Prediction of Soai Reaction Enantioselectivity Induced by Crystals of N

Nanochemistry Research Institute, Department of Chemistry, Curtin University, P.O. Box U1987, Perth, Western Australia 6845 Australia. § Department o...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/crystal

Prediction of Soai Reaction Enantioselectivity Induced by Crystals of N-(2-Thienylcarbonyl)glycine Damien J. Carter,†,‡ Andrew L. Rohl,*,†,‡ Alexander Shtukenberg,§ Shudan Bian,§ Chunhua Hu,§ Lisa Baylon,§ Bart Kahr,*,§ Hiroko Mineki,⊥ Koichiro Abe,⊥ Tsuneomi Kawasaki,⊥ and Kenso Soai*,⊥ †

iVEC, 26 Dick Perry Avenue, Technology Park, Kensington, Western Australia 6151 Australia Nanochemistry Research Institute, Department of Chemistry, Curtin University, P.O. Box U1987, Perth, Western Australia 6845 Australia § Department of Chemistry, New York University, 100 Washington Square East, New York City, New York, 10003 United States ⊥ Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan ‡

S Supporting Information *

ABSTRACT: The enantioselectivity of the autocatalytic alkylation of 2-tert-butylpyrimidyl5-carbaldehyde, initiated by chiral crystals of N-(2-thienylcarbonyl)glycine, is predicted computationally. The results are in accord with the correlation of the stereochemical outcome of the reaction and the absolute structure of the crystals determined by the anomalous dispersion of X-rays and circular dichroism spectroscopy.

■

ROLE OF CRYSTALS IN THE SOAI REACTION The so-called Soai reaction1−5 is a startling example of asymmetric autocatalysis. In this process, 2-substituted pyrimidyl-5-carbaldehydes such as 2-tert-butylethynylpyrimidine-5-carbaldehyde (1) are alkylated with dialkyl zinc to give alcohols such as R/S-2-tert-butylethynyl-5-pyrimidyl alkanol (2) in large enantiomeric excess (Scheme 1). The slight stochastic

by the intercession of some other chiral influence, for instance, suspended particles ground from a single chiral crystal. The Soai reaction can be heterogeneously directed by the surfaces of chiral crystals such sodium chlorate,13 sodium bromate,14 quartz,15,16 benzil,17 hippuric acid,18 cytosine,19 1,1′binaphthyl,20 and a variety of organic co-crystals.21 Nearly any chiral crystal will do. Dextrotatory quartz or sodium chlorate produce alcohols with the S-configuration, whereas levorotatory quartz or NaClO3 produce alcohols with the R-configuration. Thus, the asymmetric autocatalytic Soai reaction gives abundant evidence of enantioselective adsorption of organic compounds to a variety of crystals,22−38 but adsorbate−crystal interactions have yet to be described. Here, we examine how computational crystallography can address some of these mechanisms.

Scheme 1

■

CHOOSING A CRYSTAL Several substances were considered for the analysis discussed herein before settling on N-(2-thienylcarbonyl)glycine (3) including quartz, sodium chlorate, sodium bromate, the γpolymorph of glycine (γ-glycine), and hippuric acid (4). Each failed to provide all the necessary characteristics for tying a computational prediction to the absolute structure of the crystals involved. In order to establish a correlation, two experimental conditions must first be met: (1) The absolute structure of the crystals must be readily assignable. This can be done using normal X-ray sources for those substances that have

deviations from ideal racemic mixtures that are generated during the early stages of the generation of chiral product are sufficient, through autocatalysis, to produce homochiral product.6−8 The stereochemical outcome of the reaction is not deterministic until slight dissymmetric biases9−12 are introduced either by the addition of enantiopure product or © 2012 American Chemical Society

Received: February 11, 2012 Published: March 12, 2012 2138

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

sufficiently large anomalous dispersion.39 (2) Crystals must have distinct cleavage so that the faces exposed on crushed particles are likewise assignable; knowledge of the interfaces is critical to building a computational model. It was difficult to find a substance that satisfied these conditions and which catalyzed the Soai alkylation. Our misses may be instructive for others interested in exploring enantioselective crystal catalysis by computation. Therefore, we lead with a brief description of an apparently stochastic journey to a suitable substance, 3, that did indeed meet the aforementioned criteria. Quartz. Quartz, the most abundant chiral crystal (space groups P3121 and P3221) on Earth, and that most likely to be relevant to biochirogenesis40−42 was the first used to influence the autocatalytic Soai reaction.15,16 Unfortunately, quartz has concoidal cleavage; assigning a dominant face or faces to crushed quartz particles is not straightforward. Moreover, as stated by Amaragilio, “Quartz is almost incapable of showing its chemical [dis]symmetry.”43 Downs and Hazen proposed an explanation for this incapability on the basis of a chirality index that they created for mineral facets.44 While different chirality functions can lead to contrary chemical judgments,45 Downs and Hazen have proposed a rather simple geometric algorithm for assessing deviations of periodic two-dimensional (2D) surface cells from mirror symmetry.46,47 According to the authors, the larger the deviation, the larger the presumed chirality. The key conclusion is that the most common quartz surfaces ({101̅0}, {101̅1}, and {112̅0}) are modestly dissymmetric. On this basis, we would anticipate that quartz would poorly express enthalpy differences for the adsorption of enantiomers. Indeed, simulations of carminic acid adsorbed to 48 D- and L-quartz were equivocal. Sodium Halates. NaClO3 and NaBrO3 are attractive targets for computational studies because their crystal structures are comparatively simple, and the cubic forms of the salts express only one set of faces, {100} and {111}, respectively, for the space group P213. In fact, the computations begun herein were initially intended as a simple exercise to what would presumably be helpful in describing computationally the adsorption of a more complex analyte to NaClO3 crystals.49,50 We presumed that if we were able to predict the correct Soai enantiomer in NaClO3 autocatalyzed alkylations, then we would be prepared to tackle analytes with many more internal degrees of freedom than the pyrimidyl aldehydes. However, it is well-known that the sodium halate salts have indistinct cleavages.51 Electron micrographs of samples ground to the 10 μm size typically employed in the Soai reaction were indeed devoid of wellformed facets despite the fact that NaClO3 and NaBrO3 grow with spectacularly sharp cube and tetrahedra facets. For this reason, we could not link computations to the previously established stereochemical outcome of the Soai reaction. γ-Glycine. Three polymorphs of glycine (α - P21/n,52 β P21, and γ - P31 and P3253) have been described.54,55 The thermodynamic stability is γ > α > β. The chiral γ-form was therefore used to direct enantioselective autocatalysis by crushing a single crystal and suspending the ∼10 μm particles in the reaction mixture. Even though γ-form is the most thermodynamically stable crystalline glycine, it is often overwhelmed in crystallization by the kinetically favored αform. Nevertheless, slow crystallization from neutral solutions,56 irradiation of the crystallization solution with planepolarized laser light,57 or the addition of additives58 can be used to favor the γ-form. But because of the extreme difficulty of assigning the absolute structure of the crystals of glycine with

X-rays, we as yet do not know which enantiomorphous crystal catalyzes the formation of which enantiomer. Attempts to assign the absolute structure using chemical methods59 or through chiroptical imaging in our laboratory were not successful. Enantiomorphous twinning may complicate the problem. The three-beam interference method would probably be the most reliable for assigning absolute structure; however this method is best executed with highly collimated synchrotron radiation60 and succeeds only in favorable cases. Enantioselective binding to this system has been explored computationally.61 Hippuric Acid. Previously, the Soai reaction was directed deterministically with single crushed crystals of hippuric acid (4, (C9H9O3N)).18 Hippuric acid crystallizes in the enantiomorphous space group P21212162 and shows perfect cleavage parallel to (100).63 Crystal data: a = 9.112(2) Å, b = 10.566(2) Å, c = 8.855(2) Å;64 orientation of refractive index ellipsoid X || [001], Y || [100], and Z || [010]; birefringence NZ − NX = 0.225, NZ − NY = 0.168, and NY − NX = 0.057; biaxial angle 2V = 66°.63 Particles from a single crystal in KBr pellets that showed a positive CD curve (300 nm) directed the alkylation of 2 to the S-isomer of 1. Naturally, crystals that showed a negative CD band produced the R-isomer. While the sign of the Cotton effect was correlated with the stereochemical outcome of the reaction, the absolute structure of crystals of 4, like glycine containing only C, H, N, and O atoms, has never been determined. N-(2-Thienylcarbonyl)glycine. Thienyl rings serve to replace phenyl rings in molecular crystals isomorphously.65 We obtained N-(2-thienylcarbonyl)glycine (3, C7H7NO3S) with the expectation that this sulfurous compound would be isomorphous to 4 as well as amenable to the assignment of absolute structure. Crystals of 3 were grown by slow evaporation from acetone. The crystal structures of 10 samples were refined in the space group P212121 at 100(2) K (see Supporting Information). For comparison, lattice constants of a 10th sample of 3 was measured at 298 K (a = 8.653(6) Å, b = 10.643(8) Å, and c = 9.467(9) Å) and were very close to those of 4 (see above). Here, and for comparison with computations, we will use a nonstandard crystallographic setting with a < c < b. The packing of 3 and 4 is nearly identical. The crystals are indeed isomorphous. The only substantive difference is that the thienyl ring is disordered; 9% of the rings are flipped about the C− C(O) bond, wholly consistent with the isomorphous replacement of phenyl by thienyl. The sulfur atoms takes up the same amount of space as a pair of adjacent phenyl carbons. The crystals are bounded by major {110} and {101} faces and sometimes smaller {100} and {011} (Figure 1a). They have distinct {001} cleavage as shown in Figure 2. Slight crushing of large single crystals between glass slides showed that only {001} planes are exposed by mechanical action. Examination with a polarizing microscope showed that this was also the optic axial plane. The optic axes emerge at ∼75° to {110}. There is a secondary imperfect cleavage system parallel to {101}. Orientation of the optical indicatrix NX || [100], NY || [001], and NZ || [010] coincides with that for 4. The measured birefringences are NZ − NX = 0.246(10), NZ − NY = 0.161(5), and NY − NX = 0.085(5). The biaxial angle 2V = 72(2)° (Figure 1b) is similar to that of 4, further evidence of structural similarity. 2139

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

Figure 3. Top: CD spectra (mdeg) of enantiomorphous crushed crystals in KBr pellets. Bottom: Enantiomorphous crystal structures of 3 viewed along the c axis. Dotted lines represent hydrogen bonds. Thienyl rings with yellow sulfur atoms are only represented in their major orientation. Force-field calculations were based on coordinates for (M)-[CD(+)300KBr]-3 with the left-handed helix.

Figure 1. Habit of N-(2-thienylcarbonyl)glycine crystals grown from aqueous solution. (a) Micrograph of as-grown crystal. (b) Schematic outline of the (001) cleavage section showing orientation of crystallographic axes, principal refractive indices, and optic axes.

Table 1. Correlations of Absolute Structure of Crystals of 3 and Absolute Configuration of Product, 2 from Asymmetric Autocatalysis pyrimidyl alcohol 2

Figure 2. SEM image of one crystal of 3 ground with mortar and pestle. Flat surfaces that are {001} cleavage planes.

The simplest way of distinguishing single crystal enantiomorphs of 3 is by solid-state circular dichroism (CD) spectroscopy66 of powdered samples in KBr pellets. The enantiomorphous crystals show oppositely signed Cotton effects at 300 nm. Individual crystals of 3 exhibit a positive (CD(+)300KBr) or negative (CD(−)300KBr) Cotton effect (Figure 3) However, we do not know which enantiomorph is associated with which Cotton effect. The absolute configuration of eight crystals was determined by the method of the anomalous dispersion of X-rays in conjunction with Bijvoet pair scatter plots generated using PLATON 2006.67,68 3-(CD(+)) are composed of left-handed helices of CO---HO−C(O)hydrogen bonds in the crystal lattice; 3-(CD(−)) are right handed (Table 1).

■

crystal identifier

screw configuration by anomalous dispersion

Cotton effect 300 nm

mmol (3)

yield (%)

ee

configuration

NYC1 NYC2 NYC3 NYC4 NYC6 NYC7 NYC8 NYC9 Tokyo1 Tokyo2 Tokyo3 Tokyo4

right handed left handed L R R R R R ND ND ND ND

− + + − − − − − + − + −

− − 0.010 − − 0.030 0.028 0.032 0.075 0.075 0.075 0.075

−

−

−

87 − − 87 78 84 95 86 75 81

75 − − 70 19 90 62 89 27 54

S − − R R R S R S R

an asymmetric autocatalytic reaction: the starting material (1) and the product (2). They are discrete, neutral molecules, unencumbered by zinc coordination and excessive conformational flexibility. As the asymmetric bias is established early on, the reactant might well be the culprit, as might be the adsorption of the first product molecules that form. As the addition of a small amount of enantiopure product induces the autocatalysis, the second scenario is quite likely. Any computational model requires some assumptions. All the details of the Soai reaction have yet to be revealed. Here, we test two hypotheses: First, the starting material (1) is adsorbed with either its pro-R or proS faces exposed to the reagent. The product established in this way is responsible for the autocatalysis. Second, the product (2) is adsorbed enantioselectively so as to create an enantiomeric excess of the enantiomer in solution that adsorbs least well which thereby generates higher order intermediates that promote asymmetric autocatalysis. Atomistic simulations of 1 and the R and S enantiomers of 2 with the most stable surfaces of left-handed (M)-crystals of 3 were performed. A large number of potential orientations of the docking species were sampled by simulated annealing on surfaces, the most stable of which were then used as starting configurations for molecular mechanics (MM) calculations. All MM calculations were performed

COMPUTATIONAL METHODOLOGY

As 3 had never before been used to direct the Soai reaction, we were in a position to make predictions of stereochemical outcome by computation. All the calculations described herein were completed before any of the reactions with 3 were carried out (see next section). We assumed that the crystals, through adsorption, bias the reaction or the reaction mixture. There are many conceivable intermediates that could be enantioselectively adsorbed by chiral crystals including the starting material, the products, and any intermediate including proposed dimers and tetrameric clusters (see Discussion). As a starting point, we take into account the only two species in the reaction mixture whose structures, and concentrations, are known during the development of 2140

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

with the Materials Studio software package.69 Electrostatic interactions were calculated using the Ewald summation, with an accuracy of 1 × 10−5 kcal/mol. Atomic charges were assigned by the forcefield. van der Waals interactions were calculated by an atom-based summation with a cutoff of 18.5 Å. Structural optimization of 3 was performed using the Forcite module within Materials Studio, utilizing the COMPASS70,71 force field. Calculations were applied to the cleavage plane {001}, and the principal growth face {110} as well as a secondary surface predicted to be the second most stable face {100}. All MM calculations have been performed using three-dimensional (3D) periodic simulation cells, where the (100), (001), and (110) surfaces are separated by a vacuum region. Each surface can be cleaved in a number of different ways. To determine the most stable surface cut, the attachment energies and the surface energies were calculated for each reasonable cleavage plane.72 The surface energy (Esurf) was determined by the equation:

The results from the simulating annealing calculations were then analyzed to determine the most stable docking orientations (between 6 and 12) for each surface. Full atomic relaxations were then performed on each configuration using the Forcite module in Materials Studio. To determine which docking configuration was most stable on each surface, the binding energies (Eb) were calculated using the equation: Eb = Edock − (Eslab + Emol) where Edock is the total energy of the surface with the adsorbate molecule contained within it, Eslab is the total energy of the relaxed surface slab, and Emol is the energy of an isolated, relaxed adsorbate molecule.

Esurf = (Eslab − Eequivbulk )/2A where Eslab is the energy of the surface slab with a vacuum gap, Eequiv bulk is the energy of the surface slab with no vacuum gap, and A is the surface area. Esurf is divided by two because each slab has two surfaces and thus the surface energy is an average of the slab “top” and “bottom”. More stable surfaces have lower surface energies. The attachment energy (Eattach) is the energy released when a new slice of depth dhkl is attached to a crystal face: ∞

Eattach(hkl) =

∑ Ei(hkl) i=1

where Ei(hkl) is the interaction per molecule between the slice of thickness dhkl and the ith surface layer. A more exothermic (more negative) attachment energy indicates a less, stable, faster growing surface. The surface energies and attachment energies for each cut of the (100), (001), and (110) surfaces are summarized in Table 2, with the most stable of a set of parallel cuts in bold.

Table 2. Surface and Attachment Energies of Cuts Consistent with (100), (001), and (110) of (M)-3a surface

cut

Eattach (kcal/mol)

Esurf (J/m2)

(100)

1 2 1 2 1 2 3 4

−109.466 −84.021 −70.601 −110.082 −80.091 −107.012 −80.091 −50.186

0.307 0.231 0.224 0.343 0.385 0.534 0.385 0.211

(001) (110)

a

The most stable of a set of parallel cuts is indicated in bold.

Docking calculations were performed on supercells with a 20 Å vacuum gap in the direction normal to the surface to ensure that the docking molecule did not interact with periodic images. For the (100), (001), and (110) surfaces we used supercells with dimensions of 3 × 2 × 6 (21.38 × 27.19 × 43.87 Å), 3 × 2 × 6 (24.72 × 21.38 × 48.52 Å), and 2 × 3 × 6 (27.19 × 26.99 × 41.43 Å), respectively. Simulated annealing calculations were performed with the Adsorption Locator module in Materials Studio. Surfaces were fixed but the adsorbate molecules 1 and 2 were allowed complete freedom of motion, including rotations, translations, and internal degrees of freedom. Each simulated annealing calculation involved 1000 loading steps, 1000 heating cycles per run (with starting and final temperatures of 10 000 and 300 K, respectively), and 100 steps per run. The geometry was optimized at the end of each run. In all cases, the entire simulated annealing run was repeated between four and six times. The fact that the most stable orientations appeared in numerous runs gave us confidence that we had sufficiently sampled the entire configurational space.

Figure 4. The most stable orientations of 1 on the (a) (100), (b) (001), and (c) (110) surfaces, respectively, viewed from above the surface. The most stable orientations 1 on the (d) (100), (e) (001), and (f) (110) surfaces, respectively, viewed from the side. Hydrogen bonds between the adsorbate and the surface are indicated by the dashed yellow lines. The most stable docking configurations of 1 on (100), (001), and (110) surfaces are shown in Figure 4. In general, the most stable orientations show that the adsorbate lies more or less flat on the surface so as to maximize van der Waals interactions. Additionally, there is one strong73 hydrogen bond on the (100) and (110) surfaces (1.735 and 1.732 Å, respectively, between the carbonyl oxygen of 1 and the COOH hydrogens of 3 in the surfaces) and no strong bonds on (001). 2141

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

Table 3. Binding Energies for the Three Most Favorable Orientations of 1 Docked on the (100), (001), and (110) Surfaces of (M)-3 surface

configuration

Eb (kcal/mol)

enantiomer

(100)

1 2 3 1 2 3 1 2 3

−24.845 −23.848 −23.388 −27.171 −25.756 −25.062 −24.534 −22.429 −21.982

S S S S S S R R S

(001)

(110)

The binding energies for the three most stable docking configurations of 1 on the (100), (001), and (110) surfaces of (M)3 are given in Table 3. We assigned the predicted alcohol configuration (R or S) on the basis of which pro-stereogenic face is exposed to the alkylating agent. In the aggregate, the results predict that (M)-3 will generate S product. The most exothermic binding configuration in Table 3, by almost 1.5 kcal/mol, presents the pro-S face on the cleavage plane. The three most stable docking configurations of 1 on the (100) and (001) surfaces expose the prostereogenic face that leads to the S enantiomer. In contrast, the two most stable configurations on the (110) surface are for the R enantiomer. A Boltzmann distribution law can be calculated based on the binding energy differences of the most stable docking configurations. In this way it is possible to predict a population or fraction of docking molecules that will be oriented on the surface with a particular enantiomer (R or S) configuration. Using a temperature of 298 K, a Boltzmann distribution law was calculated for each surface using all of the most stable docking configurations, which were designated as either the R or S enantiomer. For both the (100) and (001) surfaces, this results in 96% of 1 molecules oriented so as to yield the S enantiomer. On the other hand, the (110) surface, 98% of 1 molecules are oriented so as to give the R enantiomer. Given the predominance of (001) surfaces after grinding to ∼10 μm particles, it is likely that the prediction made on the cleavage plane is most relevant to experiment, exposure of the pro-S face on (M)-3. An alternative mechanism for bias during autocatalysis may result from selective adsorption of product from solution (of course, this logic applies to any reaction intermediates that were not explored computationally). We examined the interactions of 2 with the (100), (001), and (110) surfaces of (M)-3. The most stable docking configurations on the (100), (001), and (110) surfaces are shown in Figure 5. The binding energies in Table 4 show that the R enantiomer of 2 is more tightly adsorbed. As observed for the adsorption of 1, the (001) surface, the cleavage plane, is the preferred binding surface (largest binding energy) followed by the (100) and (110) surfaces, respectively. Using a Boltzmann distribution law at 298 K for the binding energy, we can again predict which enantiomer is preferred and by what fraction. For the (100) surface, this results in an equivocal 59% preference for the (R)-2 adsorption. R isomer is favored by 69% and 75%, respectively, on the (001) and (110) surfaces, respectively. Even though this discrimination is modest, the wonder of asymmetric autocatalysis is the amplification of a slight bias. For 2 on (100), there is a strong H-bond between the alcohol −OH and the amide carbonyl group (1.801 Å), and between a pyrimidine N and carboxylic acid H (1.810 Å). On the (001), there is one strong Hbond between the alcohol and the carboxylic acid group of 3 at a distance of 1.757 Å. Finally on the (110) surface, 2 forms two strong H-bonds to the carboxylic acid group of 3 with the −OH group as donor to the acid carbonyl of 3 (1.671 Å) and acceptor to an underlying −COOH hydrogen atoms (2.218 Å).

Figure 5. The most stable orientations of 2 on the (a) (100), (b) (001), and (c) (110) surfaces, respectively, viewed from above the surface. The most stable orientations 2 on the (d) (100), (e) (001), and (f) (110) surfaces, respectively, viewed from the side. Hydrogen bonds between the adsorbate and the surface are indicated by the dashed yellow lines.

Table 4. Binding Energies for the Three Most Favorable Orientations of 2 Docked on the (100), (001), and (110) surfaces of (M)-3 surface

configuration

Eb (kcal/mol)

enantiomer

(100)

1 2 3 1 2 3 1 2 3

−29.848 −29.321 −28.930 −30.244 −29.908 −29.863 −26.630 −25.568 −25.467

R S S R S R R S S

(001)

(110)

■

ASYMMETRIC AUTOCATALYSIS We performed asymmetric autocatalysis in the presence of single ground crystals of 3 as the chiral initiator. As shown in Table 1, when 1 and diisopropylzinc (i-Pr2Zn) were reacted in the presence of left-handed (M)-[CD(+)300KBr]-3, enantioenriched (S)-2 was obtained; right-handed (P)-[CD(−)300KBr]-3 induced enantio-enrichment of (R)-2. This correlation was established for eight crystals of 3, no exceptions. Half 2142

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

qualitatively. Do they predict the correct enantiomer in the asymmetric autocatalysis revealed by experiment? Indeed, they do. Still, any one such prediction cannot be considered decisive as it has a 50/50 chance of predicting the correct enantioselectivity; however highly instructive computational analyses of enantioselective crystal chemistry claimed more.32 For our methodology to be robust, we would ideally need to make the correct prediction of enantioselectivity a statistical number of times for a variety of different crystalline additives. However, as we outlined in great detail in the beginning of the manuscript, identifying crystals with simple cleavages and welldetermined absolute structures that direct the Soai reaction is no easy task. It took years to arrive at 3. How best to acquire the necessary data for a statistical test of the computational methodology outlined herein? To date, studies of the Soai reaction have used enantiomorphous crystals of achiral molecules such as NaClO3,13 benzil,17 and 4,18 among others. Conglomerates of achiral compounds are comparatively rare. Chiral compounds and their associated chiral crystals are abundant. One merely needs to identify such crystals with excellent cleavage to support a computational investigation. Unfortunately, it would be very difficult to distinguish between the action of crystals, and the action of a small quantity of dissolved chiral molecules that would inevitably enter solution and bias the Soai reaction. The results from chiral crystals would only be meaningful when the enantioselectivity of crystals was opposite that of dissolved molecules. This hitch would undoubtedly limit the use of chiral compounds, but chiral compounds would still most likely yield data more rapidly than the search for suitable conglomerates.

of the crystals whose absolute structures were determined in New York City (Table 1: NYC3, NYC7, NYC8, NYC9) were added to the reaction mixtures without revealing the structural assignments to the Tokyo chemists who performed the asymmetric autocatalysis. The results of the New York City absolute structure assignments were known only to S.B. and C.H.H. and sealed and signed in a dated envelope. These crystals were sent to Tokyo. The enantioselectivities of the resulting reactions were then returned to New York City by mail, and comparisons between these results and the absolute structures were made after opening the sealed results at B.K.’s laboratory meeting. Complete reproducibility was obtained as shown in Table 1. The results of the chemistry are in accord with the computational prediction. Both computational models indicated a preference for enantio-enrichment of (S)-2 in the presence of (M)-[CD(+)300KBr]-3 crystallites. Indeed, that is the stereochemical outcome of the reaction as indicated in Table 1: S enantio-enrichment with (M)-[CD(+)300KBr]-3 and R enantio-enrichment with (P)-[CD(−)300KBr]-3. The chemical enantioselectivites overall were modest. To the extent that this is a reflection of the modest computational enantioselectivities is impossible to judge at this stage.

■

DISCUSSION Clearly, the crystalline chirality of 3, arising from the helical arrangement of molecules (Figure 3) is responsible for the enantioselective i-Pr2 Zn addition to aldehyde 1. This dissymmetry induces a tiny enantiomeric imbalance during the formation of the zinc alkoxide in the initial stage of the reaction. During the subsequent asymmetric autocatalysis, this imbalance is amplified to afford the enantio-enriched 2. 3 works phenomenologically just like many of the other crystals previously investigated that direct the Soai reaction as described above. A prerequisite of any computational investigation of the role of crystals in the Soai reaction is an accounting of the mechanism of autocatalysis and amplification as it is presently understood. Blackmond and co-workers74−79 established the order of the reactants and intermediates. Brown and coworkers11,80−82 established by NMR and computation the structures of some predominant solution aggregates. These facts were combined in a model of a catalytic cycle83−86 by Ercolani and Schiaffino that neatly accounts for both autocatalysis and chirality amplification. Key steps in the afore-cited Ercolani−Schiaffino mechanism involve the formation of an aggregate of four homochiral zinc complexes that disassociates into two pairs one of which re-enters the cycle by capturing and then reducing two additional aldehyde reactants. Surely, this is not the last word defining the Soai mechanism but our understanding has been advanced considerably. Nevertheless, all of the experimental and theoretical investigations thus far have focused on the autocatalysis in solution. The deterministic role of crystals remains a mystery. Herein, we made a computational prediction of the outcome of the reaction based on adsorption to crystal surfaces. We cannot expect these predictions to be quantitatively accurate given our ignorance of the mechanism and the many features not embodied in any force-field computation. Moreover, the enantioselectivity of the Soai reaction in the presence of 3 is modest (the ee’s are low compared to other crystal systems), and the predicted energetic differences are comparatively small. We might nevertheless aspire to use the computations

■

CONCLUSIONS Many chiral crystals will establish, deterministically, the outcome of the enantioselective autocatalytic alkylation known as the Soai reaction. Reckoning the effect of a particular chiral crystal requires the determination of the absolute structure of the crystal additive, and an expectation of the predominant surfaces that are created by abrasion. Only then can one hope to consider the differential binding of enantiomeric reagents, intermediates, and products, with chiral crystal surfaces that must underlie the enantioselectivity. After preliminary experiments and computations with crystals of NaClO3, NaBrO3, γ-glycine, and 4, we finally achieved the requisite condition for 3. Compound 3 did indeed direct the Soai reaction enantioselectivity. (M)-3 gave (S)-2, and (P)-3 gave (R)-2. Molecular modeling predicted that 1 and 2 will preferentially bind to surfaces of (M)-3 in the order of most preferred to least preferred of (001) > (100) > (110). A Boltzmann distribution law for the binding energies of 1 predicts that the pro-S face will be exposed on two of three surfaces calculated. A Boltzmann distribution law for the binding energies of 2 predicted that the R enantiomer will be preferentially adsorbed on all three surfaces leading to enantio-enrichment of the S isomer in solution for the (M)-3. In brief, these results are wholly in accord with experiment.

■

EXPERIMENTAL SECTION

Asymmetric Autocatalysis. Compound 3 was purchased from Shanghai Chainpharm Biomedical Technology Co. A chiral single crystal of (P)-[CD(−)300KBr]-3 (Tokyo 2) was ground into a fine powder using a pestle and mortar. i-Pr2Zn (0.08 mmol, 0.8 mL, 1.0 M 2143

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

Notes

toluene solution) was added dropwise to a finely powdered crystal of (P)-[CD(−)300KBr]-3 (13.9 mg, 0.075 mmol) and pyrimidine-5carbaldehyde 1 (4.7 mg, 0.025 mmol) at 0 °C. After the mixture was stirred for 12 h, i-Pr2Zn (0.3 mmol, 0.3 mL, 1.0 M toluene solution) was then added over a period of 1 h at 0 °C and the mixture was stirred for 2.5 h at 0 °C. A solution of 1 (18.8 mg, 0.1 mmol) in toluene (0.75 mL) was added over a period of 2 h at 0 °C, and the reaction mixture was stirred at 0 °C for 12 h. Then, toluene (5.0 mL), i-Pr2Zn (0.8 mmol, 0.8 mL, 1.0 M toluene solution), and a solution of 1 (75.3 mg, 0.4 mmol) in toluene (2.0 mL) were added over a period of 1.5 h at 0 °C and the mixture was stirred for 2 h. Once again, toluene (14 mL) and i-Pr2Zn (1.6 mmol, 1.6 mL, 1.0 M toluene solution) were added successively, and a solution of 1 (150.4 mg, 0.8 mmol) in toluene (4.0 mL) was added dropwise over a period of 3 h at 0 °C. After the mixture was stirred for 12 h, the reaction was quenched using a mixture of 30% aqueous ammonia and a saturated aqueous ammonium chloride (1/2, v/v) solution (10 mL). The mixture was extracted three times using ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. Purification of the residue using silica gel column chromatography (hexane/ethyl acetate = 2/1, v/v) gave (R)-5-pyrimidyl alkanol 2 (265.7 mg, 1.14 mmol, 89% ee) in an 86% yield. The ee value was determined by HPLC using a chiral stationary phase (Daicel Chiralpak IB column (250 × 4.6 Φ mm ID), eluent = 5% 2-propanol in hexane, flow rate 1.0 mL·min−1, 254 nm UV detector, retention time 12.0 min for (S)-2, 16.6 min for (R)-2). Circular Dichroism. Solid-state circular dichroism (CD) spectroscopic analyses were recorded by Jasco J-820 spectropolarimeters using KBr disk, which was prepared by the following method: the crystal of 3 (ca. 0.8 mg) and dry KBr (ca. 500 mg) was ground into a fine powder using a pestle and mortar. And the powdered mixture (27 mg) was compressed under high pressure in vacuo to form a disk (diameter ca. 10 mm, thickness ca. 1 mm). X-ray Diffraction. Colorless crystals of compound 3 were measured with a Bruker SMART APEXII CCD area detector on a D8 goniometer. The temperature during the data collection was controlled with an Oxford Cryosystems Series 700 plus instrument. Preliminary lattice parameters and orientation matrices were obtained from three sets of frames. Data were collected using graphitemonochromated and 0.5 mm-MonoCap-collimated Mo−Kα radiation (λ = 0.71073 Å) with the ω and φ scan method.87 Data were processed with the INTEGRATE program of the APEX2 software87 for reduction and cell refinement. Multiscan absorption corrections were applied by using the SCALE program for the area detector. The structure was solved by the direct method and refined on F2 (SHELXTL).88 Non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms on carbons were placed in idealized positions (C−H = 0.95−0.99 Å) and included as riding with Uiso(H) = 1.2 or 1.5 Ueq(non-H). Crystal data, data collection parameters, and refinement results for 10 crystal structures can be found in Supporting Information. Scanning Electron Microscopy. For scanning electron microscopy (SEM) investigations, single crystals of 3 were crushed into a powder with mortar and pestle. The samples were mounted on conductive carbon tapes adhered on aluminum holders. The images have been recorded with a MERLIN (Carl Zeiss) field emission scanning electron microscope using a standard Everhart-Thornley type detector at acceleration voltage of 1 kV.

■

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, by the U.S. National Science Foundation (CHE-08545526). D.J.C. received a fellowship from iVEC and Curtin University. We thank Erica Gunn for the halate electron micrographs and John Freudenthal for measurements of the optical properties of γglycine.

■

ASSOCIATED CONTENT

S Supporting Information *

CIF files for crystal structure determinations. This material is available free of charge via the Internet at http://pubs.acs.org.

■

REFERENCES

(1) Soai, K.; Kawasaki, T. Top. Curr. Chem. 2008, 284, 1−33. (2) Kawasaki, T.; Soai, K. Bull. Chem. Soc. Jpn. 2011, 84, 879−892. (3) Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382−390. (4) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767−768. (5) Gehring, T.; Busch, M.; Schlageter, M.; Weingand, D. Chirality 2010, 22, E173−182. (6) Soai, K.; Sato, I.; Shibata, T.; Komiya, S.; Hayashi, M.; Matsueda, Y.; Imamura, H.; Hayase, T.; Morioka, H.; Tabira, H.; Yamamoto, J.; Kowata, Y. Tetrahedron: Asymmetry 2003, 14, 185−188. (7) Singleton, D. A.; Vo, L. K. Org. Lett. 2003, 5, 4337. (8) Mislow, K. Collect. Czech. Chem. Commun. 2003, 68, 849. (9) Kawasaki, T.; Matsumura, Y.; Tsutsumi, T.; Suzuki, H.; Ito, M.; Soai, K. Science 2009, 324, 492−495. (10) Singleton, D. A.; Vo, L. K. J. Am. Chem. Soc. 2002, 124, 10010− 10011. (11) Islas, J. R.; Lavabre, D.; Grevy, J.-M.; Lamoneda, R. H.; Cabrera, H. R.; Micheau, J.-C.; Buhse, T. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 13743−13748. (12) Brown, J. M.; Gridnev, I.; Klankermayer, J. Top. Curr. Chem. 2008, 284, 35−65. (13) Sato, I.; Kadowaki, K.; Soai, K. Angew. Chem., Int. Ed. Engl. 2000, 39, 1510−1512. (14) Sato, I.; Kadowaki, K.; Ohgo, Y.; Soai, K. J. Mol. Catal. A: Chem. 2004, 216, 209−214. (15) Soai, K.; Osanai, S.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Sato, I. J. Am. Chem. Soc. 1999, 121, 11235−11236. (16) Sato, I.; Kadowaki, K.; Urabe, H.; Jung, J. H.; Ono, Y.; Shinkai, S.; Soai, K. Tetrahedron Lett. 2003, 44, 721−724. (17) Kawasaki, T.; Harada, Y.; Suzuki, K.; Tobita, T.; Florini, N.; Palyi, G.; Soai, K. Org. Lett. 2008, 10, 4085−4088. (18) Kawasaki, T.; Suzuki, K.; Hatase, K.; Otsuka, M.; Koshima, H.; Soai, K. Chem. Commun. 2006, 1869−1871. (19) Kawasaki, T.; Suzuki, K.; Hakoda, Y.; Soai, K. J. Am. Chem. Soc. 2008, 47, 496−499. (20) Soai, K.; Sato, I. Chirality 2002, 14, 548−554. (21) Kawasaki, T.; Jo, K.; Igarashi, H.; Sato, I.; Nagano, M.; Koshima, H.; Soai, K. Angew. Chem., Int. Ed. Engl. 2005, 44, 2774−2777. (22) Bonner, W. A. In Exobiology; Ponnamperuma, C. P., Ed.; North Holland: Amsterdam, 1972; pp 170−234. (23) Bonner, W. A.; Kavasmaneck, P. R.; Martin, F. S.; Flores, J. J. Origins Life Evol. Biospheres 1975, 6, 367−376. (24) Bondy, S. C.; Harrington, M. E. Science 1979, 203, 1243−1244. (25) Addadi, L.; Berkovitch-Yellin, Z.; Weissbuch, I.; Lahav, M.; Leiserowitz, L. Top. Stereochem. 1986, 16, 1−85. (26) Mason, S. Chem. Soc. Rev. 1988, 17, 347−359. (27) Cody, A. M.; Cody, R. D. J. Cryst. Growth 1991, 113, 508−519. (28) Weissbuch, I.; Popovitz-Biro, R.; Lahav, M.; Leiserowitz, L. Acta Crystallogr. 1995, B51, 115−148. (29) Kahr, B.; Lovell, S.; Subramony, J. A. Chirality 1998, 10, 66−77. (30) Feringa, B. F.; van Delden, R. A. Angew. Chem., Int. Ed. 1999, 38, 3418−3438. (31) Gurney, R. W.; Mitchell, C. A.; Ham, S.; Bastin, L. D.; Kahr, B. J. Phys. Chem. B 2000, 104, 878−892.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (B.K.). 2144

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145

Crystal Growth & Design

Article

(70) Sun, H. J. Phys. Chem. B 1998, 102, 7338−7364. (71) Sun, H.; Ren, P.; Fried, J. R. Comp. Theor. Polym. Sci. 1998, 8, 229−246. (72) Hartman, P.; Bennema, P. J. Cryst. Growth 1980, 49, 145−156. (73) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in Structural Biology and Chemistry; Oxford University Press: Oxford, 2001. (74) Blackmond, D. G.; McMillan, C. R.; Ramdeehul, S.; Schorm, A.; Brown, J. M. J. Am. Chem. Soc. 2001, 123, 10103−10104. (75) Buono, F. G.; Blackmond, D. G. J. Am. Chem. Soc. 2003, 125, 8978−8979. (76) Blackmond, D. G. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5732−5736. (77) Buono, F. G.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 2099−2103. (78) Klussmann, M.; Iwamura, H.; Mathew, S. P.; Wells, D. H.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621− 623. (79) Blackmond, D. G. Tetahedron 2006, 17, 584−589. (80) Gridnev, I. D.; Serafimov, J. M.; Quiney, H.; Brown, J. M. Org. Biomol. Chem. 2003, 1, 3811−3819. (81) Gridnev, I. D.; Brown, J. M. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5727−5731. (82) Gridnev, I. D.; Serafimov, J. M.; Brown, J. M. Angew. Chem., Int. Ed. 2004, 43, 4884−4887. (83) Schiaffino, L.; Ercolani, G. Angew. Chem., Int. Ed. 2008, 47, 6832−6835. (84) Ercolani, G.; Schiaffino, L. J. Org. Chem. 2011, 76, 2619−2626. (85) Schiaffino, L.; Ercolani, G. Chem.Eur. J. 2010, 16, 3147−3156. (86) Schiaffino, L.; Ercolani, G. ChemPhysChem 2009, 10, 2508− 2515. (87) APEX2 (version 2011.4), Program for Bruker CCD X-ray Diffractometer Control; Bruker AXS Inc.: Madison, WI, 2011. (88) Sheldrick, G. M. SHELXTL, version 6.14, Program for Solution and Refinement of Crystal Structures; Universität Göttingen: Germany, 2009.

(32) Orme, C. A.; Noy, A.; Wierzbicki, A.; McBride, M. T.; Grantham, M.; Teng, H. H.; Dove, P. M.; DeYoreo, J. J. Nature 2001, 411, 775−779. (33) Kahr, B.; Gurney, R. W. Chem. Rev. 2001, 101, 893−951. (34) Cintas, P. Angew. Chem., Int. Ed. 2002, 41, 1139−1145. (35) Hazen, R. M.; Sholl, D. S. Nat. Mater. 2003, 2, 367−374. (36) Addadi, L.; Geva, M. CrystEngComm 2003, 140−146. (37) Weissbuch, I.; Lahav, M. Chem. Rev. 2011, 111, 3236−3267. (38) Weissbuch, I.; Leiserowtiz, L.; Lahav, M. Isr. J. Chem. 2011, 51, 1017−1033. (39) Bijvoet, J. M.; Peerdeman, A. F.; van Bommel, A. J. Nature 1951, 168, 271−272. (40) Soai, K.; Kawasaki, T. Chirality 2006, 18, 469−478. (41) Blackmond, D. G. Cold Spring Harbor Persp. Biol. 2010, 2, a002147. (42) Lahav, M.; Weissbuch, I. Chem. Rev. 2011, 111, 3226−3267. (43) Amariglio, A. C. R. Seances Acad. Sci. Ser. C: Sci. Chim. 1969, 268, 1981−1984. (44) Downs, R. T.; Hazen, R. M. J. Mol. Cat. A. Chem. 2004, 216, 273−285. (45) Buda, A. B.; auf der Hedye, T.; Mislow, K. Angew. Chem., Int. Ed. Engl. 1992, 31, 989−1007. (46) Downs, R. T.; Hazen, R. M. J. Mol. Catal. A: Chem. 2004, 216, 273−285. (47) A chirality index for bulk quartz was introduced. See YogevEinot, D.; Avnir, D. Tetrahedron: Asymmetry 2006, 17, 2723−2725. (48) Kahr, B.; Chittenden, B.; Rohl, A. Chirality 2005, 18, 127−133. (49) Bing, Y.; Kaminsky, W.; Kahr, B.; Viterbo, D. Angew. Chem., Int. Ed. Engl. 2009, 48, 2−8. (50) Bing, Y.; Selassie, D.; Paradise, R. H.; Isborn, C.; Kramer, N.; Sadilek, M.; Kaminsky, W.; Kahr, B. J. Am. Chem. Soc. 2010, 132, 7454−7465. (51) von Groth, P. Chemische Kristallographie; Wilhelm Engelmann: Leipzig. (52) Iitaka, Y. Acta Crystallogr. 1960, 13, 35−45. (53) Iitaka, Y. Acta Crystallogr. 1961, 14, 1. (54) Bernal, J. D. Z. Krystallogr. 1931, 78, 363−369. (55) Torbeev, V. Yu.; Shavit, E.; Weissbuch, I.; Leiserowitz, L.; Lahav, M. Cryst. Growth Des. 2005, 5, 2190−2196. (56) He, G.; Bhamidi, V.; Wilson, S. R.; Tan, R. B. H.; Kenis, P. J. A.; Zukoski, C. F. Cryst. Growth Des. 2006, 6, 1746−1749. (57) Sun, X.; Garetz, B. A.; Myerson, A. S. Cryst. Growth Des. 2006, 6, 684−689. (58) Weissbuch, I.; Leiserowiz, L.; Lahav, M. Adv. Mater. 1994, 6, 952−956. (59) Weissbuch, I.; Leiserowitz, L.; Lahav, M. Chirality 2008, 20, 736−748. (60) Weckert, E.; Hummer, K. Acta Crystallogr., Sect. A 1997, 53, 108−143. Claborn, K.; Herreros Cedres, J.; Cedres, J.; Isborn, C.; Zozulya, A.; Weckert, E.; Kaminsky, W.; Kahr, B. J. Am .Chem. Soc 2006, 14746−14747. (61) Carter, D. J.; Kahr, B.; Rohl, A. L. Theor. Chem. Acc. 2012, 131, 1125. (62) Nagaraja, H. S.; Upahyaya, V.; Rao, P. M.; Aithal, P. S.; Bhat, A. P. J. Cryst. Growth 1998, 193, 674−678. (63) Winchell, A. N. The Optical Properties of Organic Compounds; McCrone Research Institute: Chicago, 1987; p 113. (64) Nagaraja, H. S.; Upahyaya, V.; Rao, P. M.; Aithal, P. S.; Bhat, A. P. J. Cryst. Growth 1998, 193, 674−678. (65) Vaida, M.; Shimon, L. J. W.; Weisinger-Lewin, Y.; Frolow, F.; Lahav, M.; Leiserowitz, L.; McMullan, R. K. Science 1988, 241, 1475− 1479. (66) Castiglioni, E.; Biscarini, P.; Abbate, S. Chirality 2009, 21, E28− 36. (67) Hooft, R. W. W.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96−103. (68) Flack, H. D.; Bernardinelli, G. Chirality 2008, 20, 681−690. (69) Materials Studio Release Notes, Release 4.4; Accelrys Software Inc.: San Diego, 2008. 2145

dx.doi.org/10.1021/cg300207d | Cryst. Growth Des. 2012, 12, 2138−2145