Ternary complexes of chiral disulfonimides in transfer-hydrogenation of imines: the relevance of late intermediates in ion pair catalysis
In ion pairing catalysis, the structures of late intermediates and transition states are key to understanding and further development of the field. Typically, a plethora of transition states is explored computationally.However, especially for ion pairs the access to energetics via computational chemistry is difficult and experimental data is rare. Here, we present for the first time extensive NMR spectroscopic insights about the ternary complex of a catalyst, substrate, and reagent in ion pair catalysis exemplified by chiral Brønsted acid-catalyzed transfer hydrogenation. Quantum chemistry calculations were validated by a large amount of NMR data for the structural and energetic assessment of binary and ternary complexes. In the ternary complexes, the expected catalyst/imine H-bond switches to an unexpected O-H-N structure, not yet observed in the multiple hydrogen-bond donor-acceptor situation such as disulfonimides (DSIs). This arrangement facilitates the hydride transfer from the Hantzsch ester in the transition states. In these reactions with very high isomerization barriers preventing fast pre-equilibration, the reaction barriers from the ternary complex to the transition states determine the enantioselectivity, which deviates from the relative transition state energies. Overall, the weak hydrogen bonding, the hydrogen bond switching and the special geometrical adaptation of substrates in disulfonimide catalyst complexes explain the robustness towards more challenging substrates and show that DSIs have the potential to combine high flexibility and high stereoselectivity.
Introduction<!>Model systems and experimental setup<!>Hantzsch ester binding and Z-imine complex<!>NMR structural investigations of E-ternary complexes<!>Conformational screening by computational methods<!>Quantitative assessment of binary complexes<!>Ternary complexes<!>DFT computations of NMR spectra<!>From ternary complexes to transition states<!>Conclusions
<p>The detection and identication of reaction intermediates in asymmetric catalysis still poses considerable challenges to the experimental setup as well as to the computational elucidation of possible structures. This quest is even more difficult in the area of noncovalent organocatalysis, where well-dened hydrogen-bonded or ion-pair intermediates are rather scarcely detected and offsets between experimental and computational populations limit the explanatory power of calculations. 1,2 One of the central model systems for mechanistic investigations in ion pair catalysis is the enantioselective Brønsted acid-catalysed transfer-hydrogenation of imines. [3][4][5] This reaction represents a general and mild route to the synthesis of chiral amines, which are valuable structural units found in many bioactive compounds. [6][7][8] The early intermediates in the corresponding catalytic cycle, the binary complexes of the catalysts and imines as well as their dimers, have already been experimentally detected. 9,10 Even the dynamic behaviour of these species could be followed by NMR. 11 However, later intermediates and transition states were proposed for the purely organocatalytic chiral phosphoric acid (CPA)-catalysed reaction only by theoretical calculations. [12][13][14][15][16] The computed active transition states suggested that the reaction proceeds via the bifunctional binding of both the substrate and the reagent by the catalyst. [17][18][19] So far mechanistic studies have focused mainly on popular catalysts employed for the transfer-hydrogenation such as chiral phosphoric acids e.g. TRIP 1, and the more acidic disulfonimides 2 (see Fig. 1A). [20][21][22][23][24][25][26] These widely used catalysts benet from the axially chiral BINOL backbone, whose 3,3 0 -substituents can be ne-tuned for the desired reactivity and selectivity. 14 The role of the catalysts in the catalytic cycle was studied using experimental and computational methods. The rst step of the proposed catalytic cycle is the formation of an E-imine binary complex. Given sufficient thermal energy, the catalyst is capable of isomerizing the E-complex into a Z-imine complex, which are in slow exchange at 180 K, as shown by NMR studies by our group (Fig. 1B). 27 We have also reported that for the complexes of CPAs, a strong, charge-assisted hydrogen bond is formed, as evidenced by the detection of 1 J NH and 3 J PH scalar couplings across the H-bond, with additional noncovalent CH-p and p-p interactions. This evidence is supported by the correlation of hydrogen bond strength and NMR parameters such as 1 H and chiral DSIs form rather weak hydrogen bonds with imines and the complexes have more ion-pair character, allowing some additional structural exibility. 28,29 The reducing agent then approaches the binary complex. The reaction utilizes a sacricial hydrogen donor, such as Hantzsch ester, to transfer a hydride ion to the LUMO-activated imine. [30][31][32] The chiral catalyst in the complex is proposed to establish a new hydrogen bond to the reducing agent due to its bifunctional nature, thus enhancing the thermodynamic driving force for the hydride transfer (see Fig. 1C for principal arrangements in case of DSI). 33 An analogous activation has been suggested in a bifunctional thiourea-catalysed transfer hydrogenation. 34 With such dual activation offering an opportunity for efficient chirality transfer, a ternary complex is formed and chiral information is transmitted. The catalyst is then liberated from the complex and a proton transfer from the formed pyridinium ion ensures the regeneration of the catalyst, which can enter a new catalytic cycle. Based on extensive experimental evidence, the E/Z-isomerization and the ternary complex formation have been proposed to be the potential rate-determining steps in the cycle. 35 As a result, the availability and detectability of the ternary complex in the reaction mixture is extremely limited.</p><p>Moreover, the bifunctional binding mode is a crucial factor for the reactivity, oen overriding the acidity of the catalyst towards faster reaction rates. This has been demonstrated by comparing the reaction rates of DSI or its simple analogues compared to HCl as the monofunctional catalyst. 36 Moreover, we have shown that a very acidic bis(sulfonic) acid catalyst gave the slowest reaction most likely due to the intramolecular Hbond stabilization of the resulting monosulfonate. 28 However, the bifunctional binding of the substrate and reducing agent to the classical CPAs has not been experimentally disclosed so far. This topic is even more pressing with the far more complex situations in multiple H-bond acceptors present in the recently developed, highly-acidic ion pair catalysts. To the best of our knowledge, NMR based experimentswithout extensive NOE map and the geometries proposed only by semi-empirical methodswere obtained exclusively for an organometallic Ir-catalyst and imine. 37 In addition, many computational methods reproduce geometries of ion pair complexes reliably. However, the relative experimental populations of the binary complexes could not be reproduced by computations without large deviations so far, which raises questions about the correct evaluation of transition states.</p><p>Here, we present the rst experimental proof for H-bonded ternary complexes of chiral disulfonimides (DSI) with imines and Hantzsch ester based on detailed NOE analysis, H-bond detection, relaxation and diffusion studies, and chemical shi perturbation analysis. The combination of these experimental data allowed us to select a computational method, which reproduced the experimental populations of the complexes. The NMR and computational analyses revealed the switching of weak H-bonds in multi-acceptor situations from the expected N-H-N pattern to an O-H-N binding in ternary complexes (see Fig. 1D). This unexpected feature has not yet been considered in the design stage of catalyst development so far. Moreover, the data showed that the inclusion of ground states is indispensable when assessing transition states of reactions where isomerization of intermediates is a slow process.</p><!><p>Two catalysts, (R)-TRIP (1) and (R)-DSI (2) were tested as model systems. Our previous efforts in establishing the ternary complex of TRIP (1) have been hampered by the extremely low solubility of the Hantzsch ester 3a. 35 Furthermore, the inevitable formation of reaction products during the sample  19 F-HOESY experiments showed the presence of a ternary complex with soluble Hantzsch esters 3. The ternary complex is in fast exchange with the binary complex even at 180 K, and the Overhauser effect from the ternary complex can be detected.</p><p>preparation complicated the analysis of 1D 1 H NMR spectra at low temperatures. To solve both issues, we employed ester 3b which contains an additional phenyl group, distant from the potential binding site, and is also fully soluble at 180 K (see Fig. 1D). As imine we chose the small-sized N-Me imine 4 to minimize the impact of the steric interactions, since previous studies with larger imines were unfruitful. 35 Only for DSIs 2, homogenous solutions at 180 K are formed, relatively sharp peaks are present and even intermolecular NOEs/HOEs are detected between signals of iminium, catalysts 2 and Hantzsch ester 3b. Similar intermolecular NOEs/HOEs hinting at ternary complex formation were observed using Naryl imines [ 15 N]-5a and 5b (Fig. 1D). Generally, the binary complex of DSI and imine is in fast exchange with the ternary complex and only average signals are observed (e.g., d H-bond (E) 14.53/(Z) 15.06 ppm in 2b/3b/5b, signals are split by 1 J NH in the 15 N-labelled imines and Hantzsch ester) (for further discussion and exclusion of other possibilities see ESI Chapter 6.2 †).</p><p>The NMR spectra generally show the major E-and minor Ziminium ions, with the hydrogen bond in slow mutual exchange. No free imines are detected in the samples, because the imines are protonated by the acidic catalysts. There is one set of signals for the Hantzsch ester with split 2,6-dimethyl group signal; and only one set of signals for the catalyst, accompanied by averaging of the signals of its two naphthyl groups (Fig. 1D). This averaging suggests a fast equilibrium with the binary complex coupled to a fast rotation around the catalyst's C 2 -axis. Interestingly, the rotation of the 3,3 0 -substituents is hindered in DSI complexes. For example, two distinct 19 F signals are present for the catalyst 2a, and two 1 H AB systems for catalyst 2b. Thus, we could conrm the presence of the ternary complex with DSI catalysts by NMR and exclude the possibility of the Overhauser effects stemming from separate Hantzsch ester complexes.</p><!><p>To address the binding site and the binding constant, the chemical shi perturbation upon the binding of Hantzsch ester to the binary complex was investigated. Therefore, 3b (0.5-15 eq.) was sequentially added to the binary complex 2a/5a (20 mM) and 1 H and 1 H, 13 C-HSQC spectra were recorded at 180 K to allow for chemical shi mapping (Fig. 2A). In general, the signals of the Zcomplex showed signicantly larger chemical shi perturbations than the E-complex (see 1D spectrum in Fig. 2A). For the Zcomplex the iminium 15 NH was shied followed by protons Z-1/ Z-2 (see Fig. 2A and ESI Chapter 8 †). Fitting these data for two distinct sites (Z-NH and Z-2 CH) revealed a binding constant K a ¼ $22, indicating a weak binding of the Hantzsch ester to the binary Z-complex. For the E-complex, only the iminium NH and the methoxy group showed small chemical shi differences (see E-NH and E-1 in Fig. 2A and in the 1 H, 13 C-HSQC spectrum ESI Chapter 8 †). The nearly linear change suggests a much weaker binding of the E-complex.</p><p>The population of Z-complexes was then doubled from 15% to 31% by photoisomerisation (back isomerization is stopped at Fig. 2 Chemical shift mapping and NOE/HOE analysis proves bifunctional binding in the ternary complex: (A) stronger binding of Z-imine from chemical shift mapping: NMR titration of (CF 3 ) 2 -DSI 2a/5a E/Z mixture (20 mM) with 0-15 eq. Hantzsch ester 3b, followed by 1 H NMR and 1 H, 13  180 K). One intermolecular NOE contact between Z-2 of the iminium and the Hantzsch ester could be detected (see structure in Fig. 2A), which ts perfectly to the chemical shi perturbation and the calculated bifunctional structure of the ternary Z-complex. Thus, the chemical shi perturbation study in combination with the NOE detected corroborates the bifunctional binding of both imine and Hantzsch ester in the ternary complex for the rst time spectroscopically.</p><!><p>Next, structural insights about the E-ternary complex were gained. Here, we prepared exclusively E-iminium complexes to reduce chemical shi overlap and to compensate for the smaller binding constant by increased concentrations. These samples were prepared by mixing solutions of imines and catalysts/ Hantzsch ester mixtures at À80 C to avoid any acidpromoted, thermal E/Z isomerization. Despite the low binding constant, 2D 1 H, 1 H-NOESY spectra (CD 2 Cl 2 , 180 K) with short mixing times (50-100 ms) showed unexpectedly many intermolecular NOEs and (and HOEs) especially between the Hantzsch ester 3b, the catalyst 2a and the E-imine 5a signals (see Fig. 2B) proving again the existence of a ternary complex. To exclude potential spin diffusion artifacts, 38,39 we collected 2D 1 H, 1 H-ROESY data, which conrmed the observed contacts as genuine. A relevant population of a ternary complex is indicated by the signicant intensity of the ROESY and 1 H, 19 F-HOESY crosspeaks between the catalyst and the Hantzsch ester, as well as between the Hantzsch ester and the imine. The NOE/ HOE signals to the Hantzsch ester are thus decisive about the ternary structure (Fig. 2B).</p><p>To get further insight about this potential conformational exibility within the ternary complex, we utilized imine 5b with an additional CF 3 group as a spectroscopic sensor together with catalyst CF 3 -DSI 2b. The three CF 3 groups allowed us to observe 1 H, 19 F-HOESY signals between both the catalyst and Hantzsch ester as well as imine and Hantzsch ester (Fig. 3A and B), originating from the transiently formed ternary complex. Additionally, DOSY experiment at 180 K showed the three components -Hantzsch ester, imine, and the catalystdiffuse together, corroborating the formation of a supramolecular complex (see ESI Chapter 11 †). The estimated molecular mass matches the mass of the ternary complex. Typical NOE contacts were found for the two different conformations of the previously established E-imine binary complex (see Fig. 3C): EI (E N /E O I) which has the imine aryl next to the naphthyl group of the catalyst; and EII, which has the N-aryl ring close to the catalyst naphthyl ring. Since NOE contacts between the catalyst and the imine observed in the ternary mixtures originate from both binary and ternary complexes, we used only the contacts of the Hantzsch ester to the catalyst or the imine to reveal the ternary complex conformations (see ESI Chapter 7 †). However, it seems that a new conformation, not populated in binary complexes is adopted which can accommodate all the observed NOE/HOE contacts. This anticipated structure could have an intermediate position of the imine between EI and EII structures, as was already observed for CPAs, namely in the CPA/imine dimeric species 10 and in calculated transition state structures. 18 The Hantzsch ester would be stacked above or below the imine. The evidence for this conformation comes from the NOE/HOE contacts that could not be assigned to EI and EII structures (Fig. 3B, right).</p><p>With the data in hand, we addressed the orientation of the bound Hantzsch ester in the ternary complex. The NOE/ROEs network detected indicates a bifunctional binding of the Hantzsch ester (via a very weak H-bond) and the imine to the catalyst as proposed previously for the CPAs by theoretical calculations and is already shown in Fig. 2B. In the case of the bifunctional binding mode, the Hantzsch ester interacts via its NH group. Indeed, only the neighboring 2,6-dimethyl groups show a signicant diastereotopic splitting upon binding in the ternary mixture and show the largest reduction in T 2 relaxation time (further details see ESI Chapter 10 †). In addition, these 2,6dimethyl groups show the strongest intermolecular NOE/ROEs (see ESI Chapter 6.2.3 and 6.2.4 †). Thus, the bifunctional binding mode is conrmed and further insight into the position of the Hantzsch ester is exemplied by the relative NOE buildup rates upon selective irradiation of these Hantzsch ester methyl groups (Fig. 3D, right) and a 1D ROESY spectrum (Fig. 3D, le). The close proximity between the two hydrogen bonds in the ternary complex was further conrmed by a selective NOE experiment from the proton of the catalyst/imine hydrogen bond (d H 14.53 ppm) to the Hantzsch ester methyl protons and vice versa.</p><p>For the rst time, direct spectroscopic evidence is provided for the bifunctional binding mode of a Brønsted acid catalyst with the substrate the reagent. In addition, the investigated ternary complexes might show conformational exibility that reects the situation in the binary complexes, or a single new conformation with intermediate imine/Hantzsch ester position.</p><!><p>The NMR investigations provided qualitative insight about the contacts within the ternary complex. However, the fast exchange between the binary and the ternary complexes and any potential ternary complex conformational exchange allowed only a qualitative analysis of the NOE patterns discussed above. Therefore, the conformational space of the ternary complex was investigated by computational methods so that the resulting 3D structures could be compared with the experimental data.</p><!><p>Previously, ve hydrogen-bonded DSI binary complex conformations have been identied in agreement with the NMR data. 28 These structures correspond to the type E N , with iminium bound to nitrogen; E O I, and E O II-types bound to the oxygen; and ZI and ZII. Type I structures bring the parent ketone part of the imine closer to the binaphthyl backbone of the catalyst, whereas in type II structures the N-aryl substituent is located near the binaphthyl core (for principal contacts see Fig. 3C). Out of these ve binary complexes, the previous computational approaches always favoured the E N -complex while the experiments revealed a signicant population of the Zcomplexes. 28 This large energetic overestimation of the E-imine binary complexes in Brønsted acid catalysis by the applied theoretical methods has been a general problem so far. 10 Since hydrogen bonds and p,p-interactions dominate the interaction mode revealed by NMR, we tested the B97-D functional, as it was developed to adequately describe hydrogen-bonded DNA base pairs. 40,41 Indeed, calculating the Gibbs free energies of the binary complexes by the B97-D/def2-QZVPP/SMD//TPSS-D3(BJ)/ def2-SVP/SMD level of theory correctly reproduces for the rst time the experimental E/Z ratio (2a/5a exp. E/Z ¼ 88%/12% at 180 K; calc. E/Z ¼ 87%/13%). Out of the ve conformations for (CF 3 ) 2 -DSI 2a/5a the major structures are E N ($87% population), and ZII (12%). Furthermore, from 8 tested methods using ORCA computational soware, 42 the next best energetic estimation was provided by a more advanced, robust double hybrid B2PLYP/CBS (E N $ 93% population, ZI $ 6.5%; see ESI Chapter 14.7 †). 43,44 Moreover, the reaction Gibbs free energy of the Hantzsch ester 3d binding to the binary complex (CF 3 ) 2 -DSI 2a/ Z-5a was best reproduced also by this method (exp. À4.6 kJ mol À1 ; calc. À9.9 kJ mol À1 ; see ESI Chapter 14.10 †). Thus, an almost quantitative assessment of both relative energies of binary complexes and the binding of the Hantzsch ester could be achieved by selected computational methods.</p><!><p>Having established the methods required, we addressed the Eternary complexes because only for those sufficiently detailed structural information was available from the NMR experiments (see above). First, we identied the principal conformers by a conformational search of the ternary complex containing CF 3 -DSI 2b, simplied dimethylester 3c, and imine E-5b using GFN2-xTB metadynamics. 45 This search resulted in E N structures containing an NHN-hydrogen bond to the imine as well as an OHN hydrogen bond to the Hantzsch ester. Additionally, these E O structures have the iminium bound to a catalyst oxygen. Next, we performed a more extensive search to cover full conformational spacestarting from the previous lowest energy structure (E O ) with a more stable conformation of 3cand generated 300 conformers (annotated with quotation mark). Then, we optimized the most stable structures with TPSS-D3(BJ)/def2-SVP method (with implicit solvation model) and obtained exclusively conformers containing hydrogen-bonded species (E N as well as E O structures for both the imine and the Hantzsch ester). The most energetically favorable candidates from the conformational analyses are the E N I 00 structure and the E 00 O structure presented in Fig. 4A (for energetic assessment see discussion below). The structure E N I 00 resembles in principle the relative position of the imine towards the catalyst in the EI transition states calculated for CPAs. 18 In addition, the special binding site of the DSI allows for the new conformation E 00 O . In the conformation E N I 00 the Hantzsch ester is far away from the imine, making the hydride transfer event unfavourable. In contrast, in the E 00 O conformation, both the imine and the Hantzsch ester occupy central positions in close proximity, making this conformation a prospective candidate for the transition state.</p><p>However, the E N I 00 conformation cannot accommodate all of the experimental NOE contacts alone in contrast to the conformation E 00 O . Its presence at 180 K is corroborated experimentally by all the NOE and HOE contacts. Indeed, this E O complex is easily accessible at ambient temperature reaction conditions with the reactive form of 3 such as 3a and is a direct precursor to the E-transition state. Detailed structural analysis is given below. To our knowledge, this is the rst complex in ion pair catalysis, in which an O-H-N hydrogen bond is preferred over an N-H-N hydrogen bond in presence of a multiple Hbond donor-acceptor system. So far, only for a free IDPi catalyst dimer dynamic structure, 46 and our DSI binary complexes, 28 the possibility of switching between oxygen and nitrogen atoms was proposed.</p><p>Next, we calculated the Gibbs free energies of the ternary complexes with different methods for the single-point energy calculation: B97-D and B2PLYP discussed above, one additional double hybrid functional, 47 and SCS-MP2 used previously for CPA complexes in our group (Fig. 4A). 27 We evaluated the methods based on the experimental data in which substantial populations of some E N conformers or a substantial population of E 00 O are required to potentially detect the distinct NOE contacts and especially the NOE build-up rates discussed above (Fig. 3C and D). However, based on the optimized ternary complex structures and a thorough NOE analysis, it then became clear that the E 00 O structure ts all the NOE and HOE data (see ESI Chapter 7.2 †). For instance, the 2a/ E-5b/3b complex showed intermolecular HOE contact between methyl group of the imine parent ketone and the 3-substituent of the catalyst, which cannot be found in any of the E N structures (Fig. 4A).</p><p>This E 00 O conformation develops considerable dispersion areas between the imine (parent ketone part aromatic ring), the 3,3 0 -substituent and the Hantzsch ester that compensate for the lack of interactions of the N-substituent with the catalyst (for  1 shows DG (DCM,180 K) for the principal conformations (free energy corrections and solvation corrections at the geometry optimization level of theory were added to the single-point total electronic energies). Table 2 illustrates the relative stabilities DG (DCM,180 K) of the conformationally refined structures. (B) Binding of the Hantzsch ester occurs at the oxygen atoms as evidenced by electrostatic potential map of the binary E N and ternary E O complexes. (C) Noncovalent interaction plot of complex E 00 O , suggesting that dispersion contributes significantly to stabilization of the ternary complex. (D) Dispersion interaction density plot confirms the importance of dispersion within complex E 00 O (computed at DLPNO-CCSD(T)/def2-TZVP level of theory).</p><p>NCI plot see Fig. 4C and ESI Chapter 14.8.7 †). This may explain high enantioselectivities of N-methyl and N-unsubstituted imines. Therefore, appropriate computational methods should reect a high population of the E 00 O complex. All the computational methods predict E 00 O as the most stable conformation for the solution-phase geometry-optimized structures from both conformational searches (see Fig. 4A). In addition, aer the principal conformational search, we conducted a DLPNO-CCSD(T) calculation that conrms the energetic bias between the principal E O and a similar E N conformation towards the E O structure. This was in agreement with the other computational methods used in the principal conformational search (see ESI 14.8 †). 48,49 Local energy decomposition at DLPNO-CCSD(T)/def2-TZVP level of theory shows the dispersion, electrostatics and exchange contribution in two complexes compared to binary E N complex (see ESI 14.9.1 †). [50][51][52] A stabilizing dispersion interaction develops between the imine and the Hantzsch ester in the ternary complex.</p><p>Moreover, the binding energy was decomposed, conrming larger binding energy of the E O complex. The energy decomposition showed that the electron preparation (destabilization by geometrical strain) is compensated by the gain in electrostatic energy (presumably including the hydrogen bond), and the extra stabilization which is provided by dispersion and exchange energy can aid in the ternary complex formation. Indeed, for the E O conformation, the electron preparation penalty is lower than in the E N complex and less geometrical distortion is thus required in the binding process. The dispersion interaction density plot of the E 00</p><p>O complex shows the interaction between the CF 3 -DSI catalyst 2b and imine 5b, where the strongest dispersion is at the catalyst O and N atoms constituting the hydrogen bond (Fig. 4D). Dispersion is thus vital in stabilization of the pre-reacting complexes.</p><p>In line with the energy decomposition, the electrostatic potential surface map of CF 3 -DSI 2b/imine 5b/Hantzsch ester 3c revealed the potential binding sites as the sites providing electrostatic or hydrogen-bond interactions with the Hantzsch ester. This map shows signicant negative charge located at the nitrogen and oxygens of the DSI catalyst in its E N binary complex (Fig. 4B), attracting the Hantzsch ester to develop a hydrogen bond resulting in the bifunctional activation. The negative charge is slightly reduced upon the binding of the Hantzsch ester to form the ternary complex.</p><p>The energetic preference of conformation E 00 O , which matches the NMR data, is given by the B2PLYP method and is in line with the binary complex energetics and Z-binding equilibrium calculations. Therefore, this method seems to be universal to describe the energetics in this study, in contrast to other methods which over-or underestimate some of the species.</p><p>Overall, for the rst time the ratio of E-and Z-imine binary complexes were correctly reproduced by computational methods. The calculations for the DSI E-ternary complexes revealed the major conformation E 00 O and disfavored E N I 00 conformation. The E 00 O conformation has an intermediate position of both the imine and the Hantzsch ester; and resembles a precursor for the transition state. In addition, E 00 O provides exclusively dispersion areas to the 3,3 0 -substituents and the Hantzsch ester, which may explain the high enantioselectivities for N-Me imines and NH imine hydrochloride salts. 36</p><!><p>The binary complexes of the DSIs and imines are in fast exchange with the ternary complex. Therefore, we computed NMR data to distinguish between the binary and ternary complex contributions. To calibrate the computed NMR parameters (d H , d N ) on direct experimental data, rst a set of DSI E-and Z-imine binary complexes as well as free imines and Hantzsch ester were selected as model systems. We plotted the computed chemical shis at the TPSS/pcSseg-3/SMD level of theory against the experimental chemical shis to derive a linear scaling factor. 53 Then, this computed NMR scaling was applied to the calculated NMR parameters (d H , d N ) of ternary structures (see ESI Chapters 14.11-14.13 for details †). Indeed, these conformations do not show signicantly different chemical shis. Thus, calculations corroborate the small chemical shi difference for the E-complexes upon binding of the Hantzsch ester.</p><!><p>Two transition state structures, TS-E-R and TS-Z-S (+40.1 kJ mol À1 ), were found based on the most stable E-and Zternary complexes. Interestingly, all the transition state complexes are O,O-bonded transition structures (Fig. 5A and C). The structures of TS-E-R and TS-Z-S and their noncovalent interactions (NCI) plots are given in Fig. 5A. 54,55 There is no notable dispersion area in the TS-Z-S structure, similar to the situation in the ternary Z-complex. In contrast, the TS-E-R reveals a very prominent interaction areaa triple-stacked p-pcomplexwhere imine is stacked between a catalyst 3,3 0substituent and Hantzsch ester (see ESI Chapter 14.8.7 †). These attractive interactions compensate for the steric repulsion which is prominent in the non-compact E-ternary complexes and transition states. Both interactions seem to be negligible in the more compact Z-complexes which explains the comparable energies of E-and Z-complexes. The relative energetics of the transition states are in accordance with the major product, the (R)-enantiomer. However, the high energetic difference would predict its exclusive formation, which is in contrast with the experimentally observed enantioselectivity (er 69 : 31). Recently, an exceptional example was reported of the conformational search and energetics' evaluation of hundreds of transition structures in ion-pair catalysis. 52 However, in our investigated transfer-hydrogenation reaction the high activation barriers prohibit the reverse reactions or equilibration.</p><p>This means the transfer hydrogenation is under kinetic control and the reaction barriers from the intermediate complexes to the transition states determine the stereoselectivity. 56 Moreover, additional photoisomerization/backisomerization experiments show that the thermal E/Z-isomerization barrier within the binary complex is higher than the hydride step at 298 K (see Fig. 5B and ESI Chapter 12 †). As a result, this very slow isomerization of the binary complexes cannot be regarded as a fast E/Z pre-equilibrium. Thus, the classic Curtin-Hammett principle cannot be applied, 57 as "the product composition is formally related to relative concentrations of the conformation isomers". 58 Therefore, for the DG ‡ values, not only individual transition states energies but also the stabilities of the intermediates have to be considered. In addition, in this study multiple experimental data are available about the ground states and the energetics of late intermediates.</p><p>The calculated reaction energy prole (Fig. 5C) allows for the energetic barrier assessment from E 00 O to TS-E-R (DG ‡ DCM,298 40.5 kJ mol À1 ). Compared to that, the energetic barrier from the lowest energy Z O -ternary complex to the transition state TS-Z-S is higher in energy (DG ‡ DCM,298 63.2 kJ mol À1 ). While this energetic offset still suggests the exclusive formation of the major R-enantiomer (experimental er 69 : 31 R : S), the inclusion of the intermediate energetics shis the theoretical values towards the correct experimental enantioselectivity.</p><p>Within this combined analysis of experimental and computational data, each step of computational level was backed by experimental data and used for the selection of the theoretical method. Overall, this approach shows the importance of ground states and their energetics when investigating stereoselectivity in kinetically controlled reactions without fast pre-equilibration of the intermediates.</p><!><p>In summary, we present detailed experimental data about 6 Eand Z-ternary complexes between DSI catalysts, imines and a Hantzsch ester. This is to our knowledge the rst detailed experimental data of ternary complexes in ion pairing catalysis at all. Extensive intermolecular NOE and HOE contacts at low temperatures, chemical shi mapping, diffusion and relaxation data were used as the experimental basis for the structure elucidation. In this study, experiments and calculations together indicate the unexpected energetic preference of the iminium binding to an oxygen in the presence of a nitrogen as an H-bond acceptor. This is reected in the higher population of the ternary complex E 00 O compared to the E N -complexes which is typical for the binary complexes. Furthermore, this is to our knowledge the rst detailed spectroscopic proof for a bifunctional binding mode proposed earlier for CPAs by theoretical work and thermodynamic arguments.</p><p>Moreover, this study convincingly demonstrates that the combination of experimental and computational analyses of late intermediates in ion pair catalysis is necessary for the interpretation of transition states. The correct energetic assessment of ion pairs is most critical in computational chemistry, so in this study, the complexes and binding events were used as key to select computational tools and to validate the essential calculations. This approach allowed us for the rst time to reproduce correct populations of the binary complexes. Furthermore, the consideration of the reaction barriers from the ternary complexes to TSs showed the importance of structures and energetics of late intermediates in case of high isomerization barriers.</p><p>Overall, this study shows that ternary complex formation is favoured for catalysts with an open binding site and that in case of multiple hydrogen-bond donors the hydrogen bond can switch between the binary and ternary complexes leading to more favourable conformers resembling the transition states. The rather weak binding of the second substrate and the preferential stabilization of the transitions states by hydrogen bonding resembles enzymatic catalysis. In contrast to the CPAs, in which the strong hydrogen bond, rigid complexes and specic noncovalent interactions govern the stereoselectivity, the DSIs can adopt a more favourable conformation by hydrogen bond switching in the ternary complexes. For DSIs a strong and rigid hydrogen bond as adopted in CPAs would be detrimental to the stereoselectivity. In the dynamic system of the DSIs the substrate position in the TS provides mainly interactions of the parent ketone part of the imine with catalyst 3,3 0 -substituent. This explains the enhancement in enantioselectivity for N-methyl imines with no additional stabilization from the N-substituent. On the other hand, decrease in enantioselectivity with the electronic variation of the aryl imines corroborates a demand for a weak hydrogen bond. Thus, DSIs have the potential to combine high exibility and high stereoselectivity, which offers an advantage over enzymatic catalysis, where more exible and promiscuous enzymes are also less selective. 59 It may also conrm the concept of structural exibility as a vital point in asymmetric catalysis. 60</p>