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Cation–p interactions in iminium ion activation: correlating quadrupole moment & enantioselectivity† a ab M. C. Holland,a J. B. Metternich,a C. Mu ¨ ck-Lichtenfeld and R. Gilmour*
Received 28th October 2014, Accepted 21st November 2014 DOI: 10.1039/c4cc08520e www.rsc.org/chemcomm
A linear correlation between quadrupole moment (Qzz) and enantioselectivity (es) advocates the notion that a cation–p interaction is a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan’s 1st generation catalyst. The quadrupole moment of the aryl shielding group is a useful qualitative parameter for predicting selectivity (Qzz o 0 - high es).
The success of iminium ion activation is attributable to the generic nature of this organocatalysis mode.1 Since MacMillan’s seminal report in 2000,1a the landscape of contemporary enantioselective catalysis has been dramatically altered to accommodate this evolving field. Phenylalanine-derived imidazolidinones, such as MacMillan’s 1st generation catalyst (A), have been at the forefront of this development, owing to their highly modular nature and accessibility. These unique aspects of activation generality and structural simplicity, together with the remarkable diversity of enantioselective transformations that proceed via chiral imidazolidinone-derived iminium ions (B), render their study of practical value. Specifically, delineating the factors that orchestrate selectivity in iminium ion activation has clear advantages, both in understanding reaction selectivities and in the design of improved catalyst architectures. Herein, we report a molecular editing study designed to elucidate an intramolecular cation–p interaction thought to be operational in iminium ion activation using MacMillan’s celebrated imidazolidinone. The highly pre-organised topology of this iminium system (B), allows the phenyl group to engage with the syn-methyl group of the catalyst core; this has been beautifully established by Houk’s seminal computational analyses.2 Consequently, this species is pre-disposed to benefit from a stabilising [N+CH2CH2–Hd+ Ph] interaction (Fig. 1, conformer I). This is highly reminiscent of the well documented, intermolecular cation–p interactions involving a
Organisch Chemisches Institut, and Excellence Cluster EXC 1003, Cells in Motion, ¨lische Wilhelms-Universita ¨t Mu ¨nster, Corrensstrasse 40, Mu ¨nster, Germany. Westfa E-mail: [email protected] b ¨lische Wilhelms-Universita ¨t Excellence Cluster EXC 1003, Cells in Motion, Westfa ¨nster, Mu ¨nster, Germany Mu † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc08520e
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Fig. 1 Conditions and consequences of implicating a cation–p interaction in catalysis involving the MacMillan imidazolidinone-derived a,b-unsaturated iminium salt (1). Upper centre: the [Me4N+ benzene] cation–p interaction. Lower: three staggered conformers of the MacMillan iminium salt (1; conformers I, II and III) derived from (E)-cinnamaldehyde.
benzene: most pertinent to this analysis is the tetramethylammonium cation,3 where the positive charge resides on the peripheral hydrogen atoms (Fig. 1, upper centre). Due to the highly delocalised nature of the cation, and the favourable topology of the iminium salt, the structure may be conveniently partitioned so as to emulate the [Me4N+ benzene] cation–p scenario. Rotating the aryl group by 1201 leads to conformer II, which also conceivably allows for a cation–p type interaction between the pendant iminium chain, and the aryl group.4 Both conformers I and II are related by an energetic plateau,5 and have been implicated in conferring enantioinduction.6 Further rotation by 1201, leading to conformer (III), places the aryl ring distal from the cation, thus precluding any form of postulated cation–p interaction. Mindful of a potential Curtin– Hammett scenario, it was envisaged that systems in which conformers I and II are significantly populated should lead to higher selectivities than scenarios in which III is appreciably
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populated. This would constitute a persuasive argument for the importance of a cation–p interaction in augmenting catalyst performance. In enzymatic catalysis, the cation–p interaction can often be credited with both structural and functional roles.7 This is also true for a number of synthetic, bio-inspired small molecule catalysts.8 The solid state structure of MacMillan’s first generation phenylalanine-derivative catalyst (1, conformer I) may also be a clue to the non-covalent interactions that reconcile structure and function.9 Herein, we report a combined theory and catalysis study to determine if a cation–p interaction contributes to selectivity in catalysis involving the MacMillan catalyst-derived iminium salt. Starting from a first principle analogy to the intermolecular [Me4N+ benzene] system, an intramolecular cation–p interaction can be envisaged:10 this would only be geometrically probable in two out of three possible conformers partitioned by 1201 (I and II). Thus, by correlating electronic parameters with catalyst selectivity, it is possible to probe the role of an interaction that clearly manifests itself in conformation. The proclivity of 1 to adopt conformation I, has been extensively studied by crystallographic and spectroscopic techniques.8b,c Indeed, the significant up-field shift of the syn-methyl group8e of 1 indicates that the spatial orientation and distance criteria are fulfilled to allow for a cation–p interaction. By extension, it was reasoned that this conformation would induce a polarisation of the syn-methyl group through an inductive electron-withdrawing effect from the iminium moiety resulting in a partial positive charge on the hydrogen participating in the interaction. Thus the CH–p interaction described by Houk and co-workers,2 would have notable cationic character. This electronic non-equivalence of the imidazolidinone core geminaldimethyl groups would be immediately obvious from a partial charge analysis (Fig. 2). Consequently, a Mulliken population analysis of iminium ion 1 (Ar = C6H5) and the corresponding electron deficient pentafluorophenyl derivative 2 (Ar = C6F5), both constrained in conformer I, was performed. The incorporation of electronically modulated amino acids in enzymes is a well validated approach to identify this interaction,11 by virtue of the linear relationship that connects electron density to interaction strength. As expected, the charge was largely delocalised in the pendant chain (1 and 2, 47.0% and 50.8% respectively), thus rendering the iminium moieties electron
Fig. 2 Group partial charges obtained from Mulliken population analyses (TPSS-D3/def2-TZVP) of iminium salts 1 and 2 constrained in conformation I. Mulliken population analysis (TPSS-D3/def2-TZVP) of the electron rich parent system (Ar = C6H5) and the electron deficient pentafluorophenyl analogue (Ar = C6F5) in conformer I.
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Fig. 3 An electron density difference analysis (Dr = 0.005 a.u., green: Dr 4 0, orange: Dr o 0) of the fragmented MacMillan catalyst-derived iminium salt 1 (upper, Ar = Ph) and the electron deficient pentafluoro-phenyl analogue 2 (lower, Ar = C6F5). The aryl rings have been detached, but retain the relative orientation with respect to the C–H bond of the methyl group.
deficient (14.4% and 12.3% for 1 and 2, respectively). Importantly, the geminal-dimethyl moieties carry notable partial positive charge, consistent with the working hypothesis and analogy to the [Me4N+ benzene] scenario. This is particularly pronounced for the syn-methyl group of the parent system 1 (15.0% versus 11.3%): the partial positive charge difference of the hydrogen proximal to the aryl ring is also noteworthy (19.6% versus 13.9% for 1 and 2, respectively). A similar distribution was found for the anti-methyl groups of 1 and 2. To quantify the postulated cation–p interaction, the two interacting moieties of the molecule (i.e. the aromatic ring and the remainder of the molecule) were partitioned, and an electron density difference analysis was performed (Fig. 3, 1: upper and 2: lower, Dr = 0.005 a.u.). In order to elucidate the interactions of the phenyl and the C6F5 ring with the proximal methyl group of the imidazolidinone core, the respective iminium cations were fragmented by replacing the bridging CH2 group with hydrogen atoms. The aromatic ring has been rotated around the C–H bond pointing towards it, whilst keeping the distance and angle between the ring centre and the C–H group constant. Fig. 3 shows the calculated deformation density of the interaction between the iminium cation and the aromatic ring (C6H6 and C6F5H). Consistent with the postulated interaction, the analysis revealed that both aryl rings (1: Ph, 2: C6F5) are polarised to a comparable extent, with a notable increase in electron-density directed towards the syn-methyl-group. The electronic interaction energy between the two fragments (in frozen geometry) is calculated as DE = 7.2 kcal mol 1 for C6H6 and DE = 3.4 kcal mol 1 for C6F5H, confirming the more favourable [C–Hd+ Ph] interaction with the phenyl ring in 1. Although both aromatic rings are polarized by the proximal cationic charge, only a minor density change occurs in the methyl group with C6F5H (2), due to the more positive electrostatic potential of the fluorinated ring. The enhanced stabilisation of the [C–Hd+ Ph] interaction (1) also allows for a diagnostic, shorter distance between the hydrogen atom and the centre of the aromatic ring (2.456 Å and 2.533 Å for 1 and 2, respectively). This interaction with the phenyl ring increases the polarisation of the C–H bond as might be expected. Therefore the proximal hydrogen atom carries a greater positive partial charge than the remaining portion of
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Fig. 4 Upper: electrostatic potential maps (ESP) of the substituted toluene derivatives corresponding to 1 - 9. Isosurfaces correspond to an electron density of 0.005 a.u. Color range of the electrostatic potential: 0.06 (red) to +0.06 (blue). The components of the traceless quadrupole moment tensor orthogonal to the aromatic ring (Debye–Ångstrom, Qzz) are given for the corresponding toluene derivatives (i.e. Ar–CH3). Qzz calculated using DFT (TPSS/def2-TZVP). Centre: plots of quadrupole moment (Qzz) versus enantioselectivity (es), for (i) the Friedel–Crafts reaction of N-methyl pyrrole (10) and (E)-cinnamaldehyde, (ii) the Friedel–Crafts reaction of N-methyl indole (11) and (E)-cinnamaldehyde, and (iii) the conjugate addition of benzyl tert-butyldimethylsilyloxycarbamate (12) to (E)-crotonaldehyde catalysed by MacMillan catalysts 1–9. In all cases, enantioselectivities (es) were determined for the alcohols generated by direct in situ reduction of the product aldehydes (full details in the ESI†).
the group, which is consistent with the proposed cation–p interaction. To validate this theoretical analysis with empirical data, the addition of three, representative, charge neutral nucleophiles (10, 11 and 12, Fig. 4) to a,b-unsaturated aldehydes was explored using a variety of structurally modified catalysts (1–9).6,12 Since the intrinsic properties of the cation–p interaction are related to
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electron density of the interacting p-system, catalyst molecular editing focussed exclusively on electronic modulation of the shielding ring (full details of the syntheses are reported in the ESI†). As a qualitative descriptor of electron density, the traceless quadrupole moment tensor of the aryl ring orthogonal to the y-axis (Qzz) was calculated for the corresponding toluene systems (1 - 9, Qzz +3.01 - 5.68. Fig. 4, upper). In general, electron deficient systems are characterised by a Qzz 4 0, whilst electron rich systems have a Qzz o 0. Importantly, electron rich catalysts (Qzz o 0, e.g. 9) adopt conformations that allow for stabilising cation–p interactions, either with the syn-methyl group or the pendant chain (conformers I or II, respectively, Fig. 1).9c,e Conversely, electron deficient systems (Qzz 4 0, e.g. 2) are known to display a more varied conformational behavior, often predominantly populating conformer III in which this interaction is not operational.6,9f Should a cation–p interaction be operational in iminium ion activation, then a correlation between quadrupole moment (Qzz) and enantioselectivity (es) might reasonably be expected. To probe this working hypothesis further, the organocatalytic addition of three, charge neutral nucleophiles to a,b-unsaturated aldehydes was explored (Fig. 4, lower). Initially, the organocatalytic Friedel–Crafts reactions1b of (E)-cinnamaldehyde to N-methyl indole (10) and N-methylpyrrole (11)13 were independently investigated using catalysts 1–9. In both reaction series, the enantioselectivity (es) displayed a clear, inverse dependence on quadrupole moment (Qzz), consistent with the notion that a cation–p interaction is significant in the enantiodetermining transition state. In both cases, synthetically useful levels of enantioselectivity were achieved at room temperature when using the most electron rich catalyst 9 (97% es and 72% es for N-methylpyrrole and N-methylindole, respectively). This behavior was conserved when switching from a carbon to a nitrogen based nucleophile (12) for conjugate addition.14 Again, a linear relationship was observed with catalyst 9 furnishing the product in 69% es. Importantly, quantitative conversions were achieved in all three reaction classes, irrespective of shielding group modifications. Moreover, despite the steric disparity between indolyl (e.g. 7 and 8) and phenyl substituents (e.g. 9), it has been possible to demonstrate that quadrupole moment is a useful qualitative predictor in the development of reaction guidelines (Qzz o 0 - high es). By correlating quadrupole moment to catalysis selectivity, it has been possible to implicate a cation–p interaction as being a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan’s first generation catalyst. Computational analyses indicate Mulliken charge nonequivalence in the geminal dimethyl group, mirroring the well studied interaction of tetramethylammonium cations with benzene. This observation is further corroborated by an independent electron density difference analysis. A reciprocal relationship linking quadrupole moment (Qzz), and by extension conformation (I, II or III), to enantioselectivity (es) has been established. Finally, it was possible to correlate catalysis results with conformations that would allow a cation–p interaction with the catalyst core (I and II), and those which would not (III). These data suggest that a cation–p interaction is an intrinsic feature of organocatalysis using MacMillan’s 1st generation
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catalyst. Moreover, it further underscores the value of organocatalytic intermediates as platforms from which to study non-covalent interactions.15 We acknowledge generous financial support from the WWU ¨nster, the ETH Zu ¨rich (M.H.) and the Deutsche ForschungsMu gemeinschaft (SFB 858), and Excellence Cluster EXC 1003 ‘‘Cells in Motion – Cluster of Excellence’’.
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Notes and references 1 (a) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243; (b) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370; (c) D. W. C. MacMillan, Nature, 2008, 455, 304. 2 R. Gordillo, J. Carter and K. N. Houk, Adv. Synth. Catal., 2004, 346, 1175. For an analysis of the second generation MacMillan catalyst-derived iminim salts see R. Gardillo and K. N. Houk, J. Am. Chem. Soc., 2006, 128, 3543. For an excellent review see ¨ lçu ¨m and P. H.-Y. Cheong, C. Y. Legault, J. M. Um, N. Çelebi-O K. N. Houk, Chem. Rev., 2011, 111, 5042. 3 D. A. Dougherty, Acc. Chem. Res., 2013, 46, 885. 4 Y. Mori and S. Yamada, Molecules, 2012, 17, 2161. 5 D. Seebach, U. Grosˇelj, W. B. Schweizer, S. Grimme and ¨ck-Lichtenfeld, Helv. Chim. Acta, 2010, 93, 1. C. Mu 6 M. C. Holland, S. Paul, W. B. Schweizer, K. Bergander, ¨ck-Lichtenfeld, S. Lakhdar, H. Mayr and R. Gilmour, Angew. C. Mu Chem., Int. Ed., 2013, 52, 7967. 7 (a) D. A. Dougherty, Science, 1996, 271, 163; (b) J. C. Ma and D. A. Dougherty, Chem. Rev., 1997, 97, 1303; (c) J. P. Gallivan and D. A. Dougherty, Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 9459; (d) C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urch, J. Chem. Soc., Perkin Trans. 2, 2001, 651; (e) N. Zacharias and D. A. Dougherty, Trends Pharmacol. Sci., 2002, 23, 281; ( f ) L. M. Salonen, M. Ellermann and F. Diederich, Angew. Chem., Int. Ed., 2011, 50, 4808. 8 For selected examples see (a) E. J. Corey, T. P. Loh, T. D. Roper, M. D. Azimioara and M. C. Noe, J. Am. Chem. Soc., 1992, 114, 8290; (b) T. Kawabata, M. Nagato, K. Takasu and K. Fuji, J. Am. Chem. Soc., 1997, 119, 3169; (c) S. J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horstmann and E. M. Ruel, J. Am. Chem. Soc., 1998, 120, 1629; (d) R. R. Knowles, S. Lin and E. N. Jacobsen, J. Am. Chem. Soc., 2010, 132, 5030; (e) C. Uyeda and E. N. Jacobsen, J. Am. Chem. Soc., 2011, 133, 5062; ( f ) For a recent study of anion–p catalysis see Y. Zhao, C. Beuchat, Y. Domoto, J. Gajewy, A. Wilson, J. Mareda, N. Sakai and S. Matile, J. Am. Chem. Soc., 2014, 136, 2101. 9 (a) J. C. Burley, R. Gilmour, T. J. Prior and G. M. Day, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 2008, 64, o10; (b) D. Seebach, ˇelj, M. D. Badine, W. B. Schweizer and A. K. Beck, Helv. Chim. U. Gros Acta, 2008, 91, 1999; (c) J. B. Brazier, G. Evans, T. J. K. Gibbs,
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11
12
13 14 15
S. J. Coles, M. B. Hursthouse, J. A. Platts and N. C. O. Tomkinson, Org. Lett., 2009, 11, 133; (d) D. Seebach, R. Gilmour, U. Grosˇelj, ˇak G. Deniau, C. Sparr, M.-O. Ebert, A. K. Beck, L. B. McCusker, D. ˇ Sis and T. Uchimaru, Helv. Chim. Acta, 2010, 93, 603; (e) C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2010, 49, 6520; ( f ) M. C. Holland, ¨fer and R. Gilmour, G. Berden, J. Oomens, A. J. H. M. Meijer, M. Scha Eur. J. Org. Chem., 2014, 5675. For an example of an intramolecular cation–p interaction see (a) K. Aoki, K. Murayama and H. Nishiyama, J. Chem. Soc., Chem. Commun., 1995, 2221; (b) For an example of an intermolecular cation–p interaction see X. Xiu, N. L. Puskar, J. A. P. Shanata, H. A. Lester and D. A. Dougherty, Nature, 2009, 458, 534. For the elucidation of a cation–p interaction in the mechanism of polyolefin cyclisation cascades by squalene cyclase uncovered by incorporating unnatural amino acids see N. Morikubo, Y. Fukuda, K. Ohtake, N. Shinya, D. Kiga, K. Sakamoto, M. Asanuma, H. Hirota, S. Yokoyama and T. Hoshino, J. Am. Chem. Soc., 2006, 128, 13184. For a recent demonstration of the importance of cation–p interactions in facilitating ligand discovery see T. P. C. Rooney, P. Filippakopoulos, O. Fedorov, S. Picaud, W. A. Cortopassi, D. A. Hay, S. Martin, A. Tumber, C. M. Rogers, M. Philpott, M. Wang, A. L. Thompson, T. D. Heightman, D. C. Pryde, A. Cook, R. S. Paton, ¨ller, S. Knapp, P. E. Brennan and S. J. Conway, Angew. Chem., S. Mu Int. Ed., 2014, 53, 6126. For recent studies of structurally modified imidazolidinone-derived iminium salts see (a) F. An, S. Paul, J. Ammer, A. R. Ofial, P. Mayer, S. Lakhdar and H. Mayr, Asian J. Org. Chem., 2014, 3, 550; (b) U. Grosˇelj, A. Beck, W. B. Schweizer and D. Seebach, Helv. Chim. Acta, 2014, 97, 751. In view of the counterion dependence of this reaction, the TFA salts were used throughout. See S. Lakhdar and H. Mayr, Chem. Commun., 2011, 47, 1866. Y. K. Chen, M. Yoshida and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 9328. For examples from this laboratory see: (a) C. Sparr, W. B. Schweizer, H. M. Senn and R. Gilmour, Angew. Chem., Int. Ed., 2009, 48, 3065; (b) C. Sparr, E.-M. Tanzer, J. Bachmann and R. Gilmour, Synthesis, 2010, 1394; (c) L. E. Zimmer, C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2011, 50, 11860; (d) C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2011, 50, 8391; (e) E.-M. Tanzer, L. E. Zimmer, W. B. Schweizer and R. Gilmour, Chem. – Eur. J., 2012, 18, 11334; ( f ) E.-M. Tanzer, W. B. Schweizer, M.-O. Ebert and R. Gilmour, Chem. – Eur. J., 2012, 18, 2006; ( g) Y. Rey and R. Gilmour, Beilstein J. Org. Chem., 2013, 9, 2812; (h) Y. P. Rey, L. E. Zimmer, C. Sparr, E.-M. Tanzer, W. B. Schweizer, H. M. Senn, S. Lakhdar and R. Gilmour, Eur. J. Org. Chem., 2014, 1202; (i) I. G. Molnar, E.-M. Tanzer, C. Daniliuc and R. Gilmour, Chem. – Eur. J., 2014, 20, 794; For a review of covalent organocatalytic reaction intermediates see: ( j) M. C. Holland and R. Gilmour, Angew. Chem. Int. Ed., 2015, DOI: 10.1002/anie.201409004.
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Cation–p interactions in iminium ion activation: correlating quadrupole moment & enantioselectivity† a ab M. C. Holland,a J. B. Metternich,a C. Mu ¨ ck-Lichtenfeld and R. Gilmour*
Received 28th October 2014, Accepted 21st November 2014 DOI: 10.1039/c4cc08520e www.rsc.org/chemcomm
A linear correlation between quadrupole moment (Qzz) and enantioselectivity (es) advocates the notion that a cation–p interaction is a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan’s 1st generation catalyst. The quadrupole moment of the aryl shielding group is a useful qualitative parameter for predicting selectivity (Qzz o 0 - high es).
The success of iminium ion activation is attributable to the generic nature of this organocatalysis mode.1 Since MacMillan’s seminal report in 2000,1a the landscape of contemporary enantioselective catalysis has been dramatically altered to accommodate this evolving field. Phenylalanine-derived imidazolidinones, such as MacMillan’s 1st generation catalyst (A), have been at the forefront of this development, owing to their highly modular nature and accessibility. These unique aspects of activation generality and structural simplicity, together with the remarkable diversity of enantioselective transformations that proceed via chiral imidazolidinone-derived iminium ions (B), render their study of practical value. Specifically, delineating the factors that orchestrate selectivity in iminium ion activation has clear advantages, both in understanding reaction selectivities and in the design of improved catalyst architectures. Herein, we report a molecular editing study designed to elucidate an intramolecular cation–p interaction thought to be operational in iminium ion activation using MacMillan’s celebrated imidazolidinone. The highly pre-organised topology of this iminium system (B), allows the phenyl group to engage with the syn-methyl group of the catalyst core; this has been beautifully established by Houk’s seminal computational analyses.2 Consequently, this species is pre-disposed to benefit from a stabilising [N+CH2CH2–Hd+ Ph] interaction (Fig. 1, conformer I). This is highly reminiscent of the well documented, intermolecular cation–p interactions involving a
Organisch Chemisches Institut, and Excellence Cluster EXC 1003, Cells in Motion, ¨lische Wilhelms-Universita ¨t Mu ¨nster, Corrensstrasse 40, Mu ¨nster, Germany. Westfa E-mail: [email protected] b ¨lische Wilhelms-Universita ¨t Excellence Cluster EXC 1003, Cells in Motion, Westfa ¨nster, Mu ¨nster, Germany Mu † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc08520e
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Fig. 1 Conditions and consequences of implicating a cation–p interaction in catalysis involving the MacMillan imidazolidinone-derived a,b-unsaturated iminium salt (1). Upper centre: the [Me4N+ benzene] cation–p interaction. Lower: three staggered conformers of the MacMillan iminium salt (1; conformers I, II and III) derived from (E)-cinnamaldehyde.
benzene: most pertinent to this analysis is the tetramethylammonium cation,3 where the positive charge resides on the peripheral hydrogen atoms (Fig. 1, upper centre). Due to the highly delocalised nature of the cation, and the favourable topology of the iminium salt, the structure may be conveniently partitioned so as to emulate the [Me4N+ benzene] cation–p scenario. Rotating the aryl group by 1201 leads to conformer II, which also conceivably allows for a cation–p type interaction between the pendant iminium chain, and the aryl group.4 Both conformers I and II are related by an energetic plateau,5 and have been implicated in conferring enantioinduction.6 Further rotation by 1201, leading to conformer (III), places the aryl ring distal from the cation, thus precluding any form of postulated cation–p interaction. Mindful of a potential Curtin– Hammett scenario, it was envisaged that systems in which conformers I and II are significantly populated should lead to higher selectivities than scenarios in which III is appreciably
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populated. This would constitute a persuasive argument for the importance of a cation–p interaction in augmenting catalyst performance. In enzymatic catalysis, the cation–p interaction can often be credited with both structural and functional roles.7 This is also true for a number of synthetic, bio-inspired small molecule catalysts.8 The solid state structure of MacMillan’s first generation phenylalanine-derivative catalyst (1, conformer I) may also be a clue to the non-covalent interactions that reconcile structure and function.9 Herein, we report a combined theory and catalysis study to determine if a cation–p interaction contributes to selectivity in catalysis involving the MacMillan catalyst-derived iminium salt. Starting from a first principle analogy to the intermolecular [Me4N+ benzene] system, an intramolecular cation–p interaction can be envisaged:10 this would only be geometrically probable in two out of three possible conformers partitioned by 1201 (I and II). Thus, by correlating electronic parameters with catalyst selectivity, it is possible to probe the role of an interaction that clearly manifests itself in conformation. The proclivity of 1 to adopt conformation I, has been extensively studied by crystallographic and spectroscopic techniques.8b,c Indeed, the significant up-field shift of the syn-methyl group8e of 1 indicates that the spatial orientation and distance criteria are fulfilled to allow for a cation–p interaction. By extension, it was reasoned that this conformation would induce a polarisation of the syn-methyl group through an inductive electron-withdrawing effect from the iminium moiety resulting in a partial positive charge on the hydrogen participating in the interaction. Thus the CH–p interaction described by Houk and co-workers,2 would have notable cationic character. This electronic non-equivalence of the imidazolidinone core geminaldimethyl groups would be immediately obvious from a partial charge analysis (Fig. 2). Consequently, a Mulliken population analysis of iminium ion 1 (Ar = C6H5) and the corresponding electron deficient pentafluorophenyl derivative 2 (Ar = C6F5), both constrained in conformer I, was performed. The incorporation of electronically modulated amino acids in enzymes is a well validated approach to identify this interaction,11 by virtue of the linear relationship that connects electron density to interaction strength. As expected, the charge was largely delocalised in the pendant chain (1 and 2, 47.0% and 50.8% respectively), thus rendering the iminium moieties electron
Fig. 2 Group partial charges obtained from Mulliken population analyses (TPSS-D3/def2-TZVP) of iminium salts 1 and 2 constrained in conformation I. Mulliken population analysis (TPSS-D3/def2-TZVP) of the electron rich parent system (Ar = C6H5) and the electron deficient pentafluorophenyl analogue (Ar = C6F5) in conformer I.
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Fig. 3 An electron density difference analysis (Dr = 0.005 a.u., green: Dr 4 0, orange: Dr o 0) of the fragmented MacMillan catalyst-derived iminium salt 1 (upper, Ar = Ph) and the electron deficient pentafluoro-phenyl analogue 2 (lower, Ar = C6F5). The aryl rings have been detached, but retain the relative orientation with respect to the C–H bond of the methyl group.
deficient (14.4% and 12.3% for 1 and 2, respectively). Importantly, the geminal-dimethyl moieties carry notable partial positive charge, consistent with the working hypothesis and analogy to the [Me4N+ benzene] scenario. This is particularly pronounced for the syn-methyl group of the parent system 1 (15.0% versus 11.3%): the partial positive charge difference of the hydrogen proximal to the aryl ring is also noteworthy (19.6% versus 13.9% for 1 and 2, respectively). A similar distribution was found for the anti-methyl groups of 1 and 2. To quantify the postulated cation–p interaction, the two interacting moieties of the molecule (i.e. the aromatic ring and the remainder of the molecule) were partitioned, and an electron density difference analysis was performed (Fig. 3, 1: upper and 2: lower, Dr = 0.005 a.u.). In order to elucidate the interactions of the phenyl and the C6F5 ring with the proximal methyl group of the imidazolidinone core, the respective iminium cations were fragmented by replacing the bridging CH2 group with hydrogen atoms. The aromatic ring has been rotated around the C–H bond pointing towards it, whilst keeping the distance and angle between the ring centre and the C–H group constant. Fig. 3 shows the calculated deformation density of the interaction between the iminium cation and the aromatic ring (C6H6 and C6F5H). Consistent with the postulated interaction, the analysis revealed that both aryl rings (1: Ph, 2: C6F5) are polarised to a comparable extent, with a notable increase in electron-density directed towards the syn-methyl-group. The electronic interaction energy between the two fragments (in frozen geometry) is calculated as DE = 7.2 kcal mol 1 for C6H6 and DE = 3.4 kcal mol 1 for C6F5H, confirming the more favourable [C–Hd+ Ph] interaction with the phenyl ring in 1. Although both aromatic rings are polarized by the proximal cationic charge, only a minor density change occurs in the methyl group with C6F5H (2), due to the more positive electrostatic potential of the fluorinated ring. The enhanced stabilisation of the [C–Hd+ Ph] interaction (1) also allows for a diagnostic, shorter distance between the hydrogen atom and the centre of the aromatic ring (2.456 Å and 2.533 Å for 1 and 2, respectively). This interaction with the phenyl ring increases the polarisation of the C–H bond as might be expected. Therefore the proximal hydrogen atom carries a greater positive partial charge than the remaining portion of
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Fig. 4 Upper: electrostatic potential maps (ESP) of the substituted toluene derivatives corresponding to 1 - 9. Isosurfaces correspond to an electron density of 0.005 a.u. Color range of the electrostatic potential: 0.06 (red) to +0.06 (blue). The components of the traceless quadrupole moment tensor orthogonal to the aromatic ring (Debye–Ångstrom, Qzz) are given for the corresponding toluene derivatives (i.e. Ar–CH3). Qzz calculated using DFT (TPSS/def2-TZVP). Centre: plots of quadrupole moment (Qzz) versus enantioselectivity (es), for (i) the Friedel–Crafts reaction of N-methyl pyrrole (10) and (E)-cinnamaldehyde, (ii) the Friedel–Crafts reaction of N-methyl indole (11) and (E)-cinnamaldehyde, and (iii) the conjugate addition of benzyl tert-butyldimethylsilyloxycarbamate (12) to (E)-crotonaldehyde catalysed by MacMillan catalysts 1–9. In all cases, enantioselectivities (es) were determined for the alcohols generated by direct in situ reduction of the product aldehydes (full details in the ESI†).
the group, which is consistent with the proposed cation–p interaction. To validate this theoretical analysis with empirical data, the addition of three, representative, charge neutral nucleophiles (10, 11 and 12, Fig. 4) to a,b-unsaturated aldehydes was explored using a variety of structurally modified catalysts (1–9).6,12 Since the intrinsic properties of the cation–p interaction are related to
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electron density of the interacting p-system, catalyst molecular editing focussed exclusively on electronic modulation of the shielding ring (full details of the syntheses are reported in the ESI†). As a qualitative descriptor of electron density, the traceless quadrupole moment tensor of the aryl ring orthogonal to the y-axis (Qzz) was calculated for the corresponding toluene systems (1 - 9, Qzz +3.01 - 5.68. Fig. 4, upper). In general, electron deficient systems are characterised by a Qzz 4 0, whilst electron rich systems have a Qzz o 0. Importantly, electron rich catalysts (Qzz o 0, e.g. 9) adopt conformations that allow for stabilising cation–p interactions, either with the syn-methyl group or the pendant chain (conformers I or II, respectively, Fig. 1).9c,e Conversely, electron deficient systems (Qzz 4 0, e.g. 2) are known to display a more varied conformational behavior, often predominantly populating conformer III in which this interaction is not operational.6,9f Should a cation–p interaction be operational in iminium ion activation, then a correlation between quadrupole moment (Qzz) and enantioselectivity (es) might reasonably be expected. To probe this working hypothesis further, the organocatalytic addition of three, charge neutral nucleophiles to a,b-unsaturated aldehydes was explored (Fig. 4, lower). Initially, the organocatalytic Friedel–Crafts reactions1b of (E)-cinnamaldehyde to N-methyl indole (10) and N-methylpyrrole (11)13 were independently investigated using catalysts 1–9. In both reaction series, the enantioselectivity (es) displayed a clear, inverse dependence on quadrupole moment (Qzz), consistent with the notion that a cation–p interaction is significant in the enantiodetermining transition state. In both cases, synthetically useful levels of enantioselectivity were achieved at room temperature when using the most electron rich catalyst 9 (97% es and 72% es for N-methylpyrrole and N-methylindole, respectively). This behavior was conserved when switching from a carbon to a nitrogen based nucleophile (12) for conjugate addition.14 Again, a linear relationship was observed with catalyst 9 furnishing the product in 69% es. Importantly, quantitative conversions were achieved in all three reaction classes, irrespective of shielding group modifications. Moreover, despite the steric disparity between indolyl (e.g. 7 and 8) and phenyl substituents (e.g. 9), it has been possible to demonstrate that quadrupole moment is a useful qualitative predictor in the development of reaction guidelines (Qzz o 0 - high es). By correlating quadrupole moment to catalysis selectivity, it has been possible to implicate a cation–p interaction as being a contributing factor in the addition of uncharged nucleophiles to iminium salts derived from MacMillan’s first generation catalyst. Computational analyses indicate Mulliken charge nonequivalence in the geminal dimethyl group, mirroring the well studied interaction of tetramethylammonium cations with benzene. This observation is further corroborated by an independent electron density difference analysis. A reciprocal relationship linking quadrupole moment (Qzz), and by extension conformation (I, II or III), to enantioselectivity (es) has been established. Finally, it was possible to correlate catalysis results with conformations that would allow a cation–p interaction with the catalyst core (I and II), and those which would not (III). These data suggest that a cation–p interaction is an intrinsic feature of organocatalysis using MacMillan’s 1st generation
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catalyst. Moreover, it further underscores the value of organocatalytic intermediates as platforms from which to study non-covalent interactions.15 We acknowledge generous financial support from the WWU ¨nster, the ETH Zu ¨rich (M.H.) and the Deutsche ForschungsMu gemeinschaft (SFB 858), and Excellence Cluster EXC 1003 ‘‘Cells in Motion – Cluster of Excellence’’.
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Notes and references 1 (a) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am. Chem. Soc., 2000, 122, 4243; (b) N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123, 4370; (c) D. W. C. MacMillan, Nature, 2008, 455, 304. 2 R. Gordillo, J. Carter and K. N. Houk, Adv. Synth. Catal., 2004, 346, 1175. For an analysis of the second generation MacMillan catalyst-derived iminim salts see R. Gardillo and K. N. Houk, J. Am. Chem. Soc., 2006, 128, 3543. For an excellent review see ¨ lçu ¨m and P. H.-Y. Cheong, C. Y. Legault, J. M. Um, N. Çelebi-O K. N. Houk, Chem. Rev., 2011, 111, 5042. 3 D. A. Dougherty, Acc. Chem. Res., 2013, 46, 885. 4 Y. Mori and S. Yamada, Molecules, 2012, 17, 2161. 5 D. Seebach, U. Grosˇelj, W. B. Schweizer, S. Grimme and ¨ck-Lichtenfeld, Helv. Chim. Acta, 2010, 93, 1. C. Mu 6 M. C. Holland, S. Paul, W. B. Schweizer, K. Bergander, ¨ck-Lichtenfeld, S. Lakhdar, H. Mayr and R. Gilmour, Angew. C. Mu Chem., Int. Ed., 2013, 52, 7967. 7 (a) D. A. Dougherty, Science, 1996, 271, 163; (b) J. C. Ma and D. A. Dougherty, Chem. Rev., 1997, 97, 1303; (c) J. P. Gallivan and D. A. Dougherty, Proc. Natl. Acad. Sci. U. S. A., 1999, 96, 9459; (d) C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urch, J. Chem. Soc., Perkin Trans. 2, 2001, 651; (e) N. Zacharias and D. A. Dougherty, Trends Pharmacol. Sci., 2002, 23, 281; ( f ) L. M. Salonen, M. Ellermann and F. Diederich, Angew. Chem., Int. Ed., 2011, 50, 4808. 8 For selected examples see (a) E. J. Corey, T. P. Loh, T. D. Roper, M. D. Azimioara and M. C. Noe, J. Am. Chem. Soc., 1992, 114, 8290; (b) T. Kawabata, M. Nagato, K. Takasu and K. Fuji, J. Am. Chem. Soc., 1997, 119, 3169; (c) S. J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horstmann and E. M. Ruel, J. Am. Chem. Soc., 1998, 120, 1629; (d) R. R. Knowles, S. Lin and E. N. Jacobsen, J. Am. Chem. Soc., 2010, 132, 5030; (e) C. Uyeda and E. N. Jacobsen, J. Am. Chem. Soc., 2011, 133, 5062; ( f ) For a recent study of anion–p catalysis see Y. Zhao, C. Beuchat, Y. Domoto, J. Gajewy, A. Wilson, J. Mareda, N. Sakai and S. Matile, J. Am. Chem. Soc., 2014, 136, 2101. 9 (a) J. C. Burley, R. Gilmour, T. J. Prior and G. M. Day, Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 2008, 64, o10; (b) D. Seebach, ˇelj, M. D. Badine, W. B. Schweizer and A. K. Beck, Helv. Chim. U. Gros Acta, 2008, 91, 1999; (c) J. B. Brazier, G. Evans, T. J. K. Gibbs,
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S. J. Coles, M. B. Hursthouse, J. A. Platts and N. C. O. Tomkinson, Org. Lett., 2009, 11, 133; (d) D. Seebach, R. Gilmour, U. Grosˇelj, ˇak G. Deniau, C. Sparr, M.-O. Ebert, A. K. Beck, L. B. McCusker, D. ˇ Sis and T. Uchimaru, Helv. Chim. Acta, 2010, 93, 603; (e) C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2010, 49, 6520; ( f ) M. C. Holland, ¨fer and R. Gilmour, G. Berden, J. Oomens, A. J. H. M. Meijer, M. Scha Eur. J. Org. Chem., 2014, 5675. For an example of an intramolecular cation–p interaction see (a) K. Aoki, K. Murayama and H. Nishiyama, J. Chem. Soc., Chem. Commun., 1995, 2221; (b) For an example of an intermolecular cation–p interaction see X. Xiu, N. L. Puskar, J. A. P. Shanata, H. A. Lester and D. A. Dougherty, Nature, 2009, 458, 534. For the elucidation of a cation–p interaction in the mechanism of polyolefin cyclisation cascades by squalene cyclase uncovered by incorporating unnatural amino acids see N. Morikubo, Y. Fukuda, K. Ohtake, N. Shinya, D. Kiga, K. Sakamoto, M. Asanuma, H. Hirota, S. Yokoyama and T. Hoshino, J. Am. Chem. Soc., 2006, 128, 13184. For a recent demonstration of the importance of cation–p interactions in facilitating ligand discovery see T. P. C. Rooney, P. Filippakopoulos, O. Fedorov, S. Picaud, W. A. Cortopassi, D. A. Hay, S. Martin, A. Tumber, C. M. Rogers, M. Philpott, M. Wang, A. L. Thompson, T. D. Heightman, D. C. Pryde, A. Cook, R. S. Paton, ¨ller, S. Knapp, P. E. Brennan and S. J. Conway, Angew. Chem., S. Mu Int. Ed., 2014, 53, 6126. For recent studies of structurally modified imidazolidinone-derived iminium salts see (a) F. An, S. Paul, J. Ammer, A. R. Ofial, P. Mayer, S. Lakhdar and H. Mayr, Asian J. Org. Chem., 2014, 3, 550; (b) U. Grosˇelj, A. Beck, W. B. Schweizer and D. Seebach, Helv. Chim. Acta, 2014, 97, 751. In view of the counterion dependence of this reaction, the TFA salts were used throughout. See S. Lakhdar and H. Mayr, Chem. Commun., 2011, 47, 1866. Y. K. Chen, M. Yoshida and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 9328. For examples from this laboratory see: (a) C. Sparr, W. B. Schweizer, H. M. Senn and R. Gilmour, Angew. Chem., Int. Ed., 2009, 48, 3065; (b) C. Sparr, E.-M. Tanzer, J. Bachmann and R. Gilmour, Synthesis, 2010, 1394; (c) L. E. Zimmer, C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2011, 50, 11860; (d) C. Sparr and R. Gilmour, Angew. Chem., Int. Ed., 2011, 50, 8391; (e) E.-M. Tanzer, L. E. Zimmer, W. B. Schweizer and R. Gilmour, Chem. – Eur. J., 2012, 18, 11334; ( f ) E.-M. Tanzer, W. B. Schweizer, M.-O. Ebert and R. Gilmour, Chem. – Eur. J., 2012, 18, 2006; ( g) Y. Rey and R. Gilmour, Beilstein J. Org. Chem., 2013, 9, 2812; (h) Y. P. Rey, L. E. Zimmer, C. Sparr, E.-M. Tanzer, W. B. Schweizer, H. M. Senn, S. Lakhdar and R. Gilmour, Eur. J. Org. Chem., 2014, 1202; (i) I. G. Molnar, E.-M. Tanzer, C. Daniliuc and R. Gilmour, Chem. – Eur. J., 2014, 20, 794; For a review of covalent organocatalytic reaction intermediates see: ( j) M. C. Holland and R. Gilmour, Angew. Chem. Int. Ed., 2015, DOI: 10.1002/anie.201409004.
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