chiral cyclopropenimines 
 developed in one of our laboratories are 
 emerging as a powerful class of enantioselective brnsted base 
 catalysts . the prototypical reaction of glycine imine 2 and methyl acrylate 3a catalyzed by 2,3-bis(dicyclohexylamino ) 
 cyclopropenimine 1 gives the michael adduct 4a in 99% yield with 98% ee . the rate of this transformation is approximately 
 23 orders of magnitude faster than that achieved with an analogous 
 guanidine - based catalyst . this example 
 of the superior performance of cyclopropenimines hints at the tremendous 
 potential of this new class of brnsted base catalysts . an in - depth understanding 
 of this catalyst system would be invaluable 
 to our efforts to pursue new methodological applications and further 
 catalyst development studies . with this goal in mind , we undertook 
 a mechanistic study of the title reaction using experimental c kinetic isotope effects ( kies ) and density functional theory 
 ( dft ) calculations . c kies are uniquely sensitive probes 
 of the rate - limiting transition state geometry of a reaction and have 
 been successfully used to probe the mechanism of several fundamental 
 organic reactions . herein we report identification 
 of the rate - limiting step , elucidation of stabilizing transition state 
 interactions , and the origin of enantioselectivity of this novel organocatalytic 
 reaction . we chose the reaction 
 of the glycine imine 2 and benzyl acrylate 3b catalyzed by 1 for the measurement of c kies using nmr methodology at natural abundance . complementary approaches were used for the determination 
 of c kies for the two reaction components 2 and 3b . thus , 
 the isotopic composition of 4b was measured from two 
 independent experiments taken to 21  2% and 22  2% conversion 
 in 2 and compared to samples of 4b isolated 
 from reactions taken to 100% conversion . the kies for 3b were determined by analysis of recovered starting material : samples of 3b were reisolated from 
 two independent experiments taken to 72  2% and 74  2% 
 conversion ( with respect to 3b ) and were compared to 
 samples of unreacted 3b . the experimental kies calculated 
 from the change in c isotopic composition and the fractional 
 conversion are shown in figure 1 . experimental c kies for reaction of 2 and 3b catalyzed by 1 . the two 
 sets of 
 kies for each carbon represent two independent experiments and the 
 numbers in parentheses represent the standard deviation in the last 
 digit as determined from six measurements . the experimental c kies provide qualitative 
 information 
 about the rate - limiting step in a catalytic cycle . in our initial 
 publication , we proposed a mechanism for 
 this reaction that involves initial deprotonation of 2 by 1 to generate h - bonded cyclopropenium ion - enolate 
 complex 5 ( scheme 2 ) . subsequent 
 michael addition of 5 to 3 affords adduct 7 via transition state 6 . finally , proton transfer 
 from the cyclopropenium ion to the michael adduct results in release 
 of 4 and regeneration of 1 . substantial c kies for the two bond - forming carbon atoms ( shown in red 
 in figure 1 ) suggest carbon  carbon bond 
 formation to be the rate - limiting step in the catalytic cycle . all 
 other kies are close to unity , consistent with minor rehybridization 
 occurring at this isotope - sensitive step . we next sought to gain detailed 
 insight into the organization of this enantioselectivity - determining 
 carbon  carbon bond - forming transition state through theoretical 
 studies . preliminary results reported in our initial publication suggest a key role of the dicyclohexylamino substituents 
 in mediating reaction efficiency and enantioselectivity , while the 
 nh proton and the pendant hydroxyl group in catalyst 1 are vital elements in assembling this transition state via multiple 
 h - bonding interactions . a comprehensive theoretical study of this 
 reaction is complicated by a number of factors , namely , ( 1 ) the size 
 of the system  the cyclopropenimine - catalyzed reaction of 2 and 3a involves 150 atoms , ( 2 ) the possibility 
 of several conformations for the catalyst , ( 3 ) the possibility of 
 either e or z geometry of the intermediate 
 enolate 5 and of s - cis or s - trans geometry of the acrylate 3a , and ( 4 ) several competing 
 h - bonding scenarios in the assembly of the transition state . a detailed investigation of the catalyst geometry revealed a preference 
 for a conformation wherein the cyclohexyl rings are geared in the 
 same direction and the hydrogen atom at the chiral center is oriented 
 anti to the nh proton ( the h carbon 
 bond forming transition structures leading to the major and minor 
 enantiomers of product 4a and the theoretical prediction 
 of enantioselectivity . owing to the large size of the system , initial 
 explorations of transition structures were performed using the hybrid 
 oniom ( b3lyp/6 - 31+g**:am1 ) method as 
 implemented in gaussian 09 . the oniom 
 method treats the key bond - forming and h - bonding portions of the transition 
 state using the high - level dft method ( b3lyp/6 - 31+g * * ) and the steric 
 bulk of the catalyst and reactants using the semiempirical method 
 ( am1 ) . the time efficiency of the oniom 
 method allowed us to explore a range of transition structures , including 
 those involving higher energy catalyst conformations , those involving 
 different h - bonding scenarios , and those lacking multiple h - bonding 
 interactions . the summary of the results from the oniom study is presented 
 in the supporting information . division of 
 layers for the oniom method used for initial exploration 
 of transition structures . the exploratory oniom study led to the identification of 
 a subset 
 of viable transition structures arising from four distinct binding 
 modes ( 5a  d , figure 3 ) of the catalyst enolate complex 5 . a 
 simple template that can be used to describe these  most likely after initial deprotonation of 2 by 1 , the resulting catalyst - bound enolate 5 can adopt either 
 the e or z geometry . in monocoordinated 
 binding mode 5a , the enolate is held by a single h - bonding 
 interaction between the hydroxyl group on the catalyst and the enolate 
 oxygen . the nh moiety of protonated 1 presumably directs 3a for conjugate attack by h - bonding to the oxygen atom of 3a at the transition state . four possible orientations of 
 binding mode 5a that allow for this combination of h - bonding 
 interactions are shown in figure 3 . they are 
 labeled 5are , 5arz , 5ase , and 5asz based on the binding mode 5a , the enantiomer 
 of product formed ( r or s ) , and the enolate 
 geometry ( e or z ) . a similar ( and complementary ) situation arises when the enolate oxygen is h - bonded to the nh moiety 
 of catalyst 1binding mode 5b . in 
 this monocoordinated binding mode , the enolate can once again adopt 
 either a e or z conformation and 
 the hydroxyl group directs 3a for conjugate attack via 
 h - bonding to the oxygen atom . four additional conformations , 5bre , 5brz , 5bse , and 5bsz , can be envisioned from binding mode 5b . in binding 
 modes 5c and 5d , the enolate 
 is bound to the catalyst via two h - bonding interactions : between the 
 oxygen and nitrogen acceptor atoms ( of the enolate ) and the two h - bond 
 donors in the protonated catalyst . two important features distinguish 
 these dicoordinated binding modes from the monocoordinated counterparts : 
 ( 1 ) the enolate is forced to adopt only the e conformation to accommodate the two h - bonding interactions , 
 and ( 2 ) in the transition structures for conjugate attack based on 
 binding modes 5c and 5d , the oxygen atom 
 of 3a is not involved in h - bonding with the catalyst . 
 for obvious reasons , transition structures wherein neither the nh 
 nor the oh moiety of 1 is involved in h - bonding were 
 not considered in detail . transition structures based on the 12 distinct binding modes 
 of 5 were recalculated using the b3lyp/6 - 31 g * method . the dft treatment of the whole system is expected 
 to yield a better description of the energetics of noncovalent interactions 
 ( such as ch- interactions ) compared to the oniom calculations . all reported distances are in angstroms , and 
 all reported energies are e+zpe energy from the b3lyp/6 - 31 g * calculations . frequency calculations performed on these transition structures revealed 
 one imaginary frequency corresponding to carbon  carbon bond 
 formation . shown in figure 4 ( s transition 
 structures ) and figure 5 ( r transition structures ) are the eight transition structures corresponding 
 to the eight geometries shown in figure 3 for 
 monocoordinated binding modes 5a and 5b . two features are common to all eight transition structures namely 
 ( 1 ) strong h - bonding interactions between both reactants 
 ( 2 and 3a ) and the two h - bond donors in 
 the catalyst , and ( 2 ) an s - cis conformation of 3a . the lowest energy transition 
 structures leading to each enantiomer , ts5bse ( erel = 0.0 kcal / mol , figure 4 ) and ts5arz ( erel = 1.7 kcal / mol , figure 5 ) , are highlighted 
 using green and red boxes , respectively . this energy difference ( 1.7 
 kcal / mol ) corresponds to a predicted 89% ee . consideration of a contributing 
 second transition structure leading to the major enantiomer ( ts5ase , erel = 0.9 kcal / mol ; which 
 is still lower in energy than ts5arz by 0.8 kcal / mol ) 
 gives an altered prediction of 92% ee . the exact 
 origin of the favorability of ts5bse over ts5arz is probably attributable to a complex interplay of 
 several stabilizing / destabilizing interactions . a detailed examination 
 of some of these stabilizing interactions will be discussed in a later 
 section . finally , all transition structures resulting from the dicoordinated 
 binding modes 5c and 5d ( supporting information ) were found to be over 12 kcal / mol 
 ( at least ) higher in energy than ts5bse , illustrating 
 the importance of h - bonding between the catalyst and both reacting partners at the transition state . six of the eight 
 transition structures in figures 4 and 5 are within 5 kcal / mol of the 
 lowest energy transition structure ts5bse . interestingly , 
 the two transition structures that are significantly higher in energy , ts5bsz ( erel = 11.5 kcal / mol ) 
 and ts5bre ( erel = 10.4 kcal / mol ) , 
 are almost identical except with respect to the geometry of the enolate . 
 in our attempt to understand this result , we took a closer look at 
 the key difference between these two transition structures and the 
 six lower energy transition structures . all transition structures 
 in figures 4 and 5 have 
 similar carbon  carbon bond forming distances ( 2.02.2 
  ) , and are stabilized by the two short h - bonding interactions 
 ( nho and oho in the range of 1.71.9 
  ) discussed earlier . an additional ( and rather unusual ) cho 
 interaction , in the range of 2.12.3  between the cyclohexyl  ch 
 and the hydroxyl oxygen atom , appears to be contributing to transition 
 state stabilization of the six lower energy transition structures 
 in figures 4 and 5 . intriguingly , this cho distance is significantly 
 larger in the two high - energy transition structures ts5bre ( 3.39  , figure 5 ) and ts5bsz ( 3.52  , figure 4 ) . this finding suggests 
 that the contribution of the cho interaction to 
 transition state stabilization is , crudely , around 5 kcal / mol . this 
 is based on the observation that there is no obvious deleterious interaction 
 ( apart from the elongated cho distance ) in these 
 two transition structures that is not present in one of the six transition 
 structures that are within 5 kcal / mol of the lowest energy transition 
 structure . a more detailed evaluation of this interaction will be 
 presented in a later section . transition structures leading to major ( s ) enantiomer 
 of product 4a that utilize monocoordinated binding modes 5a and 5b . all transition structures are oriented with the acrylate 
 in the foreground and the enolate in the background . transition structures leading to minor ( r ) enantiomer 
 of product 4a that utilize monocoordinated binding modes 5a and 5b . all transition structures are oriented with the acrylate 
 in the foreground and the enolate in the background . comparison of experimental ( black ) and predicted ( red ) c kies . to interpret the experimental kie results 
 described above , c kies were computed from the scaled 
 vibrational frequencies of the two lowest energy transition structures 
 leading to the major enantiomer ( ts5bse and ts5ase , as a weighted average based on their energies ) using the program 
 isoeff98 . the predicted kies , along with the experimental values obtained 
 for each carbon atom , are shown in figure 6 . the excellent agreement of experiment and theory validates the 
 transition state model and supports carbon  carbon bond formation 
 to be the rate - limiting step of the reaction . to obtain a qualitative 
 breakdown of the energy difference between the key transition structures 
 contributing to the formation of either enantiomer of product , an 
 analysis of h - bonding and other stabilizing interactions the strength of 
 an h - bonding interaction depends on both the h - bonding distance and 
 the donor  hydrogen - acceptor angle , a linear arrangement of 
 the three atoms forming the angle results in the strongest h - bonding 
 interaction . each h - bonding distance 
 is listed in table 1 along with the donor  hydrogen  acceptor 
 angle . finally , the structures have been analyzed for stabilizing 
 ch- interactions , the criterion being that the relevant hydrogen 
 is appropriately oriented with respect to the  system and that 
 the distance between the hydrogen and the closest aromatic carbon 
 atom is < 3.0  . the two main features that 
 distinguish ts5bse from 
 the other two structures are ( 1 ) the shorter c  c bond distance 
 ( 1.99  ) and ( 2 ) a stronger interaction between the acrylate 
 oxygen atom and the h - bond donor atom ( 1.69  and oho 
 = 173.2 ) . since c c bond formation is more 
 advanced in ts5bse , there is a greater buildup of negative 
 charge at the acrylate oxygen atom resulting in the stronger h - bonding 
 interaction . favorable ch- interactions were also identified 
 in both ts5bse and ts5ase that were absent 
 in ts5arz ( see supporting information for pdbs of these structures ) . a full understanding of the 
 exact origin of enantioselection in 
 this system is complicated by the accessibility of both e and z enolates and the possibility of multiple 
 binding modes for the catalyst in contrast to the vast majority 
 of asymmetric transformations , enantioselectivity in this reaction 
 is not a result of selective access of one face versus the other of 
 a single complex ; rather it appears to result from the best network 
 of h - bonding interactions , geometry of the enolate , and other stabilizing 
 interactions . the observation that the major enantiomer ( s ) is formed from two very geometrically distinct transition structures , ts5bse ( 83% ) and ts5ase ( 17% ) , 
 suggests that the prediction of enantioselectivity for other reactions 
 catalyzed by 1 ( or even the same reaction with a different 
 michael acceptor ) will require a full consideration of all possible 
 transition state assemblies . the main contribution of this work is 
 the development of a template ( figure 3 ) that 
 provides a systematic basis for the prediction of enantioselectivity 
 in reactions catalyzed by 1 . we are currently adopting 
 this template for the optimization of reactions that are in the early 
 stages of development . we 
 next turned our attention to understanding why the cy - cho 
 distance is elongated in the two high energy transition structures ts5bre and ts5bsz . among all the binding modes 
 shown in figure 3 , the bond - forming enolate 
 carbon atom is the farthest away from the pendant hydroxyl group in 
 binding modes 5bre and 5bsz . as a result , 
 the hydroxyl group has to adopt a conformation that is different ( from 
 the six other lower energy transition structures in figures 4 and 5 ) in order to stabilize 
 the oxygen atom of 3a via h - bonding at the transition 
 state . this different conformation of the hydroxyl group does not 
 allow close proximity between the cy  ch and the hydroxyl oxygen . in other words , maintaining the cho interaction 
 appears to be less important than stabilization ( via h - bonding ) of 
 the developing negative charge of the oxygen atom of 3a in these transition structures . this observation is further supported 
 by the energies of the transition structures resulting from binding 
 modes 5c and 5d , even though all four transition 
 structures ts5cre , ts5cse , ts5dre , and ts5dse had cy - cho distances 
 between 2.1 and 2.4  ( not shown , see supporting 
 information ) , they were found to be 12.0 , 13.2 , 19.5 , and 16.5 
 kcal / mol ( respectively ) higher in energy than ts5bse due 
 to lack of transition state stabilization of the acrylate oxygen atom . while the contribution of the cho interaction 
 to transition state stabilization is significant , its role in determining 
 enantioselectivity is expected to be minimal since bothts5bse and ts5arz benefit from the stabilization 
 afforded by this interaction . nevertheless , we envisioned that slight 
 perturbation of enantioselectivity could be used as an experimental 
 probe of this interaction  since the cho distance 
 is slightly different in the key transition structures . with this 
 in mind , we synthesized the deuterated version of the catalyst 1a with all four cy  chs substituted by deuterium . to 
 observe even a small kie on the enantioselectivity , a catalyst mixture 
 of 50% ( s)-d4 - 1 and 50% ( r)-1 was employed for the addition of glycine imine 2 to 3a ( figure 7 ) . a kie would be manifested 
 in the reaction in the form of a nonracemic product . the product from 
 this reaction was essentially racemic ( < 5% ee ) , however , indicating 
 a kie of 1.0 . the lack of an observed kie does not undermine 
 the importance of a transition state cho interaction . 
 indeed , because the relevant hydrogen is not participating in any 
 bond - forming or bond - breaking events , and because both the major and 
 minor enantiomer transition states likely benefit from this interaction 
 to similar extents , it is not unreasonable that any kie would be too 
 small to measure . labeling studies as an 
 experimental probe of cho 
 interaction . finally , examination 
 of this interaction in the crystal structure 
 ( 2.51  ) and computed structures ( 2.35  , 
 b3lyp/6 - 31 g * ) of the protonated catalyst revealed that it is present , 
 albeit to a lesser extent , in the ground state . the discrepancy in 
 these numbers suggests that our calculations might be slightly overestimating 
 this interaction . however , the compression 
 of this distance on going from the protonated catalyst to the transition 
 state , ( by 0.150.2  ) suggests that the role of this 
 interaction in the transition state stabilization is nontrivial . we 
 recognize that gas phase b3lyp/6 - 31 g * calculations might be inadequate 
 in accurately describing the energetic contribution of this interaction 
 but we expect higher - level calculations to exhibit similar trends 
 on going from the ground state to the transition state . the preliminary 
 investigations using oniom methods , where this interaction was calculated 
 using a 6 - 31+g * * basis set , showed similar trends in the cho 
 distance at the transition state ( 2.102.3  , see supporting information for complete details and 
 analyses of these calculations ) . experimental c kies and theoretical studies provide 
 a high - resolution picture of the enantioselectivity - determining transition 
 state of the michael addition of glycinate imines to acrylate catalyzed 
 by a chiral 2,3- bis(dicyclohexylamino ) cyclopropenimine catalyst . 
 on the basis of these studies , an unusual 
 intramolecular cho interaction has been identified 
 as a key element in transition state organization . transition structures 
 where h - bond donors on the catalyst stabilize both reactants via h - bonding 
 are favored . ultimately , enantioselection results from the best network 
 of h - bonding interactions , geometry of the enolate , and other stabilizing 
 interactions . the use of this information for the rational design 
 of novel cyclopropenimine - based brnsted base catalysts will 
 be reported in due course .
experimental 13c kinetic isotope effects have been used 
 to interrogate the rate - limiting step of the michael addition of glycinate 
 imines to benzyl acrylate catalyzed by a chiral 2,3-bis(dicyclohexylamino ) 
 cyclopropenimine catalyst . 
 the reaction is found to proceed via rate - limiting 
 carbon  carbon bond formation . 
 the origins of enantioselectivity 
 and a key noncovalent cho interaction responsible 
 for transition state organization are identified on the basis of density 
 functional theory calculations and probed using experimental labeling 
 studies . the resulting high - resolution 
 experimental picture of the 
 enantioselectivity - determining transition state is expected to guide 
 new catalyst design and reaction development .