{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:55:51Z","timestamp":1790614551351,"version":"4.1.0"},"reference-count":160,"publisher":"American Chemical Society (ACS)","issue":"42","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Am. Chem. Soc."],"published-print":{"date-parts":[[2009,10,28]]},"DOI":"10.1021\/ja9058958","type":"journal-article","created":{"date-parts":[[2009,9,24]],"date-time":"2009-09-24T18:03:24Z","timestamp":1253815404000},"page":"15358-15374","source":"Crossref","is-referenced-by-count":229,"title":["Mechanism of Amido-Thiourea Catalyzed Enantioselective Imine Hydrocyanation: Transition State Stabilization via Multiple Non-Covalent Interactions"],"prefix":"10.1021","volume":"131","author":[{"given":"Stephan J.","family":"Zuend","sequence":"first","affiliation":[{"name":"Harvard University, Department of Chemistry & Chemical Biology, Cambridge, Massachusetts 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric N.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Harvard University, Department of Chemistry & Chemical Biology, Cambridge, Massachusetts 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2009,9,24]]},"reference":[{"key":"ref1\/cit1","doi-asserted-by":"crossref","first-page":"5713","DOI":"10.1021\/cr068373r","volume":"107","author":"Doyle A. G.","year":"2007","journal-title":"Chem. Rev."},{"key":"ref2\/cit2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1021\/ar960062n","volume":"33","author":"Johnson J. S.","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref3\/cit3","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1021\/ar040063c","volume":"39","author":"Trost B. M.","year":"2006","journal-title":"Acc. Chem. Res."},{"key":"ref4\/cit4","unstructured":"Recent reviews:"},{"key":"ref4\/cit4a","first-page":"79","volume":"39","author":"Lelais G.","year":"2006","journal-title":"Aldrichim. Acta"},{"key":"ref4\/cit4b","doi-asserted-by":"crossref","first-page":"5471","DOI":"10.1021\/cr0684016","volume":"107","author":"Mukherjee S.","year":"2007","journal-title":"Chem. Rev."},{"key":"ref5\/cit5","unstructured":"For a detailed discussion, see:"},{"key":"ref5\/cit5a","unstructured":"Israelachvili, J.Intermolecular & Surface Forces,2nd ed.Academic Press:London, 1991; pp109\u2212121.The strength of repulsive non-bonding interactions is roughly proportional to (1\/r)12. Within this model, a 25% increase inrleads to a 93% decrease in interaction energy."},{"key":"ref6\/cit6","unstructured":"For a tabulation of the orientation- and distance-dependence of attractive non-covalent interactions, see: ref5, p 28. For example, the strength of a charge-dipole interaction\u2014which approximates the electrostatic component of a hydrogen bond\u2014is proportional to cos \u03b8\/r2. If the energy of this interaction is 5 kcal\/mol when bond length and orientation are optimal, then either a 25% increase in bond length or a 45\u00b0 rotation of the dipole will cost less than 2 kcal\/mol."},{"key":"ref7\/cit7","unstructured":"For a discussion of and leading references to models for enantioselectivity in biological systems, see:"},{"key":"ref7\/cit7a","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1110\/ps.3280102","volume":"11","author":"Sundaresan V.","year":"2002","journal-title":"Protein Sci."},{"key":"ref8\/cit8","unstructured":"For leading references to cooperative mechanisms in enzymatic and small-molecule catalysis, see ref16c."},{"key":"ref9\/cit9","unstructured":"For a recent discussion of additive effects in supramolecular chemistry, see:"},{"key":"ref9\/cit9a","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1002\/anie.200802947","volume":"48","author":"Schneider H.-J.","year":"2009","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref10\/cit10a","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.1021\/ja980139y","volume":"120","author":"Sigman M. S.","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref10\/cit10b","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1002\/(SICI)1521-3773(20000403)39:7<1279::AID-ANIE1279>3.0.CO;2-U","volume":"39","author":"Sigman M. S.","year":"2000","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref10\/cit10c","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1021\/ol005636+","volume":"2","author":"Vachal P.","year":"2000","journal-title":"Org. Lett."},{"key":"ref10\/cit10d","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/1615-4169(20010226)343:2<197::AID-ADSC197>3.0.CO;2-8","volume":"343","author":"Su J. T.","year":"2001","journal-title":"Adv. Synth. Catal."},{"key":"ref11\/cit11a","doi-asserted-by":"crossref","first-page":"10012","DOI":"10.1021\/ja027246j","volume":"124","author":"Vachal P.","year":"2002","journal-title":"J. Am. Chem. Soc."},{"key":"ref11\/cit11b","unstructured":"bVachal, P.Ph.D. Thesis, Harvard University, Cambridge, MA, March, 2003."},{"key":"ref12\/cit12a","doi-asserted-by":"crossref","first-page":"10558","DOI":"10.1021\/ja046259p","volume":"126","author":"Taylor M. S.","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref12\/cit12b","doi-asserted-by":"crossref","first-page":"13404","DOI":"10.1021\/ja076179w","volume":"129","author":"Raheem I. T.","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref13\/cit13","doi-asserted-by":"crossref","first-page":"7198","DOI":"10.1021\/ja801514m","volume":"130","author":"Reisman S. E.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref14\/cit14","unstructured":"For a survey of the anion binding properties of ureas and thioureas, see:"},{"key":"ref14\/cit14a","doi-asserted-by":"crossref","unstructured":"Sessler, J. L., Gale, P. A., and Cho, W.S.Anion Receptor Chemistry;RSC Publishing:Cambridge, 2006; pp193\u2212205.","DOI":"10.1039\/9781847552471"},{"key":"ref15\/cit15","unstructured":"For a review and an analysis of the anion-binding properties of urea derivatives in the context of catalysis, see:"},{"key":"ref15\/cit15a","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1039\/b801793j","volume":"38","author":"Zhang Z. G.","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"ref16\/cit16a","doi-asserted-by":"crossref","first-page":"13151","DOI":"10.1021\/ja063201x","volume":"128","author":"Hamza A.","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref16\/cit16b","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1002\/adsc.200700367","volume":"349","author":"Hammar P.","year":"2007","journal-title":"Adv. Synth. Catal."},{"key":"ref16\/cit16c","doi-asserted-by":"crossref","first-page":"15872","DOI":"10.1021\/ja0735352","volume":"129","author":"Zuend S. J.","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref17\/cit17a","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1039\/j29710000325","author":"Ogata Y.","year":"1971","journal-title":"J. Chem. Soc., B"},{"key":"ref17\/cit17b","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0040-4020(01)97226-6","volume":"30","author":"Taillades J.","year":"1974","journal-title":"Tetrahedron"},{"key":"ref17\/cit17c","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1016\/S0040-4020(01)97121-2","volume":"30","author":"Taillades J.","year":"1974","journal-title":"Tetrahedron"},{"key":"ref18\/cit18","doi-asserted-by":"crossref","first-page":"6119","DOI":"10.1021\/ja00487a025","volume":"100","author":"Ching W.-M.","year":"1978","journal-title":"J. Am. Chem. Soc."},{"key":"ref19\/cit19","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1021\/cr60280a004","volume":"72","author":"Jencks W. P.","year":"1972","journal-title":"Chem. Rev."},{"key":"ref20\/cit20","volume-title":"Catalysis in Chemistry and Enzymology","author":"Jencks W. P.","year":"1987"},{"key":"ref21\/cit21","doi-asserted-by":"crossref","first-page":"12886","DOI":"10.1021\/ja9618614","volume":"118","author":"Guthrie J. P.","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref22\/cit22","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1021\/ja9911059","volume":"122","author":"Arnaud A.","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref23\/cit23","unstructured":"In early studies, it was also proposed that solvent was involved in a proton relay step (i.e., the source of the proton on the \u03b1-aminonitrile product is solvent rather than HCN). However, no role for proton relay by water could be identified in ref22, and water was proposed to promote hydrocyanation through the formation of multiple hydrogen bridges."},{"key":"ref24\/cit24","unstructured":"Recent reviews and leading references:"},{"key":"ref24\/cit24a","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1021\/cr020038p","volume":"103","author":"Gr\u00f6ger H.","year":"2003","journal-title":"Chem. Rev."},{"key":"ref24\/cit24b","doi-asserted-by":"crossref","first-page":"4584","DOI":"10.1021\/cr050580o","volume":"107","author":"N\u00e1jera C.","year":"2007","journal-title":"Chem. Rev."},{"key":"ref24\/cit24c","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1002\/anie.200703879","volume":"47","author":"Connon S. J.","year":"2008","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref25\/cit25a","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1002\/(SICI)1521-3773(20000502)39:9<1650::AID-ANIE1650>3.0.CO;2-P","volume":"39","author":"Takamura M.","year":"2000","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref25\/cit25b","doi-asserted-by":"crossref","first-page":"11594","DOI":"10.1021\/ja011875w","volume":"123","author":"Josephsohn N. S.","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref25\/cit25c","doi-asserted-by":"crossref","first-page":"8786","DOI":"10.1021\/jo034891f","volume":"68","author":"Li J.","year":"2003","journal-title":"J. Org. Chem."},{"key":"ref25\/cit25d","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1002\/anie.200504344","volume":"45","author":"Rueping M.","year":"2006","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref25\/cit25e","doi-asserted-by":"crossref","first-page":"4070","DOI":"10.1021\/ja808715j","volume":"131","author":"Sim\u00f3n L.","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref26\/cit26","unstructured":"For a recently reported exception to this generalization, see:"},{"key":"ref26\/cit26a","doi-asserted-by":"crossref","first-page":"9339","DOI":"10.1002\/anie.200703179","volume":"46","author":"Negru M.","year":"2007","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref27\/cit27","unstructured":"Zuend, S. J., Coughlin, M. P., Lalonde, M. P., and Jacobsen, E. N.Nature, Accepted for publication."},{"key":"ref28\/cit28","unstructured":"Conversion of TMSCN to HCN could be monitored directly by in situ IR spectroscopy, or indirectly by1H-NMR spectroscopy in C6D6.Conversion of2awas determined by monitoring the height of the C\u2550N stretch at 1670 cm\u22121relative to a two-point baseline (1570\u22121770 cm\u22121)."},{"key":"ref29\/cit29","unstructured":"Non-linear least-squares fitting and statistical analysis was executed using SigmaPlot 10.0 purchased from Systat Software."},{"key":"ref30\/cit30","unstructured":"R2= 0.9955 for the fit of the data to eq1. Details and kinetic data in tabular format are included in theSupporting Information."},{"key":"ref31\/cit31","unstructured":"The kinetic modeling was executed using methods described previously (ref16c, and refs therein): experimental IR data in the formabsorbance versus timewere first converted to the formconcentration versus timeby application of Beer\u2019s Law. These data were converted to the formrate versus concentrationby least-squares fitting of theconcentration versus timedata to a 7th-order polynomial followed by analytical differentiation of the polynomial. For this approach to be effective, a high data collection rate is necessary, and IR spectra were collected every 15 s for the entire course of the reaction. This approach also requires that the reaction mixture solution be completely homogeneous, and thus IR data collected in the first few minutes after addition of the last reagent are intrinsically inaccurate. In the fastest reactions, there is insufficient data at low %-conversion to apply this approach (i.e., there are too few IR spectra collected within approximately the first 25% conversion to allow for accurate curve fitting). For consistency, all kinetic analyses used data from 25\u221295% conversion of imine (i.e. [imine] = 0.01\u22120.15 M where [imine]i= 0.20 M)."},{"key":"ref32\/cit32","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1002\/anie.200462544","volume":"44","author":"Blackmond D. G.","year":"2005","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref33\/cit33","unstructured":"We have only carried out \u201csame excess\u201d experiments at one [cat]tot, and it is possible that at other [cat]tot, some irreversible catalyst deactivation occurs."},{"key":"ref34\/cit34","unstructured":"A fit to a kinetic model that allows for reversible catalyst dimer formation provides an excellent agreement with the experimental data: rate =k[HCN] [imine](2 [cat]tot)\/(1 + \u221a\u0305(1 + 8Kdim[cat]tot),k= 1.74 \u00b1 0.04 M\u22122s\u22121,Kdim= 55 \u00b1 6 M\u22121, R2 = 0.9932. A derivation of this rate law and the corresponding figures are included in theSupporting Information. A fit torate=k[HCN][imine][cat]totprovides comparatively poor agreement with the experimental data (seeSupporting Information)."},{"key":"ref35\/cit35","unstructured":"Aggregation of thiourea catalysts is precedented:"},{"key":"ref35\/cit35a","unstructured":"aref16c."},{"key":"ref35\/cit35b","doi-asserted-by":"crossref","first-page":"6078","DOI":"10.1002\/chem.200800197","volume":"14","author":"T\u00e1rk\u00e1nyi G.","year":"2008","journal-title":"Chem.\u2014Eur. J."},{"key":"ref35\/cit35c","doi-asserted-by":"crossref","first-page":"7872","DOI":"10.1002\/anie.200801636","volume":"41","author":"Oh S. H.","year":"2008","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref36\/cit36","unstructured":"Methanol-mediated racemic imine hydrocyanation proceeds via a mechanism that involves buildup of positive charge on the imine (\u03c1 = \u22121.1): ref17a."},{"key":"ref37\/cit37","unstructured":"A concerted [3 + 2] cycloaddition mechanism is also consistent with the kinetic data, and represents an intermediate case. Gas-phase transition structures for a concerted, asynchronous [3 + 2] cycloaddition between an imine and HNC have been located using both DFT andab initiomethods. This process has a calculated activation barrier of 43 kcal\/mol. Inclusion of bulk water reduces the calculated activation free energy of the concerted process to 19 kcal\/mol. Whereas the gas phase transition structure visually approximates the aqueous transition structure, the latter is characterized by longer breaking N-H and forming C-C bonds, and is more accurately described as an iminium\/cyanide ion pair. Explicit inclusion of two water molecules decreases the activation free energy to 16 kcal\/mol, and results in a non-concerted, multi-step iminium\/cyanide ion pair mechanism: ref22."},{"key":"ref38\/cit38","unstructured":"Reactions were monitored by sequential removal of aliquots and subsequent 1H-NMR spectroscopic analysis versus 1,3,5-trimethoxybenzene internal standard. Pseudo first-order rate constants (kobsd) were obtained by a non-linear least squares fit tof(x) =ae\u2212kobsdx. Details and kinetic data in tabular format are provided in theSupporting Information."},{"key":"ref39\/cit39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1021\/cr00002a004","volume":"91","author":"Hansch C.","year":"1991","journal-title":"Chem. Rev."},{"key":"ref40\/cit40","unstructured":"A similar \u03c1 value was obtained from a series of competition experiments in imine hydrocyanation reactions catalyzed by1b(Vachal, P. Unpublished results). To our knowledge, no other Hammett studies of catalytic asymmetric imine hydrocyanation reactions have been reported; it is thus not possible to establish whether this observation is general."},{"key":"ref41\/cit41","unstructured":"The observed negative \u03c1 values are large compared with those observed in other reactions of imines. In reactions that involve imine protonation followed by nucleophilic addition (e.g., in imine hydrolysis under non-acidic conditions), the negative Hammett correlation of imine basicity approximately cancels the positive Hammett correlation of iminium ion electrophilicity. Large negative Hammett correlations have been observed for additions for the acid-catalyzed addition of amine nucleophiles to oximes. For a series of classic studies examining substituent effects on imine basicity, see:"},{"key":"ref41\/cit41a","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1021\/ja00901a037","volume":"85","author":"Cordes E. H.","year":"1963","journal-title":"J. Am. Chem. Soc."},{"key":"ref41\/cit41b","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1021\/ja01066a024","volume":"86","author":"Koehler K.","year":"1964","journal-title":"J. Am. Chem. Soc."},{"key":"ref41\/cit41c","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1021\/jo00809a006","volume":"36","author":"Archila J.","year":"1971","journal-title":"J. Org. Chem."},{"key":"ref42\/cit42","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1021\/ja00757a039","volume":"94","author":"Schubert W. M.","year":"1972","journal-title":"J. Am. Chem. Soc."},{"key":"ref43\/cit43","unstructured":"The gas phase basicity (proton affinity) ofpara-substituted benzaldehyde-derived iminesN-H imines was also computed by DFT methods (B3LYP\/6-31G(d)). Details are provided in theSupporting Information."},{"key":"ref44\/cit44","unstructured":"A mechanism that involves positive charge buildup on the organic electrophile would likely also involve negative charge buildup on the nucleophile; thus such a mechanism is expected to be characterized by high reaction rates with nucleophiles that are able to stabilize negative charge. The structural simplicity of cyanide anion that renders it ideal for computational analysis (vide infra) does not allow a direct test of this hypothesis. However, thiourea-catalyzed asymmetric imine hydrophosphonylation appears to be mechanistically related to imine hydrocyanation, and proceeds most rapidly with electron-deficient phosphites:"},{"key":"ref44\/cit44a","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1021\/ja0494398","volume":"126","author":"Joly G. D.","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref45\/cit45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1021\/ol017117s","volume":"4","author":"Schreiner P. R.","year":"2002","journal-title":"Org. Lett."},{"key":"ref46\/cit46","unstructured":"Data are included in theSupporting Information. The fit to eq2affordsR2= 0.980. A fit to rate =k[HCN]a[imine]b[cat]totcaffords:kcat= 2.8 \u00b1 0.3 M\u22122\u2009s\u22121,a= 1.03 \u00b1 0.04,b= 0.97 \u00b1 0.02,c= 1.17 \u00b1 0.02,R2= 0.987."},{"key":"ref47\/cit47","unstructured":"Achiral thiourea5catalyzes hydroalkoxylation of electron-rich olefins. The proposed mechanism for this transformation involves olefin protonation followed by alkoxide addition in a formally concerted but highly asynchronous manner:"},{"key":"ref47\/cit47a","first-page":"779","author":"Kotke M.","year":"2007","journal-title":"Synthesis"},{"key":"ref49\/cit49","unstructured":"Relative rate data were obtained under pseudo first-order conditions at 0 \u00b0C. Because enantioselectivity depends on the reaction conditions, intrinsic enantiomeric ratios (er) were estimated from experiments run at high dilution ([imine]i= 0.020 M, \u221230 \u00b0C). Details are included in theSupporting Information."},{"key":"ref50\/cit50","unstructured":"The relative rate data should be interpreted with caution, as relative rates do not necessarily correlate with the ability of catalysts to stabilize the rate-limiting hydrocyanation transition structures; differences in catalyst aggregation, internal bond rotation, and potential to catalyze hydrocyanation via higher-order mechanisms could each contribute to the relative rate constants. For a discussion on the limitations of using \u201ckrel\u201d for the elucidation of complex reaction mechanisms, see:"},{"key":"ref50\/cit50a","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1021\/ja992062z","volume":"122","author":"Sun X.","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref51\/cit51","unstructured":"For an example in the context of organocatalysis in which the free energy and enthalpy of substrate binding to an H-bond donor has been determined, see: ref45."},{"key":"ref52\/cit52","unstructured":"For a review of the Curtin\u2212Hammett principle, see:"},{"key":"ref52\/cit52a","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1021\/cr00054a001","volume":"83","author":"Seeman J. I.","year":"1983","journal-title":"Chem. Rev."},{"key":"ref53\/cit53","unstructured":"For a well-studied example of a small molecule-catalyzed reaction in which the rate of substrate-catalyst complex formation and dissociation and the rates of reaction are similar, see:"},{"key":"ref53\/cit53a","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1021\/ja00240a025","volume":"109","author":"Landis C. R.","year":"1987","journal-title":"J. Am. Chem. Soc."},{"key":"ref54\/cit54","doi-asserted-by":"crossref","DOI":"10.1002\/9780470148136","volume-title":"Computational Organic Chemistry","author":"Bachrach S. M.","year":"2007"},{"key":"ref55\/cit55","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1021\/ar0300524","volume":"37","author":"Allemann C.","year":"2004","journal-title":"Acc. Chem. Res."},{"key":"ref56\/cit56","volume-title":"Gaussian 03, Revision E.01","author":"Frisch M. J.","year":"2004"},{"key":"ref57\/cit57","unstructured":"For a comparison of these computational methods in the context of asymmetric catalysis, see:"},{"key":"ref57\/cit57a","doi-asserted-by":"crossref","first-page":"13836","DOI":"10.1021\/ja805275s","volume":"130","author":"Li X.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref58\/cit58","unstructured":"An analogous mechanism that involves proton transfer from the other thioureaN-proton has also been characterized by computational methods, and has a slightly higher activation energy."},{"key":"ref59\/cit59a","doi-asserted-by":"crossref","first-page":"5903","DOI":"10.1021\/ja00225a054","volume":"110","author":"Bordwell F. G.","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref59\/cit59b","doi-asserted-by":"crossref","first-page":"8398","DOI":"10.1021\/ja00022a029","volume":"113","author":"Bordwell F. G.","year":"1991","journal-title":"J. Am. Chem. Soc."},{"key":"ref60\/cit60","unstructured":"Expected relative rates of catalysis can be estimated from this energy difference: ratethiourea\/rateurea\u2248e(-\u0394\u0394E\u29e7\/RT)= 20\u2009000 at 0 \u00b0C."},{"key":"ref61\/cit61","unstructured":"Reactions run to greater than one catalytic turnover show substantial amounts of proton exchange both in the presence and absence of substrate, and consequently display significant proton-incorporation into the \u03b1-aminonitrile product. Details are provided in theSupporting Information."},{"key":"ref62\/cit62","unstructured":"It is possible, in principle, that the simplified computational model over-estimates the acidity of the thiourea protons or the basicity of the partially-formed \u03b1-aminonitrile anion, and that no proton transfer between thiourea and imine occurs. Within this alternative mechanism, the partially formed \u03b1-aminonitrile anion would be stabilized by H-bonding in an interaction reminiscent of those interactions present in an enzymatic oxyanion hole (see: ref16c, and refs therein). This mechanistic proposal is depicted in Scheme4A, and is inconsistent with the Hammett analysis (Figure4)."},{"key":"ref63\/cit63","unstructured":"One possible mechanism for HCN\u2212HNC isomerization is via a cyclic trimer or higher oligomer:"},{"key":"ref63\/cit63a","doi-asserted-by":"crossref","first-page":"18189","DOI":"10.1021\/jp052935d","volume":"109","author":"S\u00e1nchez M.","year":"2005","journal-title":"J. Phys. Chem. B."},{"key":"ref64\/cit64","doi-asserted-by":"crossref","first-page":"5065","DOI":"10.1021\/ja00796a058","volume":"95","author":"B\u00fcrgi H. B.","year":"1973","journal-title":"J. Am. Chem. Soc."},{"key":"ref65\/cit65","volume-title":"An Introduction to Hydrogen Bonding","author":"Jeffrey G. A.","year":"1997"},{"key":"ref66\/cit66","unstructured":"For a detailed analysis of the relative reactivity of HCN and HNC in catalyst-controlled cyanide addition to aldehydes, and leading references, see:"},{"key":"ref66\/cit66a","doi-asserted-by":"crossref","first-page":"3849","DOI":"10.1002\/chem.200401290","volume":"11","author":"Baeza A.","year":"2005","journal-title":"Chem.\u2014Eur. J."},{"key":"ref67\/cit67","unstructured":"The calculated activation barrier for the analogous process catalyzed by urea8bis 1.4 kcal\/mol higher than the process catalyzed by thiourea8a."},{"key":"ref68\/cit68","unstructured":"The conclusions described in this paper for HNC addition also apply to HCN-addition. All data for the HCN addition mode are included in theSupporting Information."},{"key":"ref69\/cit69","unstructured":"This simplified model system predicts a small preference for formation of (S)-\u03b1-aminonitrile, whereas (R)-\u03b1-aminonitrile is obtained from hydrocyanation reactions using the full catalyst. For consistency, all schemes in this chapter depict formation of (R)-\u03b1-aminonitrile. The corresponding schemes for formation of (S)-\u03b1-aminonitrile are included in theSupporting Information."},{"key":"ref70\/cit70","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1021\/ja806246h","volume":"131","author":"Donoghue P. J.","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref71\/cit71","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1021\/ja806951r","volume":"131","author":"Schneebeli S. T.","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref72\/cit72","doi-asserted-by":"crossref","first-page":"2326","DOI":"10.1021\/ja01542a075","volume":"80","author":"Streitwieser A.","year":"1958","journal-title":"J. Am. Chem. Soc."},{"key":"ref73\/cit73","doi-asserted-by":"crossref","first-page":"4201","DOI":"10.1021\/ja00430a032","volume":"98","author":"Okano V.","year":"1976","journal-title":"J. Am. Chem. Soc."},{"key":"ref74\/cit74a","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1021\/ol000164k","volume":"2","author":"Gajewksi J. J.","year":"2000","journal-title":"Org. Lett."},{"key":"ref74\/cit74b","doi-asserted-by":"crossref","first-page":"4236","DOI":"10.1021\/jo0164002","volume":"67","author":"Gajewski J. J.","year":"2002","journal-title":"J. Org. Chem."},{"key":"ref75\/cit75a","doi-asserted-by":"crossref","first-page":"15008","DOI":"10.1021\/ja038343v","volume":"125","author":"Perrin C. L.","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref75\/cit75b","doi-asserted-by":"crossref","first-page":"9641","DOI":"10.1021\/ja0511927","volume":"127","author":"Perrin C. L.","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref75\/cit75c","doi-asserted-by":"crossref","first-page":"11143","DOI":"10.1021\/ja803084w","volume":"130","author":"Perrin C. L.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref76\/cit76","unstructured":"The origins of this effect have been ascribed to a modulation of the C-H stretching frequency. See ref75bfor the determination of this EIE and a discussion of its origins. In that paper, EIEs are expressed in terms of the acidity of the conjugate acid of the amines."},{"key":"ref77\/cit77","unstructured":"Determined at 298.15 K. Explicit solvation by water likely accounts for some of the discrepancy between experiment and computation, as larger \u03b2-EIEs were observed in a more limited experimental study in DMSO."},{"key":"ref78\/cit78","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1021\/j100552a020","volume":"80","author":"Bellamy L. J.","year":"1976","journal-title":"J. Phys. Chem."},{"key":"ref79\/cit79","unstructured":"We used this computational method to allow direct comparison with the results in ref74b."},{"key":"ref80\/cit80","unstructured":"This isotope effect was calculated from the calculated 3N \u2212 6 normal mode vibrational frequencies using the isotopic partition function of Biegeleisen and Mayer atT= 298.15 K. In each case, sufficiently tight geometry optimization convergence criteria were used so that all non-vibrational frequencies (i.e., the six rotational and translational frequencies) were negligible (\u22121 to 1 cm\u22121) compared with the vibrational frequencies (> 100 cm\u22121). See:"},{"key":"ref80\/cit80a","volume-title":"Isotope Effects in Chemistry and Biology","author":"Wolfsberg M.","year":"2006"},{"key":"ref81\/cit81","unstructured":"This kinetic isotope effect was determined by1H-NMR spectroscopy through competition experiments of reactions run to approximately 70% conversion, in which the hydrogen\/deuterium ratios were determined in both product and recovered starting material. Details are provided in theSupporting Information."},{"key":"ref82\/cit82","unstructured":"We have also calculated analogous kinetic isotope effects for transition structureDin Scheme8relative to free imine at the B3LYP\/6-31G(d) level using 3N\u29e7\u2212 7 vibrational modes forD. The predictedkH\/kD= 0.86 at 298 K orkH\/kD= 0.82 at 243 K is similar to the experimentally observed KIE (eq5)."},{"key":"ref83\/cit83","unstructured":"Several lines of evidence suggest that the pathways leading to (R)- and (S)-3aare mechanistically consistent for the different catalysts. For example, the same trends in enantioselectivity are observed for both aromatic and aliphatic imines, and under a broad range of different conditions, including different temperatures, cyanide sources, and concentrations. Data are included in theSupporting Information."},{"key":"ref84\/cit84","unstructured":"Statistical analysis was performed using SigmaPlot 10.0 purchased from Systat Software."},{"key":"ref85\/cit85","unstructured":"Alanine-derived catalyst4hrepresents the large positive outlier in Figures11and12. This catalyst is also substantially less reactive than any other catalyst, perhaps as a result of catalyst aggregation. It is likely that the experimentally measured enantioselectivity reflects a significant background racemic pathway and therefore underestimates the intrinsic enantioselectivity for this catalyst."},{"key":"ref86\/cit86","unstructured":"B3LYP has been shown to under-estimate the energy of some attractive non-covalent interactions, whereas MP2 over-estimates the energy of these interactions. In this reaction, enantioselectivity is controlled only by non-covalent interactions between substrates and catalysts, and the correlation in Figures10\u221212might be expected to depend strongly of the level of theory used. This is not the case. This conclusion may be ascribed to the observation that the calculated (and experimental; see Figure4) transition structures are highly charged, and thus the non-covalent interactions responsible for asymmetric induction are expected to have a large electrostatic component. Even ab initio computational methods that do not account for electron correlation (i.e., Hartree-Fock) can account for electrostatic contributions of otherwise complex non-covalent interactions:"},{"key":"ref86\/cit86a","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1021\/ja9539608","volume":"118","author":"Mecozzi S.","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref87\/cit87","unstructured":"Calculated versus experimental selectivity plots for HCN addition are included in theSupporting Information. Statistically significant positive linear correlation is observed in all cases. HCN addition is disfavored compared with HNC addition for each catalyst at each level of theory examined (by 0.2\u22123.7 kcal\/mol). The transition structures for HNC addition and HCN addition are similar, and the ion pairs formed from HNC addition and HCN addition are almost identical; it is thus not possible to further distinguish between these two mechanistic proposals, and it is possible that both play a role in catalytic imine hydrocyanation."},{"key":"ref88\/cit88","unstructured":"The length of theN-H bond between imine and proton is 1.03\u22121.04 \u00c5 in the transition structure, and is thus effectively fully formed (i.e., the transition structure has nearly complete iminium ion character)."},{"key":"ref89\/cit89","unstructured":"This analysis ignores any role of bond angle in determining bond energy, and ignores the possibility that bond strength does not necessarily depend linearly on bond length."},{"key":"ref90\/cit90","unstructured":"See, for example:"},{"key":"ref90\/cit90a","unstructured":"aReference44."},{"key":"ref90\/cit90b","first-page":"1680","author":"Mita T.","year":"2009","journal-title":"Synlett"},{"key":"ref91\/cit91","unstructured":"For examples of cationic chiral catalysts thought to operate through non-covalent interactions see:"},{"key":"ref91\/cit91a","doi-asserted-by":"crossref","first-page":"5656","DOI":"10.1021\/cr068368n","volume":"107","author":"Hashimoto T.","year":"2007","journal-title":"Chem. Rev."},{"key":"ref91\/cit91b","doi-asserted-by":"crossref","first-page":"9228","DOI":"10.1021\/ja803370x","volume":"130","author":"Uyeda C.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref91\/cit91c","doi-asserted-by":"crossref","first-page":"7163","DOI":"10.1021\/ja012417q","volume":"124","author":"Cannizarro C. E.","year":"2002","journal-title":"J. Am. Chem. Soc."},{"key":"ref91\/cit91d","doi-asserted-by":"crossref","first-page":"7955","DOI":"10.1021\/ja800253z","volume":"130","author":"Gomez-Bengoa E.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref91\/cit91e","doi-asserted-by":"crossref","first-page":"12414","DOI":"10.1021\/ja973174y","volume":"119","author":"Corey E. J.","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"ref92\/cit92","unstructured":"For examples of anionic chiral catalysts thought to operate through non-covalent interactions, see:"},{"key":"ref92\/cit92a","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1002\/anie.200600512","volume":"45","author":"Mayer S.","year":"2006","journal-title":"Angew. Chem., Int. Ed."},{"key":"ref92\/cit92b","doi-asserted-by":"crossref","first-page":"14984","DOI":"10.1021\/ja806431d","volume":"130","author":"Hamilton G. L.","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref92\/cit92c","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1039\/b205251m","volume":"32","author":"Lacour J.","year":"2003","journal-title":"Chem. Soc. Rev."},{"key":"ref93\/cit93","unstructured":"For other examples of neutral chiral catalysts thought to operate through non-covalent interactions, see: ref1."},{"key":"ref94\/cit94","unstructured":"See, for example:"},{"key":"ref94\/cit94a","volume-title":"Catalysis in Chemistry and Enzymology","author":"Jencks W. P.","year":"1987"},{"key":"ref94\/cit94b","unstructured":"bSilverman, R. B.The Organic Chemistry of Enzyme-Catalyzed ReactionsAcademic Press:San Diego, 2002; pp18\u221220(covalent catalysis), pp 20\u221228 (general acid-base catalysis), pp 28\u221230 (electrostatic catalysis)."},{"key":"ref95\/cit95","volume-title":"Enzyme Kinetics","author":"Segel I. H.","year":"1975"},{"key":"ref96\/cit96","unstructured":"See, for example, the discussions in:"},{"key":"ref96\/cit96a","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1021\/ar00080a001","volume":"15","author":"Lipscomb W. N.","year":"1982","journal-title":"Acc. Chem. Res."},{"key":"ref96\/cit96b","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1126\/science.1085515","volume":"301","author":"Benkovic S. J.","year":"2003","journal-title":"Science"},{"key":"ref97\/cit97","unstructured":"The imine binding constant in the kinetic analysis of reactions catalyzed1bis small (KM= 0.214 \u00b1 0.009 M). Under the conditions of our kinetic analysis with catalyst4a, we estimate thatKMvalues less than 0.5 would be detectable. The differences in binding constant observed in the two analyses may be ascribed to differences in reaction temperature (\u221278 \u00b0C versus 0 \u00b0C) and\/or to the imineN-protecting group (allyl versus benzhydryl)."},{"key":"ref98\/cit98","unstructured":"Even in cases in which electrophile-thiourea interactions are productive, the binding geometry in the ground state can differ substantially from that in the transition state. For example, ketone-thiourea binding can occur through one or both lone pairs of the carbonyl group, and the calculated energies of these binding modes are nearly identical (Fuerst, D. E. Unpublished results from this laboratory). In the nucleophilic addition transition structure, the partially formed alkoxide binds in a way that resembles neither of the low-energy ground state structures (ref16c)."},{"key":"ref99\/cit99","unstructured":"For a related analysis comparing binding geometries of carbonyl compounds to chiral diols in the ground state and transition state, see:"},{"key":"ref99\/cit99a","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/ejoc.200801102","author":"G\u00f3mez-Bengoa E.","year":"2009","journal-title":"Eur. J. Org. Chem."},{"key":"ref100\/cit100","unstructured":"For an alternative approach, see:"},{"key":"ref100\/cit100a","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1126\/science.1138748","volume":"316","author":"Pluth M. D.","year":"2007","journal-title":"Science"},{"key":"ref100\/cit100b","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1021\/jo802131v","volume":"74","author":"Pluth M. D.","year":"2009","journal-title":"J. Org. Chem."}],"container-title":["Journal of the American Chemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/ja9058958","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T21:57:09Z","timestamp":1678226229000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/doi\/10.1021\/ja9058958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,24]]},"references-count":160,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2009,10,28]]}},"alternative-id":["10.1021\/ja9058958"],"URL":"https:\/\/doi.org\/10.1021\/ja9058958","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,24]]}}}