new species appears in the UV-Vis spectra (Figure 2.13b). This is due to a small binding constant between {[Me2AI]Cu}2 and 2 equiv of Ph2NNO.
t [Me2AI]NO (4) as a byproduct of reaction of {[Me2NN]Cu}2 with BuONO. At room
t temperature, when 10 equiv Cu of BuONO (0.132 g, 1.280 mmol) in 2 mL Et2O is added to a slurry of {[Me2AI]Cu}2 (0.200 g, 0.256 mmol) in 4 mL Et2O, the solution turns dark brown immediately. The reaction mixture is allowed to stir for 30 min, filtered through Celite, and concentrated to 3 mL. At -35 °C overnight, yellow crystals form and
1 are identified as [Me2AI]NO by X-ray crystallography characterization. H NMR
(benzene-d6): δ 8.696 (s, 1, imine-H), 8.653 (d, 1, Ar-H), 7.019-6.818 (m, 9, Ar-H),
13 1 6.763 (d, 2, Ar-H), 6.553 (d, 1, Ar-H), 2.305 (s, 6, Ar-CH3), 1.621 (s, 6, Ar-CH3) C{ H}
NMR (benzene-d6): δ 159.42, 151.98, 141.23, 136.35, 131.38, 130.03, 129.89, 129.84,
129.00, 128.15, 127.88, 127.36, 127.10, 124.21, 120.60, 18.50, 17.94. IR (cm-1): 2281,
1444 (νNO), 1129 (νNN). We could not get the reaction mixture free of copper and were unable to get elemental analysis on this compound. Attempts at synthesizing this molecule independently under copper-free condtions were unsuccessful.
107 a)
{[Me2AI]Cu)2
1 H NMR benzene-d6
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 n20 b)
1 Figure 2.13 a) H NMR and b) UV-Vis reaction of {[Me2AI]Cu}2 + 2 Ph2NNO in benzene-d6 or toluene.
108 [Me2NN]Cu(CNAr) (5). A solution of 2,6-dimethyphenyl isocyanide (0.054 g, 0.408 mmol) in 2 mL ether was added to a slurry of {[Me2NN]Cu}2 (0.150 g, 0.204 mmol) in 4 mL ether. The insoluble material went completely into the solution and the color remained light yellow. The solution was allowed to stir for 15 mins. The volatiles were removed in vacuo and the resulted residue was crystallized from cold pentane at –35°C overnight to give 0.190 g (93 %) of the product as yellow crystals suitable for X-ray
1 diffraction. H NMR (benzene-d6, 300 MHz, 25 °C): δ 6.884 (d, 4, m-ArH), 6.732 (t, 2, p-
ArH), 6.594 (t, 1, p-CNArH), 6.394 (d, 2, m-CNArH), 5.037 (s, 1, CHbackbone), 2.405 (s,
13 1 12, o-ArMe2), 1.810 (s, 6, Mebackbone), 1.628 (s, 6, o-CNArMe2) C{ H} NMR (benzene- d6): δ 165.89, 162.64, 153.03, 136.81, 135.65, 134.90, 130.27, 128.00, 127.49, 122.77,
-1 94.34, 22.39, 19.29, 18.00. IR (cm ): 2124 (νC≡N).
[Me2AI]Cu(CNAr) (6). A solution of 2,6-dimethyl isocyanide (0.050 g, 0.384 mmol) in
2 mL ether was added to a slurry of {[Me2AI]Cu}2 (0.150 g, 0.192 mmol) in 4 mL ether.
The insoluble material went completely into the solution and the color remained bright yellow. The solution was allowed to stir for 15 mins. The volatiles were removed in vacuo and the resulted residue was crystallized from cold pentane at –35°C overnight to
1 give 0.157 g (78 %) of the product as yellow crystals. H NMR (benzene-d6, 300 Mz, 25
°C ): δ 7.968 (s, 1, imine-H), 7.423-6.318 (m, 13, Ar-H overlapping CNArH), 2.482 (s, 6,
-1 o-Ar-Me2), 2.310 (s, 6, o-Ar-Me2), 1.576 (s, 6, o-CNAr-Me2). IR (cm ): 2131 (νC≡N).
109 DFT calculation details
The DFT calculations employed the Becke-Perdew exchange correlation
functional [1] using the Amsterdam Density Functional suite of programs (ADF 2007.01)
[2]. Slater-type orbital (STO) basis sets employed for H, C, and N atoms were of triple-ζ quality augmented with two polarization functions (ZORA/TZ2P) while an improved triple-ζ basis set with two polarization functions (ZORA/TZ2P+) was employed for the
Cu atom. Scalar relativistic effects were included by virtue of the zero order regular approximation (ZORA) [3]. The 1s electrons of C and N as well as the 1s – 2p electrons of Cu were treated as frozen core. The VWN (Vosko, Wilk, and Nusair) functional was used for LDA (local density approximation) [4]. Default convergence (∆E = 1 × 10-3
-2 -2 hartree, max. gradient = 1 × 10 hartree / Å, max. Cartesian step = 1 × 10 Å) and integration (4 significant digits) parameters were employed for geometry optimizations.
Experimental X-ray coordinates for [Me2NN]Cu-NPh2 (2) were used as the starting point for the geometry optimization of [Me2NN]Cu-NPh2 in an unrestricted (S =
1/2) calculation specifying 1 unpaired electron (spin α – spin β). ADFview [2a] was used to prepare the three-dimensional representations of the structures as well as to render the frontier Kohn-Sham MOs which appear in Figure 2.9.
110 References for calculations
[1] (a) Becke, A. Phys. Rev. A 1988, 38, 3098. (b) Perdew, J. P. Phys. Rev. B 1986,
34, 7406. (c) Perdew, J. P. Phys. Rev. B 1986, 33, 8822.
[2] (a) http://www.scm.com – last accessed July 25, 2008. (b) te Velde, G.;
Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.;
Snijders, J. G.; Ziegler, T. J. Comput. Chem. 2001, 22, 931. (c) Fonseca Guerra, C.;
Snijders, J. G.; te Velde, G.; Baerends, E. J.; Acc., T. C. Theor. Chem. Acc. 1998, 99,
391.
[3] (a) Snijders, J. G.; Baerends, E. J.; Ros, P. Mol. Phys. 1979, 38, 1909. (b) Ziegler,
T.; Tschinke, V.; Baerends, E. J.; Snijders, J. G.; Ravenek, W. K. J. Phys. Chem. 1989,
93, 3050. (c) van Lenthe, E.; Baerends, E. J.; Snijders, J. G. J. Chem. Phys. 1993, 99,
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111
II I Figure 2.13. X-band EPR spectrum and simulation for [Me2NN]Cu (ON-Me2NN)2Cu (1) (frozen toluene glass, 90 K). Simulation provides gparallel = 2.20 and gperp = 2.05 with Aparallel(Cu) = 545 MHz and Aperp(Cu) = 74 MHz. Aperp(N) = 31 MHz and Aparallel(N) = 36 MHz was used for 4 nitrogens with similar hyperfine couplings. Data were collected and simulated by Dr. Susanne Mossin of Prof. Karsten Meyer’s research group at the University of Erlangen, Germany.
112
Figure 2.14. X-band EPR spectrum and simulation for [Me2NN]CuI (3) (frozen toluene glass, 12 K). Simulation provides g1 = 2.175, g2 = 2.215, g3 = 2.030 with A1(Cu) = 410 MHz, A2(Cu) ≈ A3(Cu) ≈ 40 MHz and Aiso(N) = 43 MHz for 2 N atoms with similar hyperfine coupling. Data were collected and simulated by Dr. Susanne Mossin of Prof. Karsten Meyer’s research group at the University of Erlangen, Germany.
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117 Chapter 3
Release of NO from S-Nitrosothiols and Organic Nitrites at a
β-Diketiminato Cu(I) Complex
Abstract
An electron-rich copper(I) β-diketiminate cleaves the O-NO bond of the organic nitrite
t BuONO and the S-NO bond of the S-nitrosothiol Ph3SCNO to release NO and give the
t three coordinate copper(II) complexes [Me2NN]Cu-O Bu and [Me2NN]Cu-SCPh3. These copper(II) complexes are unstable in the presence of NO – flushing the system with N2 immediately after the addition of the organonitroso compound to remove the generated
NO(gas) allows for their quantification in 91 and 73 % yield, respectively. [Me2NN]Cu-
t O Bu reacts with NO to give ½ equiv {[Me2NN]Cu}2( -OH)2 while [Me2NN]Cu-SCPh3 reacts with NO to give a new copper(II) complex possessing two β-diketiminate ligands, one of which has undergone nitrosation at the β-diketiminate backbone methine C-H.
Introduction
Many NO related biological functions such as anti-platelet aggregation, vasodilation, and pre-eclampsia1 have been directly associated with RSNOs, either via the release of NO or as the RSNO itself.2 These compounds are believed to be involved in the storage and transport of NO and are considerably less oxygen sensitive than NO itself.3-6
118 There is much evidence to support NO as the endothelium derived relaxing factor
(EDRF). New studies are emerging, however, that support the EDFR to be a more stable source of NO, namely an S-nitrosothiol.7 Provided that facile pathways to release NO from S-nitrosothiols are available, NO can be deemed to circulate in the blood primarily
as RSNO species. Free NO has a blood concentration of < 0.012 nM at aPm = 4.5 cm/s
8 and Hct = 45% (Pm-permeability of red blood cell to NO, Hct-hematocrit). Thus, it is unlikely that NO is directly exported or generated from the red blood cell as an intravascular signaling molecule because its concentration would be too low to exert a physiological role. The nitroso adduct of serum albumin (S-nitrosoalbumin, MWT =
66000 Da) has a blood concentration of 5 M and composes about 80 % of the blood
SNO O H HO2C N CO2H NO N H O NH2 Free NO S nitrosocysteineglutathione 4 nM 0.02 0.2 M
SNO SNO
H2N CO2H
S nitrosocysteine Ablumin Cys34 SNO 0.2 0.3 M 5 M
Figure 3.1. Concentration of NO and endogenous S-nitrosothiols in blood.
119 plasma RSNO content (Figure 3.1).9 Two other endogenous sources of RSNO are S- nitrosocysteine and S-nitrosocysteingluathione and have a blood concentration of 0.2 –
0.3 and 0.02 - 0.2 M, respectively (Figure 3.1).10-12 Administration of exogenous S- nitroso-albumin leads to vasorelaxation, a decrease in mean arterial blood pressure, and inhibition of platelet aggregation.13,14 Nitric oxide synthase (NOS) inhibitors lead to a decrease in the concentration of plasma RSNOs, vasoconstriction, and an increase in mean arterial blood pressure.15 This suggests that S-nitroso-albumin has a role functioning as a NO donor. Moreover, its formation is also dependent on NOS activity.
Kinetic studies on the decomposition of RSNO compounds in aqueous solutions did not yield consistent results until Williams, Butler, and co-workers reported that even trace amounts of copper ions (even from distilled water) catalyzed the decomposition of
RSNOs to NO and ½ equiv RSSR (Scheme 3.1).16 Williams suggested in a later study the possible biological relevance of the Cu+-induced decomposition of RSNO with the observation that Cu2+ ions complexed to amino acids, peptides, and proteins also
+ 17 decompose RSNOs via initial reduction by thiolate to Cu ..
Scheme 3.1. Activation of the S-NO bond by trace amounts of Cu ions in solution yield NO and ½ equiv of RSSR. Copper-zinc superoxide dismutase (CuZn-SOD) (Figure 3.2)18 has been considered as a possible Cu-enzyme that catalyzes NO release from RSNOs in vivo.19
The decomposition of GSNO by CuZn-SOD resulted in the sustained production of NO.
It was proposed that GSH reduces enzyme-associated Cu2+ to Cu1+ which mediates the 120 His44 His69
Asp81 His118 Cu Zn
His78 His46 His61
Figure 3.2. X-ray structure of active site of CuZn-SOD showing coordination of Cu to four histines, and Zn to three histines and one aspartic acid. Figure drawn using Open Source PyMolTM Version 0.99rc6 2007, PDB 1Q0E, Hough, M. A.; Hasnain, S. S. Structure 2003, 11, 937-946. reductive decomposition of the S-nitrosothiol to yield free NO. Thus, copper(I) appears
to be the active oxidation state for NO release from RSNOs. In fact, neocuproine (2,9-
dimethyl-1,10-phenanthroline) which is a potent chelator for copper(I) halts this
enzymatic denitrosylation.19
CuZn-SOD may represent an important physiological modulator of steady-state concentrations of low molecular weight S-nitrosothiols in vivo.19 Specifically, when glutathione is in the presence of CuZnSOD, S-nitrosoglutathione formation can be detected.19 Thiols do not form S-nitrosothiols with NO under anaerobic conditions. This implicates copper in having a role in the cleavage and formation of the RS-NO bond
(Scheme 3.2). Further studies of the copper ion-induced RSNO decomposition have confirmed the role of Cu+ in decomposition kinetics and rat vascular smooth muscle relaxation.2,20
121 Recent data suggest that either excessive or deficient levels of protein S- nitrosylation may contribute to disease. Mutations in CuZn-SOD can lead to RSNO depletion and disrupt subcellular localization of proteins that are regulated by S- nitrosylation such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH).21 These results suggest that abnormal depletion of intracellular RSNOs contributes to motor neuron death and thereby contribute to amyotrophic lateral sclerosis (ALS). These initial findings raise the possibility that deficient S-nitrosylation is a general mechanism of disease pathogenesis.22 For instance, Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in
Parkinson’s disease (PD). Parkin is S-nitrosylated in vitro as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover,
S-nitrosylation inhibits Parkin’s ubiquitin E3 ligase activity and its protective function.
This inhibition of Parkin’s ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of Parkin substrates.23
Scheme 3.2. Role of CuZnSOD in formation of GS-NO bond (left) and activation of low molecular weight RSNOs to release NO (right). 122 Organic nitrites RONO are related to S-nitrosothiols and exhibit related vasodilation behavior. For instance, butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, and isoamyl nirite have been clinically used as vasodilators and can generate NO in vivo.24 RONOs are less prone to homolytic “self-decomposition” than RSNOs
(homolytic BDE for RO-NO = 36-41 kcal/mol)25 due to the relative weakness of the RS-
NO bond (31-32 kcal/mol)26 and strength of RS-SR bond (65-66 kcal/mol) (Scheme
3.3).27 Organic nitrites are good sources of NO+. In fact, S-nitrosthiols can be synthesized from the nitrosation of thiols RSH by RONO (Scheme 3.3). S-nitrosothiols can be formed from organic nitrites in vivo since the NO+ portion of RONO can be transferred to a thiol via transnitrosation.28,29 In addition, both organic nitrites and S- nitrosothiols are both susceptible to NO loss via a 1-electron reduction.30-32
Scheme 3.3. Release of NO from RONOs requires a 1-electron reductant while homolysis can release NO from RSNOs.
The uptake of NO as NO+ by a nucleophilic ligand - reductive nitrosylation - has been observed for copper complexes (Scheme 3.6). The reaction of the five-coordinate
2+ cupric complex Cu(dmp)2(H2O) with NO in methanol leads to the formation of the
+ four-coordinate cuprous species Cu(dmp)2 along with methyl nitrite and (presumably)
33,34 H2O released in solution (Scheme 3.4). An N-bound RONO ligand in
+ [(dmp)2CuN(O)OR] has been proposed based on kinetic considerations as an
123 intermediate in the reaction of a Cu2+(ROH) complex with NO. Ford also reports an
2+ intramolecular pathway in which a secondary amine coordinated to Cu is nitrosylated to an N-nitroso secondary amine.35 In general, reductive nitrosylation of a metal-bound ligand bond with concomitant reduction of the metal is fairly common, especially for Fe3+ and Cu2+.36
2+ Scheme 3.4. Reductive nitrosylation of MeOH and NO to Cu(dmp)2(H2O) to yield + MeONO and Cu(dmp)2 .
Electron-rich metalloenzymes may serve as 1-electron reducing agents and motivate studies of model complexes to understand factors that result in cleavage of the
E-NO bond and concomitant formation of NO (Schemes I.12 and 3.5). For instance, we recently reported a β-diketiminate nickel(I) system to cleanly reductively cleave the E-
- - - NO bond (E= RS , RO , and R2N ) and form Ni(II)-E and Ni-NO in the presence of two
Ni(I) fragments.37 Understanding the process by which E-NO compounds deliver NO is crucial for the effective treatment of diseases associated with disrupted regulation of NO and the design of future NO delivery drugs. 124 Scheme 3.5. Activation of E-NO bond requires a 1-electron reduction to release NO and E-.
Scheme 3.6. Equilibrium of a) reductive nitrosylation (metal reduced) and b) reductive cleavage (E-NO bond reduced). Results and Discussion
t 3.1. Reaction of BuONO with {[Me2NN]Cu}2.
t 38 When 2 equiv. BuONO are added to yellow {[Me2NN]Cu}2 (1) in toluene at -
30 °C, the solution immediately turns red from the growth of a UV-vis band at λmax =
409 nm (Figure 3.3). Upon warming to room temperature, a brown precipitate of
39 {[Me2NN]Cu}2( -OH)2 is isolated in 90 % yield. Characterization of the reaction mixture by GC/MS and 1H NMR reveals tBuOH as a byproduct of the reaction. Since we
t anticipated the formation of [Me2NN]Cu-OBu (2) (Scheme 3.7), we sought its synthesis
t t by a related oxidative route. Addition of 1 equiv. BuOOBu to {[Me2NN]Cu}2 (1) in
t toluene results in a similar UV-Vis spectra (Scheme 3.8). [Me2NN]Cu-OBu may be isolated on a preparative scale employing tBuOOBut in 86 % as red crystals from pentane
-1 -1 (UV-Vis λmax = 409 nm (1500 cm M )).
125 t Scheme 3.7. [Me2NN]Cu-OBu (2) forms from reaction of ½ equiv {[Me2NN]Cu}2 (1) t t and BuONO. [Me2NN]Cu-OBu (2) may also be prepared from the reaction of t t {[Me2NN]Cu}2 and BuOO Bu.
t Scheme 3.8. [Me2NN]Cu-OBu (2) is not stable in the presence of NO and decomposes to form ½ equiv. {[Me2NN]Cu}2( -OH)2. This copper(II)-alkoxide species is three coordinate, related in structure to other
β-diketiminato Cu(II)-phenoxide complexes prepared by Tolman (Figure 3.5).40 The X- ray crystal structure of 2 shows that the bulky tert-butyl group forces the copper(II)- alkoxide into a planar three coordinate environment despite the affinity of oxygen to
39 bridge in the related hydroxide {[Me2NN]Cu}2(µ-OH)2. The copper center has a Cu-O
126 t t Figure S#.3.3 .Reaction Reaction of ½of {[Me½ {[Me2NN]Cu}2NN]Cu}2 + BuONO,2 with BuONO0.33 mM, (0.33 0 °C, mM)10 s scans in toluene for 30 mins.at 0 °C. t 1) {[Me2NN]Cu}2 before any BuONO is added. 2) Reaction of {[Me2NN]Cu}2 with t t BuONO, [Me2NN]Cu-OBu (2) is formed and decomposed due to the presence of NOgas. 3) After 30 min, 2 decomposed to{[Me2NN]Cu}2( -OH)2 (λmax = 598 nm)
distance of 1.788(2) Å and Cu-Nβ-dik distances of 1.879(2) and 1.890(2) Å. The Cu atom is planar (sum of angles about Cu = 359.8(2)°). The alkoxide atom is bent, with a Cu-O-C angle of 123.82(12)°. Tolman’s four β-diketiminate Cu(II)-phenoxide structures have an average Cu-Ophenoxide distance of 1.810(5) Å, which is longer than the the Cu-Oalkoxide
distance in 2.
t 3.2. Reaction of BuONO with {[Me2NN]Cu}2, flushed with N2(gas).
t If [Me2NN]Cu-OBu is stable in solution overnight at room temperature (Scheme
3.7, second reaction), why is it such short lived (t1/2 ≈ 10 - 30 s at 0 °C) as monitored by
127 t UV-Vis when formed in the reaction between BuONO and 1 (Figure 3.3)? The NOgas released during the reductive cleavage of tBuONO must have a role in the decomposition
t of [Me2NN]Cu-OBu to {[Me2NN]Cu}2( -OH)2. In a sealed UV-Vis cuvette we added 2
t equiv. BuONO to a solution of {[Me2NN]Cu}2 in toluene at 0 °C. After the reagent was added we immediately flushed the cuvette with nitrogen gas for 30 min and let the cuvette sit at 0 °C for 2 hr. We then took at UV-Vis spectra and found that [Me2NN]Cu-
t O Bu had formed in 91 % yield and had not decomposed to {[Me2NN]Cu}2( -OH)2 in the absence of NO (Figure 3.4, spectrum 2). Addition of 1 equiv NO to this solution results in the formation of the hydroxide in 95 % yield within 30 min (Figure 3.4,
t spectrum 3). Both addition of BuONO to 1 as well as addition of NO to [Me2NN]Cu-
t OBu (2) have the final fate of {[Me2NN]Cu}2( -OH)2. When we conducted UV-Vis experiments at -80 °C, we were unable to see any new intermediate formation in the
t addition of BuONO to ½ equiv.{[Me2NN]Cu}2.
128 t Figure 3.4. Reaction of ½ {[Me2NN]Cu}2 with BuONO (0.33 mM, concentrations of t each) in toluene at 0 °C, then flushed with N2 gas. 1) {[Me2NN]Cu}2 before any BuONO t is added. 2) Reaction of {[Me2NN]Cu}2 with BuONO followed by flushing of N2(gas) 10 t min, spectra taken after 2.5 hr. shows [Me2NN]Cu-O Bu (2) is formed and not t decomposed due to the absence of NOgas. 3) Addition of NOgas to [Me2NN]Cu-O Bu leading to the formation of {[Me2NN]Cu}2( -OH)2.
129 N1
C22 Cu O N2
t Figure 3.5. X-ray structure of [Me2NN]Cu-O Bu (2) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.890(2), Cu–N2 1.879(2), Cu–O 1.788(2), N1– Cu–N2 96.17(7), N1–Cu–O 128.70(7), N2–Cu–O 134.94(6), Cu-O-C22 122.82(12).
130 3.3. Reaction of Ph3CSNO with {[Me2NN]Cu}2.
Reaction of {[Me2NN]Cu}2 (1) with the S-nitrosothiol Ph3CSNO initially follows a conceptually related course. Addition of 2 equiv. Ph3CSNO to {[Me2NN]Cu}2 in toluene at 0 °C results in the rapid (< 10 sec) formation of a new species with λmax = 731 nm that decomposes over 30 min to a new species with a λmax = 647 nm. Independent synthesis of the copper(II)-thiolate [Me2NN]Cu-SCPh3 (3) via reaction of [Me2NN]Cu-
t OBu and Ph3CSH confirms the identity of this first species (UV-Vis λmax = 731 nm
(5800 cm-1M-1)) (Scheme 3.9, Figure 3.6)
X-ray characterization of 3 shows a planar, three coordinate copper center despite the propensity of thiolate ligands to form bridging complexes (Figure 3.8). The Cu-Sthiolate distance is 2.137(1) Å and the Cu-Nβ-dik distances are 1.896(2) and 1.907(2) Å. The Cu atom is almost planar (sum of angles about Cu = 356.6(2)°). The thiolate atom is bent,
Scheme 3.9. [Me2NN]Cu-SCPh3 (3) forms in reaction of ½ equiv {[Me2NN]Cu}2 and Ph3CSNO. [Me2NN]Cu-SCPh3 (3) can be independently prepared from [Me2NN]Cu- t OBu and Ph3CSH. [Me2NN]Cu-SCPh3 (3) is not stable in the presence of NO and decomposes to form ½ equiv Ph3CSSCPh3 and ½ equiv {[Me2NN]Cu}([Me2NN]NO) (4).
131 Figure 3.6. Reaction of ½{[Me2NN]Cu}2 with Ph3CSNO in toluene at 0 °C (each at 0.20 mM, 10 s scans collected for 30 mins). 1) {[Me2NN]Cu}2 before any Ph3CSNO is
added. 2) Reaction of {[Me2NN]Cu}2 with 2 Ph3CSNO demonstrating rapid formation of [Me2NN]Cu-SCPh3 (3) with subsequent decomposition owing to presence of NOgas. 3) Addition of NOgas to [Me2NN]Cu-SCPh3 led to the formation of [Me2NN]Cu(NO[Me2NN) (4) in 83 % yield. with a Cu-S-C angle of 116.8(7)°. The UV-vis spectrum of 3 possesses a strong charge
-1 -1 transfer band at λmax = 731 nm (5800 cm M ). Its X-ray structure is similar to Tolman’s
i 41 previously reported [ Pr2NN]Cu-SCPh3 with a Cu-Sthiolate distance of 2.1243(8) Å, slightly shorter than 3.
3.4. Reaction of Ph3CSNO with {[Me2NN]Cu}2, flushed with N2(gas).
[Me2NN]Cu-SCPh3 (3) is unstable in the presence of NO. If a UV-Vis cuvette is flushed with N2 gas for 10 min immediately following the addition of Ph3CSNO to
{[Me2NN]Cu}2 (1) in toluene at 0 °C, we found that [Me2NN]Cu-SCPh3 (3) formed in 73
% spectroscopic yield without the formation of the band at λmax = 647 nm (Figure 3.7, 132 Spectrum 2). Addition of NO to [Me2NN]Cu-SCPh3 leads to rapid loss of this species
(Figure 3.7, Spectrum 3). We were unable to see any new intermediate when monitored by UV-vis spectroscopy in the addition of Ph3CSNO to ½ equiv of {[Me2NN]Cu}2 at -80
°C.
Figure 3.7. Reaction of ½{[Me2NN]Cu}2 with Ph3CSNO in toluene at 0 °C ( each at 0.20 mM) then flushed with N2 gas. 1) {[Me2NN]Cu}2 before any Ph3CSNO was added.
2) Reaction of {[Me2NN]Cu}2 with Ph3CSNO followed by flushing of N2(gas) for 10 min[Me2NN]Cu-SCPh3 (3) was formed and not decomposed due to the absence of NOgas. 3) Addition of NOgas to [Me2NN]Cu-SCPh3 led to the disappearance of the peak at 625 nm.
133 3.5 Isolation of decomposition products in reaction of Ph3CSNO with
{[Me2NN]Cu}2.
The reaction of ½ equiv. {[Me2NN]Cu}2 with Ph3CSNO on a preparative scale leads to formation of a green solution with a white precipitate in Et2O. The precipitate
13 determined to be Ph3CSSCPh3 in 82 % yield based on C NMR characterization and its independent synthesis. Careful crystallization of the green solution using Et2O / TMS2O allows for the isolation of green crystals of [Me2NN]Cu(NO[Me2NN]) (4) in 70 % yield
(Figure 3.9).
X-ray characterization of 4 shows a distorted square planar geometry about the copper center with N1-Cu-N3 and N2-Cu-N5 angles of 107.30(11)° and 98.25 (11)°, respectively (Figure 3.9). The Cu-N5 and Cu-NO distances are 1.962(3) and 2.037(3) Å and the Cu-Nβ-dik distances are 1.928(3) and 1.940(3) Å. The dihedral angle between the two separate N-Cu-N planes is 52.54°. The NO and imine C24-N4 distances are 1.278(3) and 1.271(4) Å which supports delocalization about the entire π-system of the κ2- nitrosated β-diketiminate ligand.
During the isolation of the major product 4, trace amounts of the copper(I) thiolate [CuSCPh3]4 (5) (Figure 3.10) and {[Me2NN]Cu}2( -OH)2 are also identified by
X-ray crystallography. The X-ray structure of 5 shows a tetranuclear copper center where each copper bound to two tritylthiolate ligands. The Cu1-S1 and Cu1-S2' distances are
2.1710(7) and 2.1674(7) Å and the Cu2-S1 and Cu2-S2 distances are 2.1556(8) and
2.1684(8) Å. This complex is very similar to another homoleptic copper(I) thiolate where
134 the R group is 2,4,6-triisopropylphenyl.42 The Cu1-Cu2 and Cu1-Cu2' distances are
2.7493(5) and 3.1041(8) Å.
135 N1
Cu S C22 N2
Figure 3.8. X-ray structure of [Me2NN]Cu-SCPh3 (3) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.896(2), Cu–N2 1.907(2), Cu–S 2.1377(6), N1–Cu–N2 95.76(8), N1–Cu–S 128.04(6), N2–Cu–S 132.79(6), Cu-S-C22 116.80(7). 136 N1 N3 Cu N5 N2 N4
O
Figure 3.9. X-ray structure of [Me2NN]Cu(NO[Me2NN]) (4) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu–N1 1.928(3), Cu-N2 1.940(3), Cu-N3 2.037(3), Cu-N5 1.962(3), O-N5 1.278(3), N1-Cu-N2 96.32(11), N1-Cu-N3 107.30(11), N1-Cu-N5 148.91(11), N2-Cu-N3 135.92(11), N2-Cu-N5 98.25(11), N3-Cu-N5 80.30(11).
137 S1 Cu1 S2'
Cu2 Cu2'
Cu1' S2 S1'
Figure 3.10. X-ray structure of [CuSCPh3]4 (5) (all H atoms omitted). Selected bond distances (Å) and angles (deg): Cu1-S1 2.1710(7), Cu2-S1 2.1556(8), Cu2-S2 2.1684(8), Cu1-S2' 2.1674(7), Cu1-Cu2 2.7493(5), Cu1-Cu2' 3.1041(5), S1-Cu2-S2 161.95(3), S1-Cu2-Cu1 50.80(2), S2-Cu2-Cu1 127.95(2), S2'-Cu1-S1 171.83(3), S2- Cu1'-Cu2' 137.74(2), S1-Cu1-Cu2 50.30(2), Cu2-S1-Cu1 78.90(3), Cu1'-S2-Cu2 91.43(8). 138 3.6. Mechanistic considerations - comparison with related nickel(I) system
t In both the reaction of BuONO and Ph3CSNO with {[Me2NN]Cu}2, the
t corresponding copper(II) products [Me2NN]Cu-OBu (2) and [Me2NN]Cu-SCPh3 (3) form in 91 % yield and 73 % yield, respectively when NO is flushed out of the system.
This is suggestive of initial binding of the O or S to the copper with subsequent cleavage of the RO-NO and RS-NO bonds to release NO (Scheme 3.10).
This mode of reactivity stands in contrast to that observed in the nickel chemistry described in Chapter 1 in which we see that [Ni](NO) rather than [Ni]-E formation is preferred in reaction with a deficit of organonitroso reagent E-NO. Nonetheless, both CuI and NiI are good one-electron reductants for reductive cleavage of the E-NO bond. The difference lays in the ability of NiI to also serve as a good trap for NO to form the nitrosyl complex [Ni](NO). Copper is less electron-rich and therefore the corresponding
[Cu](NO) formation is not as favorable.
Scheme 3.10. Suggested mechanism of E-NO activation through E coordination to I [Me2NN]Cu to form [Me2NN]Cu(ENO). The [Me2NN]Cu then reductively cleaves the II E-NO bond to form [Me2NN]Cu -E.
139 Table 3.1. Crystallographic parameters for 2, 3, 4, and 5.
Compd. 2 3 4 5
Formula C25H34CuN2O C40H40CuN2S C42H50CuN5O C38H30Cu2S2 Mol. Wt. 442.08 644.34 704.41 677.82 Temp.(K) 100(2) 100(2) 100(2) 100(2) Crystal Block Block Plate Block description Crystal color Red Blue Green Colorless Crystal size 0.0364 0.0528 0.0026 0.0132 (mm3) System Orthorhombic Monoclinic Monoclinic Monoclinic Space group P212121 P2(1)/n P2(1)/c P1(1)/n a (Å) 8.2840(12) 8.4626(10) 14.8262(3) 13.428(10) b (Å) 15.010(2) 19.083(2) 16.682(3) 8.6253(7) c (Å) 19.406(3) 10.7638(13) 15.328(2) 25.8383(19) α (deg) 90 90 90 90 β (deg) 90 107.1400(10) 95.564(2) 93.5980(10) γ (deg) 90 90 90 90 Volume (Å3) 2413.1(6) 1661.1(3) 3738.4(10) 2986.8(4) Z 4 2 4 4 θ range (deg) 1.72-28.25 1.98-27.00 1.39-27.00 1.76-28.00 Measd reflns 22055 14364 32065 26262 Unique reflns 5842 7082 8144 7110 GOF of F2 0.998 0.998 0.948 1.105
R1 ( I > 2σ(I)) 0.0319 0.0296 0.0561 0.0384 wR2 (all data) 0.0751 0.0659 0.1392 0.1054 Largest diff. 0.421 and 0.493 and 0.592 and 0.475 and - peak and hole -0.287 -0.252 -0.598 0.428 (e-.Å-3)
140 Summary
While reductive nitrosylation has become accepted as the norm in the reaction of
copper with nitric oxide to generate nitrosated organic species such as organonitrites, we
demonstrate the first examples of the opposite reaction - reductive cleavage. The
biologically relevant Cu(I) ion contained in the electron rich β-diketiminate ligand and
t cleaves BuO-NO and Ph3CS-NO substrates to release NO and form the corresponding
II t II three coordinate [Cu ]-OBu and [Cu ]-SCPh3 species. The β-diketiminate ligand again is subject to nitrosation by NO at the backbone CH, rendering it non-ideal to explore both reductive cleavage and reductive nitrosylation at a common copper complex. Chapter 4 explores the use of a more robust ligand framework less susceptible to ligand nitrosation: tris(pyrazolyl)borates.
141 Experimental procedures
General experimental details.
All experiments were carried out in a dry nitrogen atmosphere using an MBraun
glovebox and/or standard Schlenk techniques. 4A molecular sieves were activated in
vacuo at 180 ºC for 24 h. Dry toluene and dichloromethane were purchased from Aldrich
and were stored over activated 4A molecular sieves under nitrogen. Diethyl ether and
tetrahydrofuran (THF) were first sparged with nitrogen and then dried by passage through
43 activated alumina columns. Pentane was first washed with conc. HNO3/H2SO4 to remove olefins, stored over CaCl2 and then distilled before use from sodium/benzophenone. All deuterated solvents were sparged with nitrogen, dried over activated 4A molecular sieves and stored under nitrogen. 1H and 13C NMR spectra were recorded on either a Varian 300 MHz or 400 MHz spectrometer (300 or 400 and 75.4 or
100.4 MHz, respectively). All NMR spectra, including Evans method data, were recorded at room temperature unless otherwise noted and were indirectly referenced to TMS using residual solvent signals as internal standards. GC-MS spectra were recorded on a Varian
Saturn 2100T, elemental analyses were performed on a Perkin-Elmer PE2400 microanalyzer in our laboratories, and UV-Vis spectra were recorded on either an Agilent
8432 or a Cary 50 spectrophotometer. EPR measurements were carried out by collaborator, Susanne Mossin of Karsten Meyer’s group at the University of Erlangen,
Germany.
142 Tritylthiol, tert-butylnitrite, and tert-butylperoxide were obtained from Acros and
were used as received. Copper tert-butoxide was synthesized according to the published
procedure.44
Preparation of compounds.
{[Me2NN]Cu}2 (1). {[Me2NN]Cu}2 was prepared according to a modified literature
38 procedure. [Me2NN]H (2.00 g, 6.536 mmol) in 10 mL of toluene was adding to a stirring solution of copper(I) tert-butoxide (1.071 g, 7.843) in 25 mL of toluene. The solution was allowed to stir for 2 hr, filtered over Celite, and the volatiles were removed in vacuo to yield brown oil. The brown oil was washed with pentane (3 × 8 mL) to afford
1 2.25 g (92 %) of {[Me2NN]Cu}2 as a yellow powder. H NMR (benzene-d6, 400 MHz, 25
°C): δ 7.100 (d, 4, m-ArH), 6.993 (t, 2, p-ArH), 4.776 (s, 1, CHbackbone), 2.016 (s, 12, o-
ArMe2), 1.643 (s, 6, Mebackbone).
39 Isolation of {[Me2NN]Cu}2( -OH)2 from reaction of {[Me2NN]Cu}2 (2) with
tBuONO. At -30 °C, tBuONO (0.100 g, 0.972 mmol) in 2 mL of toluene was added dropwise to a stirring solution of {[Me2NN]Cu}2.(0.300 g, 0.405 mmol) in 3 mL of toluene at -35 °C. The solution immediately turned from light tan to red and then to brown within 30 minutes. A brown precipitate formed after 30 min of stirring. This precipitate was isolated in 0.298 g and found to be [Me2NN]Cu2(µ-OH)2 (96 % yield).
UV-Vis (toluene, 25 °C, nm(cm-1M-1) 308(13000), 598(550). Analysis of the reaction mixture by 1H and 13C NMR and GC/MS revealed the fate of the tBuO group to be
143 Concentration (mM)
Figure 310. Beer’s law plot for {[Me2NN]Cu}2( -OH)2 in toluene.
t 1 BuOH. H NMR (benzene-d6): δ 2.132 (br s, 1, Me3CO-H), 1.099 (s, 9, Me3COH)
13 1 C{ H}NMR (benzene-d6): δ 168.20 (Me3COH), 34.42 (Me3COH). GC/MS (m/z): 75
(M+1).
t t t Independent synthesis of [Me2NN]Cu-OBu (2). BuOO Bu (0.159, 1.086 mmol) in 2 mL of Et2O was added to a stirring slurry of {[Me2NN]Cu}2 (0.400 g, 0.543 mmol) in 4 mL of Et2O. The solution slowly turned from tan to dark red over the course of an hour.
After stirring for 2 h, the solution was filtered over Celite and the volatiles were removed in vacuo. The solid residue was extracted with pentane (3 mL), filtered over Celite, and left to crystallize overnight at -30 °C. The red crystals that formed were collected and
144 dried under vacuum to afford a total yield of 0.412 g (86 % yield) of product. UV-Vis
-1 -1 (toluene, 25 °C, nm(cm M ), 409(1500). Anal. Calcd for C25H34CuN2O: C, 67.92; H,
7.75; N, 6.34. Found C, 67.61; H, 7.63; N, 6.38. EPR (X-band, frozen toluene glass, 30
K): Simulation provides g1 = 2.233, g2 = 2.057, g3 = 2.037 with A1(Cu) = 120 G, A2(Cu)
Concentration (mM)
t Figure 3.11. Beer’s law plot of [Me2NN]Cu-O Bu.
≈ A3(Cu) ≈ 0 G and Aiso(N) = 12.9 G.
Ph3CSNO. Trityl-S-nitrosothiol was synthesized according to a modified literature
45 procedure. Ph3SH (0.500 g, 1.812 mmol) was dissolved in 8 mL Et2O and 3 equiv
tBuONO (0.560 g, 5.435 mmol) was added to the stirring solution at -35 ºC. The solution
145 immediately turned dark green and was allowed to stir for 15 minutes. The solvent was
removed in vacuo and the residue was extracted with ether (2 × 5 mL) and filtered. The
solution was concentrated to ca. 2 mL. The solution was left to crystallize at –35˚C
overnight. The mother liquor was removed and the crystals were dried in vacuo to afford at total yield of 518 mg (94 % yield) green crystals. The product was stored in the dark at
1 -35 ºC to avoid disulfide formation. H NMR (benzene-d6): δ 7.368-7.289 (m, 9, Ar-H),
13 1 7.221-7.172 (m, 6, Ar-H) C{ H}NMR (benzene-d6): δ 143.78 (Ar-C1´), 130.00 (Ar-C),
-1 127.98 (Ar-C), 127.37 (Ar-C4´), 75.99 (Ph-C-SNO). IR (cm , 25 °C) υNO = 1490
15 46 (reported value for Ph3CS NO υ15NO = 1514 ). In the a previous report on the IR
-1 spectrum of Ph3CSNO a broad band was reported between 1490 and 1530 cm as being due to rotational isomers of the -SNO group.47 In a later study no evidence for rotational isomers was observed in the crystal structure and the IR spectrum from dark green
15 crystals of either the unlabeled or N-labeled compounds showed only a single υNO vibration.46
Reaction of {[Me2NN]Cu}2 (1) with Ph3CSNO. At -35 °C, Ph3CSNO (124, 0.408 mmol) in 2 mL of toluene was added dropwise to a stirring solution of {[Me2NN]Cu}2
(0.150 g, 0.204). The solution immediately turned from light tan to purple within 10 s.
The solution upon warming to room temperature and stirring for 15 mins turned green/brown. The reaction mixture was filtered over alumina to remove the copper metal containing species and the reaction mixture is analyzed by GC/MS and 13C NMR.
Ph3CSSCPh3 is found to be a product from the reaction mixture (0.184 g, 82% yield).
146 13 48 Ph3CSSCPh3 C NMR (acetone-d6) δ 149.89; 129.75, 129.04, 128.80, 70.20, UV-Vis studies were then conducted to identify the purple and green/brown species.
Independent synthesis of [Me2NN]Cu-SCPh3 (3). At -30 °C, Ph3CSH (0.187 g, 0.678
t mmol) in 2 mL of Et2O was added dropwise to a stirring solution of [Me2NN]Cu-OBu
(0.300 g, 0.678 mmol) in 3 mL of Et2O. The solution immediately turned from red to dark blue. The volatiles were removed in vacuo and the solid residue was dissolved in 3 mL of pentane. The solution was filtered over Celite and left to crystallize overnight at -
30 °C. X-ray characterization of these crystals identified them as [Me2NN]Cu-SCPh3.
After the solution sat in the freezer overnight there was an appreciable amount of white solid in the vial. This was from the decomposition of [Me2NN]Cu-SCPh3 to a Cu(I) species and Ph3CSSCPh3. The instability of the compound prevented elemental analysis or an isolated yield.
t Table 3.2. Reaction of [Me2NN]Cu-O Bu (2) and Ph3CSH to form [Me2NN]Cu-SCPh3 (3) in situ for Beer’s Law analysis. t [Me2NN]Cu-SCPh3 [Me2NN]Cu-O Bu Ph3CSH Toluene (10 mM) (10 mM) 0.28 mM 84 L 84 L 2.832 mL 0.21 mM 63 L 63 L 2.874 mL 0.13 mM 39 L 39 L 2.922 mL 0.05 mM 15 L 15 L 2.970 mL
t In situ UV-Vis spectroscopy of the reaction of [Me2NN]Cu-OBu with Ph3CSH was conducted on this reaction at room temperature to determine value of λmax and molar
t absorptivity for pure 3 (Figure 3.12). [Me2NN]Cu-OBu (0.044 g, 0.100 mmol) was 147 dissolved in 2 mL of toluene. The solution was analytically transferred to a 10.00 mL
volumetric flask and diluted to 10.00 mL with toluene to make 10.00 mL of a 10.00 mM
t stock solution of [Me2NN]Cu-O Bu. Ph3CSH (0.028 g, 0.100 mmol) was dissolved in 2 mL of toluene. The solution was analytically transferred to a 10.00 mL volumetric flask and diluted to 10.00 mL with toluene to make 10.00 mL of a 10.00 mM stock solution of
Ph3CSH. Four solutions of [Me2NN]Cu-SCPh3 were made in varying concentrations,
t 0.28 mM, 0.21 mM, 0.13 mM, 0.05 mM, by adding Ph3SH to [Me2NN]Cu-OBu and diluting to 3 mL in a quartz cuvette. The progress of the reaction was monitored by UV-
t Vis to observe the disappearance of [Me2NN]Cu-OBu and the appearance of
Figure 3.12. Beer’s law plot of [Me2NN]Cu-SCPh3.
148 [Me2NN]Cu-SCPh3. The concentration of [Me2NN]Cu-SCPh3 at maximum growth in the
t UV-Vis spectra was assumed to be equal to the concentration of [Me2NN]Cu-OBu. UV-
Vis (toluene, 25 °C, nm(cm-1M-1)) 421(2200), 483(1700), 571(1600), 731(5800).
UV-Vis reactions.
Stock solution preparation. {[Me2NN]Cu}2 (1) (0.037 g, 0.0500 mmol) was dissolved in 2 mL of toluene. The solution was analytically transferred to a 10.00 mL volumetric flask and diluted to 10.00 mL with toluene to make 10.00 mL of a 5.0 mM stock solution
t of {[Me2NN]Cu}2 and 10 mM of copper(I). BuONO (12.0 µL, 0.100 mmol) was added to a 10.00 mL volumetric flask and toluene was added to make 10.00 mL of a 10.00 mM
t stock solution of BuONO. Ph3CSNO (0.031 g, 0.100 mmol) was dissolved in 2 mL of toluene. The solution was analytically transferred to a 10.00 mL volumetric flask and diluted to 10.00 mL with toluene to make 10.00 mL of a 10.00 mM stock solution of
Ph3CSNO. The solutions were stored in at -30 °C to avoid decomposition.
t UV-Vis monintoring of the reaction of {[Me2NN]Cu}2 with 2 equiv BuONO. To a sealed quartz cuvette fitted with a rubber septa at 0 °C tBuONO (100 L, 10 mM) was added to a solution of {[Me2NN]Cu}2 (100 L, 5 mM, in 2.800 mL toluene) for a total concentration of copper to be 0.33 mM. Scans were taken every 10 s from 1000 nm to
200 nm for a total of 30 mins. A new peak at 409 nm immediately appeared and reached
t its maximum absorbance after 30 s. We attributed this speices to be [Me2NN]Cu-OBu
t t (independent synthesis with {[Me2NN]Cu}2 and BuOO Bu). This species is formed in 84
149 -1 -1 % yield, A409 nm = 0.414, 0.33 mM, ε = 1500 cm M . This peak began to disappear and a new species grew in at 598 nm. We attributed this species to be {[Me2NN]Cu}2( -
-1 OH)2. This species was formed in 85% yield, A598 nm = 0.155, 0.33 mM, ε = 550 cm M
(Figure 3.3).
t UV-Vis monintoring of the reaction of {[Me2NN]Cu}2 with 2 equiv BuONO, N2
Flush. To a sealed quartz cuvette fitted with a rubber septa at 0 °C tBuONO (100 L, 10 mM) was added to a solution of {[Me2NN]Cu}2 (100 L, 5 mM, in 2.800 mL toluene) for a total concentration of copper to be 0.33 mM. After the reactant was added the solution was flushed with nitrogen gas for 30 mins. We let the cuvette sit at 0 °C for 2 hours. We
t then took a UV-Vis spectra of this reaction mixture. We found that [Me2NN]Cu-O Bu
-1 -1 had formed in 91 % yield (A409 nm = 0.450, 0.33 mM, ε = 1500cm M ). This finding
t suggested to us that the NOgas released from the reductive cleavage of the BuO-NO bond
t by Cu(I) decomposed the [Me2NN]Cu-O Bu to {[Me2NN]Cu}2( -OH)2. We confirmed this by adding in 2.0 equiv of NOgas back into this cuvette. After 30 min we took a UV-
Vis spectra and noted that {[Me2NN]Cu}2( -OH)2 had formed (Figure 3.4).
UV-Vis monintoring of the reaction of {[Me2NN]Cu}2 with 2 equiv Ph3CSNO. To a sealed quartz cuvette fitted with a rubber septa at 0 °C Ph3CSNO (60 L, 10 mM) was added to a solution of {[Me2NN]Cu}2 (60 L, 5 mM, in 2.880 mL toluene) for a total concentration of copper to be 0.20 mM. Scans were taken every 10 s from 1000 nm to
200 nm for a total of 30 mins. A new peak at nm immeditaley appeared at 731 nm and 150 reached its maximum absorbance after 10 s (1st scan taken). We attributed this speices to
t be [Me2NN]Cu-SCPh3 (independent synthesis with [Me2NN]Cu-O Bu + Ph3CSNO). This
-1 -1 species was formed in 78 % yield, A731 nm = 0.911, 0.20 mM, ε = 5800 cm M . This peak begins to disappear and a new species grows in at 647 nm. We attributed this species to be [Me2NN]Cu(NO)[Me2NN] (4). This species formed in 83 % yield, A647 nm =
0.140, 0.10 mM, ε = 1700 cm-1M (Figure 3.6).
UV-Vis monintoring of the reaction of {[Me2NN]Cu}2 with 2 equiv Ph3CSNO, N2 flush. To a sealed quartz cuvette fitted with a rubber septa at 0 °C Ph3CSNO (60 L, 10 mM) was added to a solution of {[Me2NN]Cu}2 (60 L, 5 mM, in 2.880 mL toluene) for a total concentration of copper to be 0.20 mM. After the reactant was added the solution was flushed with nitrogen gas for 10 mins. We found that [Me2NN]Cu-SCPh3 had formed
-1 -1 in 73 % yield (A731 nm = 0.845, 0.20 mM, ε = 5800 cm M ). After standing at 0 °C for 2 hours, we then took a UV-Vis spectra of this reaction mixture and 37 % of [Me2NN]Cu-
-1 -1 SCPh3 remained in solution (A731 nm = 0.537, 0.20 mM, ε = 5800 cm M ). This finding suggested to us that the NOgas released from the reductive cleavage of the Ph3CS-NO bond by Cu(I) decomposed the [Me2NN]Cu-SCPh3. 2.0 equiv of NOgas were added tp pure [Me2NN]Cu-SCPh3. We monitored the dissapearance of the peak at 625 nm. A new species grows in with a broad peak around 500 nm and 610 nm. We have not identified this decomposition product. It is however not [Me2NN]Cu(NO[Me2NN]) (4) (Figure 3.6).
151 Synthesis of [Me2NN]Cu(NO[Me2NN]) (4). At -35 °C, Ph3CSNOs (0.248 g, 0.814 mmol) in 2 mL of Et2O was added to a stirring slurry of {[Me2NN]Cu}2 (0.300 g, 0.407 mmol) in 8 mL Et2O. A white precipitate immediately formed (Ph3CSSCPh3) and was removed by filtration through Celite. The volume of the solution was reduced to 3 mL and filtered through Celite once again. The solution was layered with 0.5 mL TMS2O and left to crystallize overnight at -35 °C. The crystals that formed were collected and dried under vacuum to afford a total yield of 0.200 g (70 % yield) of green crystals identified as
-1 -1 [Me2NN]Cu(NO[Me2NN]) (4) by X-ray. UV-Vis (toluene, 25 °C, nm(cm M ), 647
(1700).
Isolation of [CuSCPh3]4. From the reaction of described for the isolation of 4
(Ph3CSNOs (0.248 g, 0.814 mmol) + {[Me2NN]Cu}2 (0.300 g, 0.407 mmol) in 8 mL
Et2O) forms trace amounts (< 10 mg) of colorless crystals. Analysis by X-ray reveals these crysyals to be [CuSCPh3].
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156 Chapter 4
Reaction of S-Nitrosothiols and Nitric Oxide with Tris(pyrazolyl)borate
Copper Complexes
Abstract
Copper proteins in biology have been shown to have an important role in the formation
and cleavage of the S-N bond of S-nitrosothiols. Herein we show that the S-nitrosothiol
RS-NO bond is activated by TpiPr2CuII-SR, TpiPr2CuI, and TpiPr2CuI(NO) model complexes to release NO which is trapped by TpiPr2CuI in solution to form TpiPr2Cu(NO).
The formation of RSSR' from the reaction of TpiPr2CuII-SR with R'SNO points to a nitroxyl disulfide intermediate TpCu[RS(NO)SR']. In the reaction of S-nitrosothiols with the TpiPr2CuI fragment, UV-vis studies indicate that TpiPr2CuII-SR formation precedes
TpiPr2Cu(NO) formation. The electron deficient model complex Tp(CF3)2CuI(THF) does not form Tp(CF3)2CuII-SR upon exposure to RSNO, suggesting that electron-rich copper centers are required to release NO from S-nitrosothiols.
Introduction
Importance of copper in release of NO from S-nitrosothiols.
Nitric oxide is implicated in numerous biological roles ranging from signaling in the respiratory system1 to vasodilation in the cardiovascular system to host defense against microbial pathogens.2 While the various nitric oxide synthases (NOSs) generate
NO under a variety of conditions, NO itself is unstable in the plasma, with an estimated
157 half-life of 3 – 5 seconds.3 On the other hand, oxygen stable S-nitrosothiols (RSNOs) such as S-nitrosocysteine and S-nitrosoglutathione circulate at micromolar levels in the blood.4,5 Capable of serving as NO and NO+ donors,6,7 S-nitrosothiols have been implicated in a wide variety of physiological functions which often mirror those observed for nitric oxide itself.8,9 The nature of the molecular species involved in the biological reactivity of S-nitrosothiols, however, is clouded by the facile decomposition of RSNOs into free NO and disulfides by a copper-catalyzed process (Scheme 4.1).7,10
Scheme 4.1. Catalytic decomposition of S-nitrosothiols by Cu ions to form disulfide and nitric oxide.
For the copper ion-catalyzed RSNO decomposition reaction, the active species is proposed to be Cu+, which is generated by the reduction of Cu2+ by thiolate anion. This has been supported by several studies by Williams and co-workers.11-14 Williams also demonstrated the possible biological relevance of the Cu+-induced decomposition of
RSNOs through Cu2+ complexed to amino acids, peptides, and proteins that can partake in RSNO decomposition via initial reduction by thiolate to Cu+ yield nitric oxide
(Scheme 4.2).15 From this study, Williams proposed what he deems a realistic pathway for the formation of nitric oxide in vivo from S-nitrosothiols using copper sources
Scheme 4.2. The active species Cu+ in RSNO decomposition is generated by the reduction of Cu2+ to Cu1+ by a thiolate anion.
158 present in the body. This pathway could be important mechanistically in providing
an explanation for the role of S-nitrosothiols in the possible storage and delivery of nitric oxide in vivo. These results also provide a mechanism for nitric oxide generation from S-nitrosothiols administered therapeutically, which may lead to the widespread development of S-nitrosothiols as nitric oxide-releasing drugs.
2+ 2+ Scheme 4.2. CuZn-SOD releases Cu in the presence of H2O2. This free Cu can bind two GSNO molecules to release NO and from GSSR.
Figure 4.1. The structure of the copper–nitrosoglutathione complex, Figure taken from Arch. Biochem. Biophys. 1996, 372, 8-15 without permission.
159 Copper-zinc superoxide dismutase (CuZn-SOD) (Chapter 3, Figure 3.2) may
represent an important physiological modulator of steady-state concentrations of low
molecular weight S-nitrosothiols in vivo.16 This enzyme is the major source of copper in red blood cells, present at a concentration of ca 20 M.17 Endothelial CuZn-SOD effectively catalyzes the release of NO from GSNO in the presence of GSH.18 CuZn-SOD regulates NO levels in cells, by the dismutation of superoxide anion to form hydrogen peroxide (Scheme 4.2). Mechanistic studies of the release of NO from GSNO shows that the copper ion released from the Cu,ZnSOD/H2O2 reaction decomposes GSNO and that the γ-glutamyl group of GSNO and GSSG controls NO release from GSNO (Scheme
4.2).19 Copper binding to GSNO is essential to the release of NO (Figure 4.1).
While transnitrosation between S-nitrosothiols and free thiols as well as the corresponding thiolate anions has been observed in a variety of media,20-22 few molecular level details are known for transnitrosation at biologically relevant metal thiolates. Such exchange reactions are thought to proceed via nitroxyl disulfide intermediates [RS
(ON)SR']- theoretically considered by Houk et al.23and observed via 15N NMR spectroscopy by Estrin et al. in the exchange between S-nitrosocycsteine ethyl ester and its thiolate anion in methanol (Scheme 4.3).20
Scheme 4.3. Trans-s-nitrosation for RSNO and RS- with the proposed nitroxyl disulfide intermediate [RSN(O)SR']-. 160 Copper-thiolates and copper-nitrosyls in biology and model systems.
Copper proteins are defined as a protein containing one or more copper atoms and can be classified according to their biological fucntion, Cu center coodination environment, type and number of prosthetic centers, and by sequence similarity. The biological functions are either classified as catalysis or electron transfer. The catalytic copper proteins are commonly oxidases, reductases, dismutases, or hydrolases.
Type 1 Type2 Type 3 Blue Copper CuZn SOD Hemocyanin
R L HisN NHis L L O Cu Cu NHis L L HisN Cu Cu NHis Cys S O NHis L HisN NHis L = N, O or S ligands
Cu(N His)2S CysR Cu(N His)mRn O2[Cu(N His)3]2
Trinuclear Center CuA CuB (Type 2 + 3 NO2 Reductase Cytochrome C oxidase Laccase His N N His His N Cys Glu N His His N His N Cu Cu His N S O N His CuHO OH Cu Cu L Met S N His His N His N Cu Cys His N N His Fe
Cu(N His)2OH OH Cu2(N His)2O Glu [Cu(N His)3]2 S Met( S Cys)2 CuN His(N His)2L Figure 4.2. Family of copper proteins classified by coordination environment around the copper center. 161
There are six types of structurally distinct binding modes — Type 1, Type 2, Type
3, Trinuclear Center (Type 2 + Type 3), CuA, and CuB (Figure 4.2). Of greatest significance to our modeling work described below are Type 1 and CuA proteins which contain copper-sulfur centers surrounded by histidine donor ligands. Type 1 species are often called blue copper proteins. Their blue color originates from intense electronic absorption bands centered at wavelengths from 600 - 625 nm arising from a charge transfer transition from a cysteine thiolate ligand bound to the active site.24 The coordination enviornment about the copper metal gives rise to the low energy transition involving nearly trigonal arragement of two imidazole N atroms and the thiolate S atom.
A methionine ligand can be found along the trigonal axis in azurin and plastocyanin. The geometry can be described as trigonal based, distored tethrahedral.
To study the unique properties of blue copper proteins, many model complexes have been reported.25 The first successful blue copper model was TpMe2Cu(S-p-
Me2 NO2C6H4) synthesized by Ibers and Thompson in 1977 (Tp = hydrotris(3,5-dimethyl-
Figure 4.3. Synthetic models for the Type 1 copper proteins using tris(pyrazylol)borate anionic ligands.
162 a) Cytochrome C oxidase (CuB) b) Cu-nitrite Reductase (end on NO) (side on NO)
Figure 4.4. Two examples of copper nitrosyls found in biological systems. a) Cytochrome C oxidase with a Cu-NO bound end on, Figure taken from Vos, et al. Biochemistry 2001, 40, 7806, used without permission. b) Cu-nitrite reductase with a Cu- NO bound side-on.Tocheva et al. Science, 2004, 304, 867-870.
1-pyrazolyl)borate anion) (Figure 4.3).26 This model complex was able to reproduce the
-1 -1 intense blue color (λmax = 588 nm (3900 M cm )), but no X-ray analysis was carried out on this model complex. In a later study, Kitajima reported two structurally characterized
iPr2 iPr2 Cu(II)-thiolate complexes Tp Cu(SC6F5) (1) and Tp Cu(SCPh3) (2) using the hydrotris(3,5-diisopropyl-1-pyrazolyl) borate anion (Figure 4.3).27 In each case copper centers exhibit a distorted tetrahedral geometry due to the tripodal ligand forcing a distored four coordinate configuration. Both 1 and 2 show an intense blue color owing to an absorbance maximum centered around 600 nm with λmax for 1 and 2 at 672 nm (5960
M-1cm-1) and 625 nm (6600 M-1cm-1), respectively.
Nitric oxide is involved in the regulation of respiration by acting as a competitive ligand for molecular oxygen at the at the iron center binuclear active site of cytochrome c
28 oxidase (CcO). CcO is a large transmembrane protien that serves to convert O2 to two
163 molecules of H2O. The complex contains two hemes, one cytochrome a and one
29 cytochrome a3, and two copper center (CuA and CuB). The dynamics of NO in and near this site are not well understood. Simulated structures of the active site of cytochrome c oxidase have been proposed based on flash photolysis studies. The heme a3 active site can accommodate two NO molecules, one at the Fe and the other at the CuB (Figure 4.3).
This is only a proposed stucture which has not been isolated and unambiguously structurally characterized (Figure 4.4a).28
Nitrite reductase (NiR) is an enzyme that uses type 1 and type 2 copper sites to reduce nitrite to nitric oxide during bacterial denitrification. Few Cu-nitrosyl complexes, including that of NiR, are well characterized, presumably because of their instability and sensitivity to oxygen. A copper-nitrosyl intermediate is a proposed, yet poorly characterized feature of the NiR catalytic cycle. This intermediate is formally described as Cu(I)-NO+ and is proposed to be formed at the type 2 copper site after nitrite binding and electron transfer from the type I copper site.30 The crystal structure of a type 2 copper-nitrosyl complex of nitrite reductase reveals an unprecedented side-on binding mode in which the nitrogen and oxygen atoms are nearly equidistant from the copper cofactor (Figure 4.4b).30 This stable copper-nitrosyl complex is described as Cu(II)-NO- regardless of the starting oxidation state of the metal.31 Isolation of the proposed intermediate Cu(I)-NO+ has not been possible and may require development of single turnover techniques in crystallography.31 The authors have concluded that the isolated
Cu(II)-NO- bound end-on is not relevant for the catalytic cycle of the enzyme.
164 In order to understand the fundamental chemistry of CuNO species, small
molecule model complexes have been synthesized and some structurally characterized.32-
34 The tris(pyrazolyl)borate ligand system provides a good scaffold for isolation and structural characterization of mononuclear Cu-NO complexes, TpR,R'Cu(NO) (Figure
4.5).32-34 These complexes were studied by FT-IR, NMR, and/or UV-Vis in solution and serve to model a possible copper intermediate in NiR during nitrite reduction. The
TpCu(NO) complexes disproportionate in the presence of excess NO to N2O and
R,R' Tp Cu(NO)2. Manometery studies show that the NO binding is weak, reversible, temperature dependent, and that the NO ligand can be irreversibly replaced by MeCN or
CO. For TpPh2Cu(NO) and TptBuHCu(NO) the unpaired electron resides primarily in the
π*(NO) orbital. TpMesHCu(NO) is EPR silent and exhibits an 1H NMR spectrum with sharp diamagnetic signals. TpCF3,CH3Cu(NO) is EPR silent and is not amenable to 1H
NMR characterization as the only species seen in the 1H NMR spectrum is the
TpCF3CH3Cu(MeCN). The EPR spectrum of TptBu,iPrCu(NO) is in agreement with the copper(I)-nitrosyl electronic structure. It is interesting to note that subtle changes in the ligand can lead to significant differences in the stability of the Cu-NO linkage.
165 Figure 4.5. TpR,R'Cu(NO) model complexes.
In light of the rich literature using the tris(pyrazolyl)borate supporting ligands to
isolate Cu(II)-thiolates and Cu(I)-NO complexes, we sought to study how each of these
species would react with S-nitrosothiols.
Results and Discussion
4.1. Synthesis and stability of TpiPrCuII-SR complexes.
iPr2 Addition of 2 equiv. RSH (R = C6F5, CPh3) to {Tp Cu}2( -OH)2 at -20 °C results in an immediate color change from green to dark blue yield TpiPr2Cu-SR in 70 -
78% yields. These complexes are unstable toward air and result in the formation
iPr2 35 iPr2 27 iPr2 27 (Tp Cu}2(µ-CO3). While both the Tp Cu-SC6F5 (1) and Tp Cu-SCPh3 (2) are isolable and able to be characterized by X-ray crystallography, they are short lived in
Scheme 4.4. Synthesis of TpiPr2Cu-SR from reaction of TpiPr2Cu-OH with RSH. 166 iPr Figure 4.6. Decomposition of Tp Cu-SC6F5 (1) in CH2Cl2 at room temperature following second order plot kinetics with respect to 1.
solution and decompose to form the corresponding TpCuI species along with ½ equiv.
RSSR (Scheme 4.4). We believe that the mechanism for decomposition is different for 1 and 2.
iPr When Tp Cu(SC6F5) (1) is allowed to decompose at room temperature in CH2Cl2
(0.30 mM) the plot of 1/Concentration (M-1) vs. time (s) gives a straight line (Figure 4.6).
iPr2 iPr2 I Scheme 4.5. Bimolecular decomposition of Tp Cu-SC6F5 to form 2 equiv. Tp Cu and C6F5SSC6F5.
167 Monitoring the decrease in the band centered at λ = 666 nm in CH2Cl2, concentration data were able to be obtained from its reported molar absorptivity (ε = 5960 M-1 cm-
1 27,36 iPr2 ). These data suggest that Tp Cu-SC6F5 decomposes via a bimolecular pathway.
Formation of a dinuclear complex would facilitate electron transfer to yield 2 equiv.
iPr I Tp Cu and C6F5SSC6F5 (Scheme 4.5).
iPr2 The decomposition pathway for Tp Cu-SCPh3 (2) in CH2Cl2 does not follow the
iPr2 same bimolecular pathway of Tp Cu-SC6F5 (1). The peak at 625 nm decreases over time and a new peak at 353 nm grows in (Figure 4.7). There is an isobestic point at 610 nm indicating that the mechanism for conversion of 2 to the new product at 353 nm does not go through an observable intermediate. We have been unable to identify this new
λ = 625 nm iPr2 Tp Cu-SCPh3 λ = 353 nm TpiPr2CuI?
iPr2 Figure 4.7. Disappearance of band at λ = 625 nm for Tp CuSCPh3 in its thermal decomposition in CH2Cl2 with appearance of new species with λmax = 353 nm.
168 iPr I species with λmax = 353 nm. It does not have the same UV-vis spectrum as does Tp Cu
iPr2 37 (synthesized from Tp Cu(MeCN) followed by tituration with CH2Cl2 / pentane to
iPr2 32 likely form (Tp Cu)2 but is likely a copper(I) species owing to the lack of any strong bands in the visible. The trityl group is quite large compared to that of the pentafluorophenyl group and sterically discourages bimolecular interactions, forcing an
iPr2 alternative pathway for decomposition. When Tp Cu-SC6F5 decomposes it does not form a new peak at 353 nm. Rather, the solution decolorizes and has a UV-Vis spectra like that of TpiPr2CuI.
iPr2 Plots of concentration (M) vs. time (s) for the decomposition Tp Cu-SCPh3 in
CH2Cl2 of are linear over a temperature range of 0 - 40 ºC (Figure 4.8) as judged by
iPr2 Figure 4.8. Plots of concentration vs time for decomposition of Tp Cu-SCPh3 (1) in CH2Cl2 from 0 – 40 °C, zero order kinetics followed. 169 -1 -1 25 monitoring the loss of the band of 2 at λmax = 625 nm with ε = 6600M cm ).
Eyring analysis of the decomposition reaction allows the activation parameters