Non-Linear Effects in Asymmetric Catalysis: A Useful Tool in Understanding Reaction Mechanisms. Group Meeting Aaron Bailey 12 May 2009

Transcription

1 Non-Linear Effects in Asymmetric Catalysis: A Useful Tool in Understanding Reaction chanisms Group eting Aaron Bailey 12 May 2009

2 What is a Non-Linear Effect? In asymmetric catalysis, the ee (er) of the product can be predicted based on the enantiopurity of the chiral substrate (auxiliary or ligand) ee max = ee product /ee auxiliary By using this equation a linear correlation is obtained (line a) When products are obtained in higher enantiopurity than predicted a (+)-NLE is observed (curve d & c) Likewise, if a lower enantiopurity is obtained that what is predicted a ( )-NLE is observed (curve e & b). However, this equation cannot hold true for all reactions as aggregation of ligands occurs frequently to form homochiral and heterochiral (meso) complexes Kagan, H. B. et al. Angew. Chem. Int. Ed., 2009, 48, Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

3 First bserved Reports S Ti(i-Pr) 4 DET, H 2, t-buh S Asymmetric sulfide oxidation displayed ( )-NLE effects dependent on purity and concentration ligand Curve A= stoichiometric amounts of reagents Curve B= Substoichiometric amounts (0.5 eq Ti) Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

4 First bserved Reports H Ti(i-Pr) 4 DET, H 2, t-buh H Asymmetric epoxidation displayed (+)-NLE effects Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

5 Revision of Asymmetric Model ML* 2 Model (Differences in Reactivity) Revision of mathematical model tal complexes can (if enantioenriched) form homochiral systems (ML RR & ML SS ) as well as heterochiral (meso) dimers (ML RS ). ee max ee product /ee auxiliary must apply correction factor ee product =ee max ee auxiliary ƒ Ƒ=(1+β)/(1 + gβ) if fast equilibrium occurs between complexes then β= Where β is the relative amount of meso- to chiral-type complexes in solution And g is the relative reactivity of the meso-type complex with respect to the chiral complex Kagan, H. B. et al. J. Am. Chem. Soc. 1994, 116,

6 Reservoir Model ee eff = ee aux -αee res /(1- α) Note: Both models can operate independently but many reactions display both such NLE s e.g. if a dimeric (meso) complex is completely inactive and an energy sink ML 2 equation simplifies to ee prod = ee 0 ee aux (1+β) Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

7 Higher rder Systems-ML 3, ML 4 ML 3 ML 4 At least 4 possible structures ML RRR ML RSR ML RSS ML SSS All will be chiral Five possible structure: ML RRRR, ML RRRS, ML RRSS, ML RSSS, ML SSSS Assumes statistical distribution between ligands Homochiral complex give greater selectivity that heterochiral complex Heterochiral complex gives higher selectivity and is more reactive Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

8 Asymmetric Sulfide xidation S Ti(i-Pr) 4 DET, H 2, t-buh S From experiment Calculated data overlay with experimental bserving NLE s and using derived equations a mechanistic hypothesis can be proposed: Data consistent with ML 4 system Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

9 Asymmetric Epoxidation H Ti(i-Pr) 4 DET, H 2, t-buh H C 2 Et C 2 Et R Ti Active catalyst in solution C 2 Et R Ti C 2 Et R C 2 Et R Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, Sharpless, K. B., et al. J. Am. Chem. Soc. 1991, 113, Sharpless, K. B., et al. J. Am. Chem. Soc. 1991, 113, C 2 Et Ti R C 2 Et Ti R R C 2 Et R Homochiral dimer meso Ligand reservoir or inactive dimer

10 Proposing chanisms using NLEs N 2 H H H ZnEt 2 toluene, 0 º, 6 h * Et Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, Noyori, R. et. al. J. Am. Chem. Soc. 1989, 111, Noyori, R. et. al. J. Am. Chem. Soc. 1986, 108, %, 99:1 er A large (+)-NLE was observed using catalytic amount of DAIB ligand A 1:1 ligand:zn results in no alkylation ptimal reaction conditions used 1:2 stoichiometry Propose a mechanism that accounts for the observed NLE. Which model does it fit? ML n? Reservoir? r both?

11 chanistic Proposal I Based on early kinetic, NMR, and stoichiometric studies the mechanism above was proposed This does not necessarily account for the dramatic NLE observed Noyori, R. et. al. J. Am. Chem. Soc. 1989, 111,

12 Reservoir Effect in ZnEt 2 Additions Homochiral and Heterochiral dimers forming in solution Experimental observations sugges K DHomo =3x10 2 K Dso =1x10 5 M calculations predict meso complex energetically favored by 3.1 kcal/mol Noyori, R. et. al. J. Am. Chem. Soc. 1995, 117,

13 Absence of NLE in ZnEt 2 Additions Study wanted to examine stereochemical controlling elements of ferrocene ligands. Proposed TS Bolm, C. et al. J. rg. Chem. 1998, 63, Due to linear correlation between ee of ligand and product, authors could rule out possibility of inactive aggregates (ML n ) or reservoir effect

14 ther NLE in rganometallic Rxns L1 N H H 1. L1/A1/Ti(iPr) H 4 2. TFA TMS Ding, K. et al. Chem. Eur. J. 2002, 8, Ph A1 C 2 H N 2+ Bn H TMS StBu Ph N Cu CH 2 Cl 2 N Ph 2 SbF 6 Bn H StBu Evans, D. A. et al. J. Am. Chem. Soc. 1999, 121, Both examples show significant (+)-NLE s Elucidation of the mechanisms was achieved by observing NLE Both are thought to proceed via the reservoir model- meso-dimer favored by 2.9 kcal/mol

15 NLE in rganocatalytic Reactions N H H H Three possible roles of catalysts Jørgensen, K. A. et al. J. rg. Chem. 2003, 68,

16 ( )-NLE Provides ch. Insights Presence of ( )-NLE indicates more than one molecule of chiral amine present in stereodefining step Eq 5 is proposed mechanism with iminium intermediate and enamine formation occurring Matched-Mismatched case proposed to be responsible for lower selectivity Jørgensen, K. A. et al. J. rg. Chem. 2003, 68, N

17 Juliá-Colonna Epoxidation H 2 2, NaH poly-l-leucine riginally proposed catalytic pocket shown Kelly, D. R. et al. Chem. Comm. 2004, Kelly, D. R. et al. Chem. Comm. 2004,

18 (+)-NLE bserved for PLL Based on ML 2 system described previously, assuming statistical mixture of monomer and dimer amino acid residues as well as the heterodimer chains are not-reactive the following equation can be deduced Kelly, D. R. et al. Chem. Comm. 2004, Kelly, D. R. et al. Chem. Comm. 2004,

19 Revision of chanism Stereocontrolling element H-bonding assists epoxide formation 5 Leucine residues matched the amount of asymmetric amplification observed as well as the rate (amount of active catalyst) Kelly, D. R. et al. Chem. Comm. 2004, Kelly, D. R. et al. Chem. Comm. 2004,

20 Asymmetric Allylations Kinetic data coupled with NLE led to conclusion that two phosphoramide ligands present in stereodetermining step chanistic experiments utilizing bisphosphoramide ligands further supported hypothesis of two ligands present in stereodefining step Denmark, S. E. et al. J. Am. Chem. Soc. 2000, 122, Denmark, S. E. et al. J. rg. Chem. 2006, 71,

21 Asymmetric penings of meso- Epoxides Rate= d prod /dt=k[hmpa] 2 [epoxide] bservation of ( )-NLE along with kinetic data suggests two phosphoramides present in mechanism Was able to rule out reservoir effect and product inhibition Denmark, S. E. et al. Adv. Syn. Cat. 2007, 349, Bisphosphoramide catalysts did not improve selectivities

22 Proposed chanism Denmark, S. E. et al. Adv. Syn. Cat. 2007, 349,

23 False Positives in NLE Systems Initial studies by Kagan led to the conclusion that a ( )-NLE was present Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108, List, B. et al. J. Am. Chem. Soc. 2003, 125, List. B. et al. J. Am. Chem. Soc. 2003, 125, Recent studies have concluded the absence of a NLE

24 Solubility Differences Homochiral dimers less stabilized by H-bonding compared to Heterochiral But how does this explain observed ( )-NLE? Hayashi, Y. et al. Angew. Chem. Int. Ed. 2006, 45,

25 thod of Amino Acid Addition In experiments, L-Proline and D-Proline were added separately causing the solids to have a conglomerate equilibrium in the solvent Blackmond, D. G. et al. Angew. Chem. Int. Ed. 2006, 45, Kagan, H. B. et al. J. Am. Chem. Soc. 1986, 108,

26 Autoinduction/Autocatalysis A + B A + B Cat. Cat.-P P L= P L (5 %) H Et ZnEt H 2 (10 %) Et MS, toluene Et Et Et Et Trost, B. M. et al. J. Am. Chem. Soc. 2004, 126,

27 NLE and Autocatalysis- A Brief Introduction N H N N H Zn N ( % ee) N N H 99 % ee Based on kinetic data observed a dimeric complex is believed to be the mechanism; however, this hypothesis is speculative and debate is ongoing Soai, K. et al. Tet. Asymmetry, 2001, 12, Soai, K. et al. Nature, 1995, 378, Soai, K. et al. Chirality, 2002, 14,

28 Conclusions The observation of NLE s can have significant mechanistic implications Careful analysis of the effect coupled with kinetic data, theoretical calculations, and isolation of intermediates can help elucidate mechanisms The fundamental theory behind NLE s has contributed to much of the debate centered around asymmetric amplification/autocatalysis and the evolution of chirality theories