Cycloalkanone-Based Threo and Erythro Aldols as Supramolecular

CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 1 25-34

Articles Cycloalkanone-Based Threo and Erythro Aldols as Supramolecular Synthons in Crystal Engineering Masato Kitamura* and Keiji Nakano Research Center for Materials Science and Department of Chemistry, Nagoya University, Chikusa, Nagoya 464-8602, Japan Received August 23, 2002;

Revised Manuscript Received October 24, 2002

ABSTRACT: Aldols are bifunctional molecules possessing OH and CdO groups, which are able to act as both hydrogen donors and/or acceptors. Despite their high potential as supramolecular synthons, in comparison to their two carbon less homologues, carboxylic acids, the structures of aldols, and their crystals have not been systematically studied. We have designed synthons on the basis of the ab initio calculated syn-CdO/OH and OdC-C(R)-C(β) eclipsed conformation of the simplest aldol and have synthesized 16 cycloalkanone-based threo/erythro aldols, which are systematically installed with structural determinants. The molecular conformations, the hydrogen-bonding patterns, the location of OH protons, the crystal structures, and the packing efficiency have been analyzed by X-ray diffraction to relate synthons with crystals. Generally, the stable syn/eclipsed conformations are maintained in the C(3)-unsubstituted cyclohexanone-based aldols, and the racemic synthons crystallize via an S(6) monomer or a heterochiral dimer by way of van der Waals forces. The enantiomerically pure aldols, however, tend to form intermolecular hydrogen bonds generating a helix chain. Introduction of a C(3) substituent completely destroys the stable conformation yielding an unusual C(2)-C(3) trans-diaxial conformation. This enables the formation of an intermolecularly hydrogen-bonded long chain column with a screw axis or glide plane, which can crystallize through CH‚‚‚O or van der Waals interaction. Introduction Three-dimensional structural control at a supramolecular level is referred to as crystal engineering and has important implications for the development of new chemical or physical functional materials.1 The predictability of a target network in the component molecules, that is supramolecular synthons,2 is a basic requirement for the rational design of crystals. The synthons essentially contain all of the information on the recognition events, but the network topologies are too sensitive to slight changes in synthon structures. At the present state of knowledge, the algorithms relating supramolecular structures with synthons can only be sought empirically. Among many noncovalent interactions between molecules known to induce crystal growth, the hydrogen bonds of the OH‚‚‚O and NH‚‚‚O types in carboxylic acids, amides, and imides have been used with considerable success as controllers of molecular arrays of various shapes.3 This may be ascribed to the fact that strong bonds (3-10 kcal/mol)4 may direct the molecular * To whom correspondence should be addressed. E-mail: kitamura@ os.rcms.nagoya-u.ac.jp.

frame so as to prevail over the packing of the molecule. The packing geometry is, however, still not completely deducible a priori because of the existence of many other unpredictable controlling factors. From this viewpoint, to successfully investigate supramolecular synthons, structural determinants including stereochemical, steric, and electronic factors must be at least systematically incorporated. In this paper, we describe an attempt to bridge the large gap between a molecule and its crystal by focusing on aldols, which have, as yet, in contrast to their two carbon less homologues, carboxylic acids, not been utilized as synthons in crystal engineering.5 Experimental Section Instruments. Nuclear magnetic resonance (NMR) spectra were measured on a JEOL JNM-A400 (1H NMR, 400 MHz; 13C NMR, 100 MHz). The chemical shifts are expressed in parts per million (ppm) downfield from Si(CH3)4. Signal patterns of NMR are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal. X-ray crystallographic analyses were conducted at 20 °C on a Rigaku automated four circle diffractometer AFC-7R using graphite-monochromated Cu KR radiation. Liquid chromatographic purifications were performed by flash column chromatography, using glass columns packed with Fuji Devison BW300. For preparative high-

10.1021/cg025575h CCC: $25.00 © 2003 American Chemical Society Published on Web 11/15/2002

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Kitamura and Nakano

Table 1. Crystallographic Data and Geometric Parameters compd mol formula mol wt cryst syst lattice type space group cell dimens a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) vol (Å3) Z Fcalcd (g cm-3) packing coeffb graph set geometric param ω1 ω2 hydrogen bond geometry θ (intramolecular) θ (intermolecular) φ (intramolecular) φ (intermolecular) compd mol formula mol wt cryst syst lattice type space group cell dimens a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) vol (Å3) Z Fcalcd (g cm-3) packing coeffb graph set geometric param ω1 ω2 hydrogen bond geometry θ (intramolecular) θ (intermolecular) φ (intramolecular) φ (intermolecular) a

rac-threo-1a C13H22O2 210.31 monoclinic primitive P21/a

rac-erythro-1a C13H22O2 210.31 monoclinic primitive P21/c

rac-threo-1b C13H16O2 204.27 monoclinic primitive P21/n

rac-erythro-1b C13H16O2 204.27 monoclinic primitive P21/a

rac-threo-1c C14H18O2 218.29 monoclinic primitive P21/c

rac-erythro-1c C14H18O2 218.29 monoclinic primitive P21/c

ep-threo-1ba C13H16O2 204.27 monoclinic primitive P21

ep-erythro-1ba C13H16O2 204.27 monoclinic C-centered C2

10.5975(5) 10.1387(7) 11.5644(5) 90 100.719(3) 90 1220.8(1) 4 1.140 0.702 S(6)

11.465(2) 10.190(1) 11.667(1) 90 114.924(10) 90 1236.1(3) 4 1.130 0.693 N1 ) S(6)‚R22(12) N2 ) R22(4)

10.252(3) 11.273(3) 10.421(2) 90 112.67(2) 90 1111.3(5) 4 1.215 0.716 S(6)

15.577(4) 5.714(5) 26.195(3) 90 106.31(1) 90 2237(2) 8 1.213 0.712 R22(12)

5.6823(7) 25.2337(6) 8.7846(8) 90 92.939(10) 90 1257.9(2) 4 1.153 0.685 N1 ) S(6)‚R22(12) N2 ) R22(4)

14.900(2) 5.743(1) 15.803(1) 90 115.555(6) 90 1220.0(3) 4 1.188 0.707 R22(12)

10.076(2) 11.782(1) 10.599(2) 90 114.99(1) 90 1140.4(4) 4 1.190 0.698 S(6)

21.3075(9) 5.7687(8) 10.1720(8) 90 111.954(4) 90 1159.6(2) 4 1.170 0.686 N1 ) S(6)‚C(6) N2 ) C(2)

-7.6 8.9

-5.9 -65.8

-4.8 56.9

-2.7, -4.2 88.7, 89.0

-1.7 63.9

-5.7 -68.6

5.9, 9,7 5.3 -58.7, -55.8 68.0

62.7

55.2 77.6 -5.7 65.2

69.7

ep-threo-1ca C14H18O2 218.29 orthorhombic primitive P212121

ep-erythro-1ca C14H18O2 218.29 monoclinic C-centered C2

8.554(3) 24.382(3) 5.903(2) 90 90 90 1231.1(5) 4 1.178 0.700 C(6)

102.0 47.1

8.9

64.2 31.0

66.2, 82.1

63.5 67.2 6.4 58.5

rac-threo-2a C15H26O2 238.37 monoclinic primitive P21/c

rac-erythro-2a C15H26O2 238.37 monoclinic primitive P21/a

rac-threo-2b C15H20O2 232.32 tetragonal primitive P4/n

rac-erythro-2b C15H20O2 232.32 monoclinic C-centered Cc

rac-threo-3a C14H24O2 232.32 monoclinic primitive P21/a

rac-erythro-3b C14H18O2 218.29 orthorhombic primitive Pbca

20.817(3) 5.835(3) 11.104(2) 90 113.83(1) 90 1233.7(6) 4 1.175 0.699 N1 ) S(6)‚C(6) N2 ) C(2)

9.456(2) 5.989(1) 25.338(1) 90 100.40(1) 90 1411.4(5) 4 1.122 0.701 C(6)

9.654(1) 13.835(2) 10.6001(8) 90 98.179(8) 90 1401.3(2) 4 1.130 0.706 C(6)

18.217(3) 18.217(3) 8.387(3) 90 90 90 2782.3(8) 8 1.109 0.667 N1 ) R44(24)‚R44(8) N2 ) R21(6)

22.200(7) 11.977(4) 10.360(7) 90 102.61(4) 90 2688(1) 8 1.148 0.691 D‚C(6)

9.249(6) 14.702(7) 10.628(6) 90 110.08(4) 90 1357(1) 4 1.098 0.680 C(6)

23.425(4) 14.245(3) 7.318(2) 90 90 90 2442(1) 8 1.187 0.706 C(6)

5.1 66.9

-111.3 54.9

-109.5 -174.8

-110.7 51.3

-102.4, -102.9 -56.4 178.2, 163.0 -53.6

-46.7 63.0

79.8

74.7

32.0

77.5

54.6

70.4

42.5

36.6

12.3

45.1

41.3

21.4

57.1 73.0 0.2 39.1

88.7, 89.0 10.0

55.9, 66.1 88.8 10.3, 12.0 65.0

54.5 67.8 8.0 49.3

b

The absolute configuration is not determined. Obtained from the Gavezzotti atom volumes (ref 23).

performance liquid chromatography (HPLC), a Shimadzu LC10AD instrument equipped with a system controller SCL-10A, a degasser DGU-4A, an autosampler SIL-10AXL, a fraction collector GILSON MODEL 201, and a Shimadzu SPD-10A UV detector were used. All apparatus for the moisture sensitive reactions were used after drying at ca. 400 °C for 5 min. Aldols. The racemic aldols, rac-threo-1a, rac-erythro-1a, racthreo-1b, rac-erythro-1b, rac-threo-2a, rac-erythro-2a, racthreo-2b, rac-erythro-2b, rac-threo-3a, and rac-erythro-3b,6 were synthesized by the reported methods.7-9 The compound ep-threo-1b6 in 89% enantiomeric excess (ee) was prepared according to Yamamoto’s method.10 The enantiomeric purity was increased to 100% by recrystallization from ether (5 mL/ g). The 1:2 mixture of rac-threo-1c and rac-erythro-1c was obtained by the reported method.11 The diastereomers were separated by flash column chromatography (40:1 silica gelsample ratio; eluent, 3:1 hexanes-ether mixture). The enantiomers of the racemic aldols were separated by HPLC with a chiral stationary phase (conditions: column, CHIRALCEL-OF (0.46 cm × 25 cm); eluent, a mixture of 4:1 hexane-2-propanol;

flow rate, 0.5 mL min-1; temperature, 30 °C; detection wavelength, 254 nm light; retention time (tR), 32 and 38 min for ep-threo-1c; tR, 17 and 20 min for ep-erythro-1c). The absolute configurations are unknown. The relative stereochemistries were confirmed by comparison of the 1H NMR spectra with the reported one.12 The compound ep-erythro-1b was obtained by the kinetic resolution of rac-erythro-1b on the basis of (S)-BINAP-Ru-catalyzed hydrogenation13 as follows. Methanol (hydrogenation grade) was dried, degassed, and purified by refluxing under argon in the presence of Mg for 6 h and finally distilled into a Schlenk flask. (S)-BINAP was donated from Takasago Co. All manipulations in the BINAPRu-catalyzed hydrogenation were carried out using the normal Schlenk technique on a dual manifold vacuum/Ar system. The compounds rac-erythro-1b (5.0 g, 25.0 mmol) and CH3OH (30 mL) were placed into a dry, Ar-filled 20 mL Schlenk tube. The solution was degassed by three freeze-thaw cycles, and RuCl2[(S)-BINAP](DMF)n (30 mg, 40 µmol as RuCl2[(S)-BINAP]) was added. The yellow solution was transferred via a stainless cannula to a stainless steel autoclave. Argon in the autoclave

Aldols as Supramolecular Synthons

Crystal Growth & Design, Vol. 3, No. 1, 2003 27

Figure 1. Geometric parameters for aldols. The ω1 and ω2 values are defined as the OdC-C(R)-C(β) and C-C(R)C(β)-O dihedral angles, respectively. The θ and φ parameters show hydrogen bond directionality in a spherical coordinate system. was replaced three times with 4 atm of hydrogen, and the mixture was stirred under an initial H2 pressure of 100 atm at 23 °C for 90 min. After the pressure was released and the solvent was removed, the crude mixture was analyzed by 1H NMR to be a 16:84 mixture of ep-erythro-1b and the hydrogenation product 2-(1-hydroxy-1-phenylmethyl)cyclohexanol. The mixture was separated by flash column chromatography (50:1 silica gel-sample ratio; eluent, a mixture of 4:1 hexanesether) to give ep-erythro-1b in >95% ee (740.0 mg, 14.8% yield) and 2-(1-hydroxy-1-phenylmethyl)cyclohexanol (4.2 g, 83% yield). The 1H NMR spectrum of ep-erythro-1b was identical with that reported.14 The ee was determined by 1H NMR analysis after conversion of ep-erythro-1b to the (R)-MTPA ester15 (C(β)H δ 6.55 (d, J ) 3.4 Hz) and 6.56 (d, J ) 5.4 Hz)). X-ray Diffraction (XRD) and Structure Solution. X-ray crystallographic analyses of the racemic aldols rac-threo-1a, rac-erythro-1a, rac-threo-1b, rac-erythro-1b, rac-threo-2a, racerythro-2a, rac-threo-2b, rac-erythro-2b, rac-threo-3a, and racerythro-3b have already been reported.7-9 ORTEP drawings with numbering schemes, tables of atomic parameters, anisotropic temperature factors, and complete listings of bond angles and interatomic distances have already been uploaded to Cambridge Structural Data Base. Single X-ray quality crystals of ep-threo-1b, ep-erythro-1b, rac-threo-1c, ep-threo1c, rac-erythro-1c, and ep-erythro-1c were obtained by recrystallization from ether at 23 °C for several days. For the collection of the XRDs, the crystals of ep-threo-1b, ep-erythro1b, rac-threo-1c, and ep-threo-1c were sealed in capillaries (diameter 0.3 or 0.5 mm), and the crystals of rac-erythro-1c and ep-erythro-1c were connected by use of epoxy type adhesive agent on the top of glass fiber. The single crystal XRD data are provided in the Supporting Information as a CIF file. The crystallographic data are listed in Table 1 for all of the crystalline aldols.

Results and Discussion Aldols as Synthons: Design Concepts. Aldols are molecules that combine the hydroxy group and the carbonyl group through two carbon atoms. Figure 1 shows the general geometries of aldols having an intramolecular and intermolecular hydrogen bond.9 The position of the OH proton is defined by the angles θ and φ in the polar coordinate system. Unless otherwise constrained, the conformational energy is minimized at OdC-C(R)-C(β) dihedral angles (ω1) of 0, 120, and -120°, and C(CdO)-C(R)-C(β)-O dihedral angles (ω2) of 60, 180, and -60°. A density functional theory (DFT)

Figure 2. Stable syn-CdO/OH and OdC-C(R)-C(β) eclipsed conformations of 3-hydroxypropanal (a) intramolecular hydrogen bond, (b) no intramolecular hydrogen bond, and the cyclohexanone-derived aldol fixed to the stable conformation (c).

calculation of the simplest aldol, 3-hydroxypropanal, at the B3LYP/6-311++G(d,p) level indicates that the optimized conformation approximates, as shown in Figure 2, an “eclipsed” shape with ω1 ) -5.2°, ω2 ) 62.7°, θ ) 66.3°, and φ ) 8.3°.9 Regardless of the presence or absence of a hydrogen bond, the conformation is little changed (Figure 2a,b). The hydrogen bond stabilizes the six-membered cyclic structure by 3.8 kcal/ mol in comparison to the nonhydrogen-bonded syn-Cd O/OH structure (destabilized by a dipole repulsion) and by 2.6 kcal/mol with respect to the anti-CdO/OH conformation. Thus, the calculation suggests that simple aldols in a vacuum inherently favor the eclipsed conformation where torsional strain is the major factor controlling the geometry. On the basis of this view, we designed and synthesized the cycloalkanone-derived aldols 1-3 as supramolecular synthons in careful and systematic consideration of the following five structural parameters. First, as shown in Figure 2c, the aldol 2-hydroxymethylcyclohexanone can be created from the simplest aldol, 3-hydroxypropanal, without any bond rotation in the optimized conformation. The eclipsed syn- or anti-Cd O/OH conformation with ω1 ) 0° and ω2 ) 60, 180, or -60° is able to be maintained. Second, the introduction of a substituent at C(R) gives rise to chirality, and further substitution at C(β) generates the threo/erythro relative configuration. Thus, with the racemic threo or erythro aldols, the synthons can interact with each other in both homochiral and heterochiral manners,16 giving conglomerates and racemates, respectively. The third point is that the presence of a trans-alkyl substituent at C(3) in aldols 2 acts as a factor destabilizing the Od C-C(R)-C(β) eclipsed conformation due to the substan-

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tial gauche repulsion of the large vicinal substituents. The dihedral angle ω1 is set to ca. 0 or 120° by the absence or presence of the C(3) substituent. The fourth important parameter is the ring size of the cycloalkanone. The aldols 3 are cyclopentanones possessing vicinal, trans substituents at C(2) and C(3). Unlike in the cyclohexanone aldols 2, the ω1 value is forced to increase to 45 or 75° for the half-chair form and to 60° for the envelope structure. The final parameter is concerned with a weak CH/π interaction.9,17 The relative stabilities of aldol conformers are further controlled by various attractive and repulsive interactions. Subtype a (R ) c-C6H11) denotes the aldols produced from cyclohexanecarbaldehyde, while subtype b and c (R ) C6H5; R ) p-CH3C6H4) aldols are derived from benzaldehyde and tolaldehyde, respectively. The difference in the aliphatic and aromatic groups may affect the conformational stability of the aldols.

Figure 3. Hydrogen bond patterns of aldols with graph set analysis.

Such stereochemical, steric, and electronic factors are strongly related to each other and affect the mode and degree of the intramolecular or intermolecular hydrogen bonds and eventually the arrays of the molecular assemblies. As shown in Figure 3, seven types of hydrogen bonds are possible in Etter’s graph set analysis,18 which is based on the atom numbers between hydrogens of hydroxy groups in a repetitive system and the manner of molecular frame growth. Intramolecular hydrogen bonds, for example, generate the S(6) motif, which forms crystals by use of weak interactions other than hydrogen bonds. The dimers are formed by use of four patterns of hydrogen bonds: D with the OH‚‚‚Od C bond, D with the OH‚‚‚OH bond, R22(12) (n ) 2 in Rnn(6n)), and R22(4) (n ) 2 in Rnn(2n)). The heterochiral and homochiral dimers in the R22(12) and R22(4) patterns possess the inversion center and rotation axis, respectively. On increasing the repetition number, the dimer grows in a heterochiral or homochiral cyclic aggregate in which mutual interaction results in a column with a ring hole in the center. When aldols continuously make the hydrogen bond without closure of the ring, a C(6) or C(2) pattern will appear, resulting

in the generation of crystals with translation plane, glide plane, or screw axis. Syntheses of Crystalline Aldols. Figure 4 summarizes the synthetic methods for a series of aldols investigated as supramolecular synthons. Diastereomeric threo- and erythro-1a were synthesized stereoselectively by reacting lithium19 and tetrabutylammonium20 enolate of cyclohexanone with cyclohexanecarbaldehyde, respectively.9 The aldol reaction of cyclohexanone with benzaldehyde in aqueous sodium hydroxide solution afforded rac-threo-1b and rac-erythro-1b in a 33:67 ratio.11 In a similar way, a 35:65 mixture of racthreo-1c and rac-erythro-1c was obtained by use of tolaldehyde instead of benzaldehyde. The C(3)-ethylated aldols, rac-threo-2a and rac-threo-3a, were synthesized with a >99:1 threo/erythro stereoselectivity by Cu(I)catalyzed 1,4-addition of diethylzinc to cycloalkenones followed by aldol reaction of the Zn enolate with cyclohaxanecarbaldehyde.7,8 The vicinal carbon-carbon bond formation occurred with perfect trans selectivity. When boron trifluoride was added in the Zn enolate reaction, rac-threo- and rac-erythro-2a were produced in a 50:50 ratio. With benzaldehyde, the aldols 2b and 3b were produced as an 81:19 and 55:45 mixture of threo and erythro isomers. All of the diastereochemically pure racemic aldols were obtained by chromatographic separation followed by recrystallization from ether, pentane, or hexane. Enantiomerically pure ep-threo-1b was prepared by recrystallization of threo-1b in 89% ee, which was obtained by (R)-BINAP-Ag(I)-catalyzed aldol reaction10 of the tin enolate of cyclohexanone with benzaldehyde.


Figure 4. Preparation of aldols.

The racemic erythro-1b was kinetically resolved by (S)BINAP-Ru-catalyzed hydrogenation13 with a kfast/kslow ratio of 14.4,21,22 giving after 84% conversion ep-erythro1b in >95% ee. The enantiomers of threo-1c and erythro-


1c were separated by HPLC using a chiral stationary phase (CHIRALCEL-OF; eluent, 4:1 hexane-2-propanol mixture). These optically active samples were recrystallized from ether. The 16 different crystalline aldols thus obtained were subjected to X-ray crystallographic analysis. The compound rac-threo-3b was not crystallized. The crystallographic data and geometric parameters ω1, ω2, θ, and φ, the molecular structures in the crystals, and the crystal structures in the unit cell are listed in Table 1 and Figures 5 and 6, respectively. With this information, the structures of aldols and their crystals are discussed in the next section. Structures of Aldols and Their Crystals. The racemic cyclohexanone-derived aldols 1 with no ethyl substituent at C(3) crystallized in the monoclinic P21/ a, P21/c, or P21/n space group. These crystals, except for that of rac-erythro-1b, have four molecules in the unit cell of 1111-1258 Å3. The Z value of rac-erythro1b is eight, and the unit cell volume is doubled (2237 Å3). The hydroxy proton in rac-threo-1a, rac-erythro-1a, rac-threo-1b, and rac-threo-1c interacts intramolecularly with the carbonyl oxygen to form a six-membered cyclic framework of S(6)-based graph set with OH‚‚‚Od C bond distances of 1.81, 2.48, 2.15, and 2.34 Å and the O‚‚‚H-O bond angles of 133.4, 132.0, 133.0, and 125.6°, respectively (Figure 5). In rac-erythro-1a and rac-threo1c, the OH proton interacted not only with the CdO oxygen in the same molecule but also with the CdO of the other enantiomeric aldol with the graph sets of N1 ) S(6)‚R22(12) and N2 ) R22(4), giving a heterochiral dimer with an inversion center (Figure 6b,e). The hydroxy protons are located at the intersection point of θ ) 55.2-69.7° and φ ) -5.7 to 10.0°, in good agreement with the calculated values for 3-hydroxypropanal. Because the OH bond is shorter than the C-C and CdO bonds (typically 1.0 Å vs 1.5 and 1.2 Å), a near-right CdO‚‚‚H angle with a low value of φ (-5.7 to 10.0°) is realized in the six-membered OdC-C(R)-C(β)-O-H cyclic system. The rac-erythro-1b and rac-erythro-1c synthons form no intramolecular hydrogen bonds but interact with the enantiomeric aldol via an intermolecular OH‚‚‚OdC hydrogen bond to give a heterochiral dimer with the R22(12) graph set (Figure 6d,f). In these dimeric aldols, the electrostatic repulsion is minimized by rectangular positioning of the two carbonyl oxygen atoms and the two hydroxy hydrogen atoms. Thus, both θ and φ values are increased to 88.7-89.0° and 65.0-82.1°, respectively, and the intermolecular OH‚‚‚OdC bond becomes near linear. In contrast to the racemic 1, the enantiomerically pure ep-1 crystallized in the monoclinic system with a P21 or C2 space group or in the orthorhombic P212121 space group, in which four molecules are contained in the unit cell with 1140-1234 Å3 (Table 1). Both the racemic and the enantiomerically pure threo-1b have the same S(6) graph set. The hydrogen bond patterns of ep-erythro-1b, ep-erythro-1c, and ep-threo-1c, however, are altered from R22(12) (rac-erythro-1b and -1c) to N1 ) S(6)‚C(6)/N2 ) C(2) (ep-erythro-1b and -1c) and from N1 ) S(6)‚R22(12)/N2 ) R22(4) (rac-threo-1c) to C(6) (ep-threo-1c), and the crystal structures are changed from the heterochiral dimer-based array to helix poly-

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Figure 5. Molecular structures of cycloalkanone-derived aldols in crystals.

mer with a 21 screw axis (Figure 6h-j). The compounds ep-threo-1b, ep-erythro-1b, and ep-erythro-1c contain an intramolecular hydrogen bond forming a six-membered cyclic framework with the OH‚‚‚OdC bond distances of 2.02 (1.99), 2.48, and 2.41 Å and the CdO‚‚‚H bond angles of 130.7 (125.6), 112.5, and 134.7°, respectively (Figure 5g,h,j). The hydroxy protons are located at the intersection point of θ ) 54.5-66.1° and φ ) 0.2-12.0°. The molecular structures are very close to those of the racemic aldols. On the other hand, rac-threo-1c and epthreo-1c show a totally different profile in both the molecular structure and the crystal, although little change between rac-threo-1b and ep-threo-1b. Thus, as expected, the series of simple cyclohexanone-derived aldols 1 has an equatorially oriented C(2) substituent with respect to the chairlike cyclohexanone framework possessing staggered C(sp3)-C(sp3) linkages and a small OdC-C(R)-C(β) dihedral angle (ω1), -7.6 to 9.7°, close to the standard 0°, while ep-threo-1c has an intermo-

lecular hydrogen bond and takes an axially oriented C(2) substituent with a large ω1 value of 102.0°. The hydroxy proton in ep-threo-1c points in the direction of the lone pair electrons of the CdO oxygen with θ ) 64.2° and φ ) 31.0°. The packing profile of rac- and ep-threo-1c is also very different from those observed in threo-1b and erythro-1b and -1c. The racemic aldols, rac-threo-1b, rac-erythro-1b, and rac-erythro-1c, pack in the crystals more efficiently than the corresponding enantiomerically pure aldols (0.707-0.716 vs 0.686-0.699), being consistent with the Wallach’s rule.24 Contrary to this rule, however, the packing efficiency of rac-threo-1c is lower than that of ep-threo-1c (0.685 vs 0.700), and the value is the lowest among the aldol 1 series. The introduction of a methyl group at the para position of phenyl ring in rac-threo-1b significantly increases the unit cell volume from 1111 to 1258 Å3. Destabilization of the crystal occurs, as expected, when the packing coefficient decreases from 0.716 to 0.685.25 This may



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Kitamura and Nakano

Figure 6. Crystal structures of aldols in the unit cell. Upper figure: hydrogen bond patterns and molecular orientation in the unit cell; lower figure: the molecular assembly seen from the top of the column.


cause the complete alteration of the aldol geometry and the crystal shape of ep-threo-1c. A similar tendency was observed by the introduction of an ethyl group at C(3) trans to the C(2) hydroxyalkyl substituent into the racemic aldols 1. The compounds rac-threo- and rac-erythro-2a crystallized in the monoclinic system possessing four molecules in the unit cell with a P21/c space group. The unit cell volumes are increased by ca. 15% in comparison with the original rac-threo- and rac-erythro-1a (1221-1236 Å3 vs 14011411 Å3), although the packing coefficients shows little change (0.702 vs 0.701, 0.693 vs 0.706). The crystals of rac-threo- and rac-erythro-2b were tetragonal with a P4/n space group and monoclinic with Cc, respectively, and they contain eight molecules in the unit cell. The volumes of the unit cells were larger by 20-25% per molecule than those of rac-threo- and rac-erythro-1b. The ω1 dihedral angles of aldols 2 range from -102.4 to -111.3°, comparable to the standard value of -120°, while the C(sp3)-C(sp3) linkages have a normal staggered geometry. The standard syn-CdO/OH and OdCC(R)-C(β) eclipsed conformation observed in aldols 1 is altered to syn-CdO/OH and OdC-C(R)-H eclipsed one. The cyclohexanone skeletons are characterized by the trans-diaxial substituents at C(2) and C(3) with the dihedral angles ranging from 152.0 to 168.8° (Figure 5k-n). Such unusual conformations are due to the substantial repulsion of the vicinal large substituents, but the local energetic penalty was compensated for by forming the multiple intermolecular hydrogen bonds and by improving the packing efficiency into the unit cell. None of the aldols 2 crystallized with the simplest S(6) hydrogen bond pattern. Thus, rac-threo-2a, racerythro-2a, and rac-erythro-2b have an intermolecular hydrogen bond along the direction of the sp2 lone pair of the carbonyl oxygen (θ ) 74.7-79.8°, φ ) 36.6-45.1°), generating a polymer with a 21 screw axis or glide plane. The racemic threo aldol 2b forms a homochiral tetramer having a 4-fold rotation axis with N1 ) R44(24)‚R44(8)/N2 ) R21(6) graph set. Along the rotation axis as shown in Figure 6m, the rac-threo-2b crystal has a hole of 4 Å between two oxygen atoms on a diagonal line. The cyclopentanone aldol rac-threo-3a crystallized in a monoclinic system with a P21/a space group, while racerythro-3b crystals had an orthorhombic system with a Pbca space group. Both rac-threo-3a and rac-erythro3b form polymeric structures by intermolecular OH‚‚‚ OdC hydrogen bonds. The hydroxy protons are directed toward the oxygen sp2 lone pair, although not in the CdO plane (θ ) 54.6-70.4°, φ ) 21.4-41.3°). The cyclopentanone ring of rac-threo-3a has an envelope conformation with an ω1 dihedral angle of -56.4°. In rac-erythro-3b, the cyclopentanone framework takes a half-chair conformation where the ω1 dihedral angle is -46.7°. These values are significantly different from the -102.4 to -111.3° of cyclohexanone derivatives 2. Furthermore, the C-C(2)-C(3)-C dihedral angles involving the C(2) and C(3) substituents, 86.6 and 89.6° (Figure 5o,p), respectively, are much smaller than the values of the trans-disubstituted cyclohexanones 2, 152.0-168.8°. Replacement of the cyclohexyl group with a phenyl or tolyl group at C(β) produces the CH/π interaction.17,26 The distances between one of the C(3)-H protons and


Figure 7. Schematic drawing of crystallization of aldols.

the cyclohexyl methine proton in rac-threo- and racerythro-1a are 2.22-2.65 and 2.60-2.65 Å, respectively (Figure 5a,b). These values are close to the sum of the van der Waals radii of two hydrogen atoms, 2.4 Å. The interatomic distances between the C(3)-H proton and the ipso carbon in threo-1b and -1c and erythro-1b and -1c were, however, 2.60-2.78 Å, which was 4-12% shorter than the sum of the van der Waals radii of the hydrogen atom and the sp2 carbon atom, 2.9 Å (Figure 5c-j), indicating the existence of CH/π interaction between the C(3)-H and the aromatic ipso carbon.17 In erythro-3b, a CH/π attraction is present between one of the C(3)-ethyl methylene protons (unlike C(3)-H in threo- and erythro-1b) and the phenyl carbon, as judged by the short C(sp2)‚‚‚H distance, 2.69 Å (Figure 5p). Conclusion On the basis of consideration of the stable conformation of the simplest aldol, 3-hydroxypropanal, a series of cycloalkanone-based threo/erythro aldols, endowed with systematic structural determinants such as conformation, relative and absolute configurations, gauche repulsion, and weak CH/π interaction, have been designed and synthesized. A series of aldols obtained as crystals are classified according to Etter’s graph set theory. The C(3)-unsubstituted aldols 1 retain the stable syn-CdO/OH and OdC-C(R)-C(β) eclipsed conformation, in which ω1 and ω2 values are close to the standard 0 and 60 or -60°, respectively. The racemic aldols 1 form the intramolecularly hydrogen-bonding monomer or the heterochiral dimer with an inversion center, which self-assembles via van der Waals interactions (Figure 7a,b). The hydroxy protons of the corresponding

34


single enantiomers tend to interact intermolecularly with the two CdO oxygens of the self and nonself molecules to give a 21 helix column with bifurcated hydrogen bond arrangements, which then crystallizes as shown in Figure 7c. Introduction of a C(3) substituent totally alters the standard conformation to an unusual geometry, in which the C(2) and C(3) substituents are diaxially oriented in terms of the cyclohexanone skeleton. The transformation brings about the long-chain homochiral or heterochiral column with intermolecular OH‚‚‚OdC hydrogen bonds with a 21 screw axis or glide plane. The column then assembles through CH‚‚‚O or van der Waals interaction to crystallize (Figure 7c,d). Although aldols geometries do not necessarily correspond in a simple manner with arrangements of aldols in crystals, a trend can be deduced. We are still far away from the rational de novo design of aldol crystals, but the accumulation of such basic information will be helpful for future materials science.1 Acknowledgment. This work was aided by the Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan. We are grateful to Professor R. Noyori for valuable discussions and financial support. We thank Mr. T. Noda for constructing the reaction vesseles used in the aldol preparations. Supporting Information Available: X-ray crystallographic information files (CIF) for ep-threo-1b, ep-erythro-1b, rac-threo-1c, rac-erythro-1c, ep-threo-1c, and ep-erythro-1c. This material is available free of charge via the Internet at http://pubs.acs.org.

Kitamura and Nakano

(6) (7) (8) (9) (10) (11) (12) (13)

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CG025575H

Cycloalkanone-Based Threo and Erythro Aldols as Supramolecular

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