Stereochemistry of aldols: Configuration and conformation of aldols derived from cycloalkanones and aldehydes

Article abstract of DOI:10.1021/ja0110978

The structures of cycloalkanone-based threo and erythro aldols were investigated by systematic introduction of stereo-determining factors. The combination of single-crystal X-ray analysis and cryoscopic measurement and solution NMR and IR studies elucidat

Full text of DOI:10.1021/ja0110978

J. Am. Chem. Soc. 2001, 123, 8939-8950
8939
Stereochemistry of Aldols: Configuration and Conformation of
Aldols Derived from Cycloalkanones and Aldehydes
Masato Kitamura,* Keiji Nakano, Takashi Miki, Masato Okada, and Ryoji Noyori*
Contribution from the Department of Chemistry and Research Center for Materials Science,
Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan
ReceiVed April 30, 2001
Abstract: The structures of cycloalkanone-based threo and erythro aldols were investigated by systematic
introduction of stereo-determining factors. The combination of single-crystal X-ray analysis and cryoscopic
measurement and solution NMR and IR studies elucidated the detailed geometry of these typical aldols.
Currently, X-ray diffraction is the only reliable spectroscopic method to determine the relative configuration
of aldols. Empirical NMR analysis can be safely applied in only limited cases. In hydrocarbon solvents, many
aldols exist as monomers with an intramolecular OH‚‚‚OdC hydrogen bond, but some compounds are in an
equilibrium with higher aggregates via intermolecular hydrogen bonds. The aldols take various staggered
conformers, where the relative stabilities are controlled largely by torsional strain affected by the size and
nature of substituents. The intramolecular and intermolecular hydrogen bonds, gauche interactions between
the vicinal substituents, and sometimes CH/π attractions significantly influence the distribution of conformers.
The preferred structure in solution often differs greatly from the crystalline-state geometry.
Introduction
biological, chemical, and physical functions.6 In addition, aldols
are useful in synthetic chemistry, because their structural char-
acteristics allow various transformations via functional group
modifications and carbon-carbon bond-forming reactions.7,8a
The threo/erythro relative configuration, coupled with steric and
electronic properties of the R and â substituents and the
intramolecular or intermolecular hydrogen bond between the
hydroxy hydrogen and carbonyl oxygen, strongly affects the
conformation of aldols as well as the mode of intermolecular
interaction. Such features further exert a significant effect on
the nature and degree of the functions of aldol compounds and
their assembly or complexes.
Aldol is the generic name for â-hydroxy carbonyl compounds.
Threo and erythro1 (or anti and syn2) diastereomers are possible
when the compound possesses two consecutive stereogenic
carbons at the R and â positions. These stereoisomers are
selectively produced by many fundamental organic reactions,
such as the aldol reaction of ketones and aldehydes,3 reduction
of R-substituted â-keto carbonyl compounds,4 and nucleophilic
ring opening of R,â-epoxy carbonyl compounds.5 This grouping
is widely found in organic compounds that show a range of
(1) (a) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1981, 103,
2106-2108. (b) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1983,
105, 1598-1608. This unambiguous terminology accommodates mostly the
conventional aldol naming and is also applicable to the system in which
selection of the skeletal backbone is difficult. The threo and erythro
diastereomers correspond to the anti and syn isomers, respectively.2
(2) (a) Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angew.
Chem., Int. Ed. Engl. 1980, 19, 557-558. (b) Masamune, S.; Kaiho, T.;
Garvey, D. S. J. Am. Chem. Soc. 1982, 104, 5521-5523.
(3) (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000,
39, 1352-1374. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res.
2000, 33, 432-440. (c) Saito, S.; Yamamoto, H. Chem.sEur. J. 1999, 5,
1959-1962. (d) Heathcock, C. H. The Aldol Reaction: Acid and General
Base Catalysis. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 133-179. (e) Heathcock,
C. H. The Aldol Reaction: Group I and Group II Enolates. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 181-238. (f) Kim, B. M.; Williams, S. F.;
Masamune, S. The Aldol Reaction: Group III Enolates. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 239-275. (g) Rathke, M. W.; Weipert, P. Zinc Enolates:
The Reformatsky and Blaise Reactions. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, pp 277-299. (h) Paterson, I. The Aldol Reaction: Transition Metal
Enolates. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 301-319. (i) Evans, D.
A.; Nelson, J. V.; Taber, T. R. In Topics in Stereochemistry; Eliel, E. L.,
Wilen, S. H., Eds.; Wiley-Interscience: New York, 1982; Vol. 13, pp
1-115. (j) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, Chapter 2.
(4) Greeves, N. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8, pp 1-24. Noyori,
R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1994; pp 56-82.
(5) Tanner, D.; Sellien, M.; Blackvall, J.-E. J. Org. Chem. 1989, 54,
3374-3378.
(6) Biologically active compounds: Fujii, I. In ComprehensiVe Natural
Product Chemistry; Barton, D., Nakanishi, K., Meth-Cohn, O., Eds.;
Elsevier: Oxford, U.K., 1999; Vol. 1, p 424. Richardson, M.; Khosla, C.
In ComprehensiVe Natural Product Chemistry; Barton, D., Nakanishi, K.,
Meth-Cohn, O., Eds.; Elsevier: Oxford, U.K., 1999; Vol. 1, p 482. Staunton,
J.; Wilkinson, B. In ComprehensiVe Natural Product Chemistry; Barton,
D., Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier: Oxford, U.K., 1999;
Vol. 1, pp 495-532. MacMillan, J.; Beale, M. H. In ComprehensiVe Natural
Product Chemistry; Barton, D., Nakanishi, K., Meth-Cohn, O., Eds.;
Elsevier: Oxford, U.K., 1999; Vol. 2, pp 220-223. Gates, K. S. In
ComprehensiVe Natural Product Chemistry; Barton, D., Nakanishi, K.,
Meth-Cohn, O., Eds.; Elsevier: Oxford, U.K., 1999; Vol. 7, pp 507-508.
Xi, Z.; Goldberg, I. H. In ComprehensiVe Natural Product Chemistry;
Barton, D., Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier: Oxford, U.K.,
1999; Vol. 7, pp 568-571. Chemical function: Ashmann, S. M.; Arey, J.;
Atkinson, R. J. Phys. Chem. A 2000, 104, 3998-4003. Physical function:
Watanabe, H.; Seto, N. Jpn. Kokai Tokkyo Koho 1989, JP01318953.
(7) (a) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1-30. (b) Hoffmann, R. W. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 489-503. (c) Martin, S. F.; Lee, W.-C.; Pacofsky,
G. J.; Gist, R. P.; Mulhern, T. A. J. Am. Chem. Soc. 1994, 116, 4674-
4688. (d) Peterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M.
A. J. Am. Chem. Soc. 1994, 116, 11287-11314.
10.1021/ja0110978 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/24/2001

8940 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Kitamura et al.
Background and General Consideration
The determination of the relative configuration of aldols,
either threo or erythro, has long been a problem. Although X-ray
crystallographic analysis8 and chemical correlation are the most
reliable methods, the assignment is often made by the 1H NMR
method that was first postulated by Stiles in 19649 and later
extended by House (Stiles-House method).10 This empirical
rule assumes the formation of intramolecularly hydrogen-bonded
six-membered structures as shown in Figure 1. The threo isomer
exists in a conformational equilibrium between Tap and T+sc
,
in which the HR/Hâ relationship is antiperiplanar and (+)-
synclinal, respectively. In the erythro isomer, each of the two
conformers, E+sc and E-sc, has a (+/-)-synclinal HR/Hâ
relationship. Stiles originally and cautiously stated that, if both
diastereomers are monomeric with an intramolecular OH‚‚‚Od
C hydrogen bond (confirmed by IR in a dilute solution) and
the difference in the vicinal coupling constant, JR,â, is distinct,
namely, ∼2 Hz (erythro) versus large (threo), then the NMR
method can be safely used for the determination of relative
configurations. Later, considering, for some unclear reason, that
the R and â substituents prefer the equatorial orientation in an
imaginary chairlike conformation with respect to the hydrogen-
bonded HsOsCsCsCdO six-membered system,11,12 House
postulated that threo aldols possess JR,â values of 6-9 Hz and
erythro isomers show values of 2-4 Hz. This method, in fact,
was frequently used for the structural determination of cross
aldol products. However, many examples were found for open-
chain aldols which did not fit this empirical rule.13 Sometimes
the method was used rather arbitrarily without precaution, for
example, without confirming the intramolecular hydrogen bond,
resulting in serious misassignments. Gaudemer,14 Evans,3i and
Figure 1. Hydrogen-bonded conformations of (a) threo and (b) erythro
aldols. In both diastereomers, the carbonyl substituents are omitted for
convenience.
Figure 2. Possible conformations of 3-hydroxypropanal.
Heathcock3j advised that the Stiles-House method should be
carefully used for aldols having a bulky substituent at the â
position, where the enhanced gauche interaction destabilizes the
hydrogen-bonded six-membered ring. Furthermore, the forma-
tion of intermolecular hydrogen bonds likely causes a confor-
mational change which makes the NMR structural assignment
difficult.
The configuration of aldols is related to their conformation.
Carbonyl compounds are considered to form a hydrogen bond
in the CdO plane along the direction of the sp2 lone pairs of
the oxygen atom, although the Cambridge Structural Database
shows a rather broad distribution.15 On the basis of this tendency,
flexible hydrogen-bonded aldols are often depicted by a half-
chair conformation. Figure 2a shows the putative geometry of
the simplest aldol, 3-hydroxypropanal, which is characterized
by the in-plane hydrogen bond and a staggered conformation,
with respect to the R and â sp3 carbons. However, this
formulation is not appropriate. Instead, the geometry of skel-
etally unrestricted aldols approximates an “eclipsed” conforma-
tion, regardless of the presence or absence of a hydrogen bond.
Figure 2b illustrates the structure of 3-hydroxypropanal, which
possesses, among other relationships, a syn-CdO/OH relation-
ship and a C(R)sC(â) linkage coplanar with the CdO plane.
The C(R)/C(â) unit has a staggered conformation, while the OH
proton is out of the CdO plane.
(8) (a) Yoshikawa, N.; Yamada, Y. M. A.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 4168-4178. (b) Kutulya, L. A.; Vashchenko,
V. V.; Shishkin, O. V.; Drushlyak, T. G. IzV. Akad. Nauk, Ser. Khim. 1998,
2251-2257. (c) Chughtai, J. H.; Gardiner, J. M.; Harris, S. G.; Parsons,
S.; Rankin, D. W. H.; Schwalbe, C. H. Tetrahedron Lett. 1997, 38, 9043-
9046. (d) Kutulya, L. A.; Patsenker, L. D.; Vashchenko, V. V.; Kuznetsov,
V. P.; Kulishov, V. I.; Surov, Y. N.; Kravets, V. V. IzV. Akad. Nauk, Ser.
Khim. 1995, 1247-1255. (e) Kutulya, L. A.; Vashchenko, V. V.; Kuznetsov,
V. P.; Lakin, E. E. Zh. Strukt. Khim. 1994, 35, 133-135. (f) Schwerdtfeger,
A. E.; Chan, T. H.; Thomas, A. W.; Strunz, G. M.; Salonius, A.; Chiasson,
M. Can. J. Chem. 1993, 71, 1184-1199. (g) Jubert, C.; Nowotny, S.;
Kornemann, D.; Antes, I.; Tucker, C. E.; Knochel, P. J. Org. Chem. 1992,
57, 6384-6386. (h) Nakamura, E.; Kuwajima, I.; Williard, P. G. Acta
Crystallogr. 1991, C47, 984-985. (i) Joseph-Nathan, P.; Villagomez, J.
R.; Rajos-Gardida, M.; Roman, L. U.; Hernandez, J. D. Phytochemistry
1989, 28, 2397-2401. (j) Lodge, E. P.; Heathcock, C. H. J. Am. Chem.
Soc. 1987, 109, 3353-3361. (k) Haner, R.; Schweizer, W. B.; Seiler, P.;
Seebach, D. Chimia, 1986, 40, 97-98. (l) Heathcock, C. H.; Young, S. D.;
Hagen, J. P.; Pirrung, M. C.; White, C. T.; VanDerveer, D. J. Org. Chem.
1980, 45, 3846-3856. (m) Harlow, R. L.; Simonsen, S. H. Cryst. Struct.
Commun. 1976, 5, 471-476.
(9) Stiles, M.; Winkler, R. R.; Chang, Y.-L.; Traynor, L. J. Am. Chem.
Soc. 1964, 86, 3337-3342.
(10) House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D.
J. Am. Chem. Soc. 1973, 95, 3310-3324.
(11) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920-1923.
(12) The six-membered structures do not contain any unfavored 1,3-
diaxial repulsion, because the CdO plane is included in the ring to make
only the π orbitals axial.
(13) (a) Canceill, J.; Basselier, J.-J.; Jacques, J. Bull. Soc. Chim. Fr. 1967,
1024-1030. (b) Auerbach, R. A.; Kingsbury, C. A. Tetrahedron 1971, 27,
2069-2078. (c) Mulzer, J.; Zippel, M.; Bru¨ntrup, G.; Segner, J.; Finke, J.
Liebigs Ann. Chem. 1980, 1108-1134. (d) Heng, K. K.; Simpson, J.; Smith,
R. A. J. J. Org. Chem. 1981, 46, 2932-2934.
(14) Gaudemer, A. In Stereochemistry, Fundamentals and Methods;
Kagan, H. B., Ed.; Thieme: Stuttgart, 1977; Vol. I, pp 69-71.
(15) Quinkert, G.; Egert, E.; Greisinger, C. In Aspects of Organic
Chemistry: Structure; VCH: Weinheim, 1996; pp 431-434.

Stereochemistry of Aldols
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8941
intramolecular hydrogen bond. In accord with this view, the
Cambridge crystallographic data of certain crystalline, intramo-
lecularly hydrogen-bonded acyclic aldols gave the values of ω1
) -14.4°, ω2 ) 57.9° (or -4.4° and 72.6°, respectively), θ )
78.1°, and φ ) 7.4°.
In certain cases, an intramolecular hydrogen bond forms at
the cost of an increase in torsional strain. Thus, some oligomeric
or polymeric aldols having a similar conformation would form
via intermolecular hydrogen bonds. Here, the stabilization might
be achieved with an ideal in-plane OH‚‚‚OdC interaction (θ
) 90°).
Results and Discussion
We investigated here the structures of typical cycloalkanone-
derived aldol systems in which stereochemical and structural
determinants are systematically incorporated. The three sets of
threo and erythro aldols 1-3 were selected, because these are
products of standard stereoselective aldol reactions and also are
pertinent to the stereochemical argument. Compounds 1 and 2
are constructed from cyclohexanones and aldehydes, the dif-
ference being the absence or presence of a trans alkyl substituent
at C(3). Setting the dihedral angle ω1 to ∼0 or 120° simplifies
the argument. The aldols 3 are cyclopentanones possessing
vicinal, trans substituents at C(2) and C(3). Molecular modeling
suggests that, 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 (computer modeling). The relative
stabilities of aldol conformers are further controlled by various
attractive and repulsive interactions. Subtype a (Râ ) c-C6H11)
denotes the aldols produced from cyclohexanecarbaldehyde,
while subtype b (Râ ) C6H5) aldols are derived from benzal-
dehyde. The difference in the aliphatic and aromatic groups may
affect the conformational stability of the aldols.
Figure 3. Geometric parameters for aldols. The ω1 and ω2 values are
defined as the OdCsC(R)sC(â) and CsC(R)sC(â)sO dihedral
angles, respectively. The θ and φ parameters show hydrogen-bond
directionality in a spherical coordinate system.
Figure 4. Structure of 3-hydroxypropanal obtained by DFT calculation
at the B3LYP/6-311++G(d,p) level. For definitions of ω1, ω2, θ, and
φ, see Figure 3.
Aldols are ketones or aldehydes that possess a hydroxyalkyl
group at C(R). Thus, unless otherwise constrained, the energy
minima are obtained primarily at OdCsC(R)sC(â) dihedral
angles (ω1) of 0, 120, and -120°, and C(CdO)sC(R)sC(â)s
O dihedral angles (ω2) of 60, 180, and -60°. Figure 3 shows
the general geometries of aldols having an intramolecular and
intermolecular hydrogen bond. The position of the OH proton
is defined by the angles θ and φ in the polar coordinates. The
syn-CdO/OH eclipsed conformation of 3-hydroxypropanal in
Figure 2 has ω1 ) 0° and ω2 ) 60° and is distinct from the
half-chair conformation with ω1 ) ω2 ) 60°, θ ) 90°, and φ
) 30°. The presence of an intramolecular hydrogen bond only
slightly distorts the eclipsed geometry, as illustrated in Figure
4. A density functional theory (DFT) calculation at the B3LYP/
6-311++G(d,p) level led to an optimized geometry at ω1 )
-5.2°, ω2 ) 62.7°, θ ) 66.3°, and φ ) 8.3°. Because of the
electrostatic nature of the OH‚‚‚OdC interaction with a little
charge-transfer contribution (∼20%), the coplanarity (θ ) 90°)
seen in the half-chair form is not requisite for the cyclic
structure. In addition, the φ value is close to 0° but not to 30°.
The hydrogen bond stabilizes the six-membered cyclic structure
by 3.8 kcal/mol, in comparison to the non-hydrogen-bonded syn-
CdO/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 the torsional
strain is the major factor controlling the geometry. With
skeletally flexible aldols, nine staggered conformers are possible,
while two of these conformers having a syn-CdO/OH relation
(ω1 ) 0° and ω2 ) 60 or -60°) are stabilized by an
The degree of aggregation was determined by a cryoscopic
method, while the nature of the hydrogen bonds was elucidated
by IR and NMR. A detailed examination revealed that the
unambiguous determination of relative configuration can be
made only by X-ray crystallographic analysis or chemical
transformation from/to stereoauthentic compounds. The con-
formations in the crystalline and solution phases were shown
to be subtly affected by various intramolecular and intermo-
lecular forces. NMR analysis provided useful information for
the structures in solution, but such data should be treated
carefully.
Preparation of Standard Aldols. Racemic aldols were used
for this investigation. Diastereomeric threo- and erythro-1a were

8942 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Kitamura et al.
synthesized stereoselectively by reacting lithium16 and tetrabu-
tylammonium17 enolate of cyclohexanone with cyclohexanecar-
baldehyde, respectively. A 33:67 mixture of threo-1b and
erythro-1b was prepared by the reaction of cyclohexanone and
benzaldehyde in aqueous sodium hydroxide solution.18 The
C(3)-ethylated compounds, threo-2a and threo-3a, were syn-
thesized with a > 99:1 stereoselectivity by Cu(I)-catalyzed 1,4-
addition19 of diethylzinc to 2-cyclohexenone or 2-cyclopenten-
one, followed by the trapping of the in situ formed ethylzinc
enolates with cyclohexanecarbaldehyde. The vicinal carbon-
carbon bond formation occurred with perfect trans selectivity.
With benzaldehyde, the aldols 2b and 3b were produced as 81:
19 and 55:45 mixtures of threo and erythro isomers. When boron
trifluoride was added in the Zn enolate reaction, threo- and
erythro-2a were produced in a 50:50 ratio. All the stereochemi-
cally pure aldols were obtained by chromatographic separation
followed by recrystallization, if possible. The eleven different
aldols thus obtained were subjected to structural elucidation by
molecular weight measurement, NMR and IR spectroscopy, and
X-ray diffraction.
Molecular Structures in Crystalline State: X-ray Struc-
tural Analysis. The configurations of the crystalline aldols 1-3
were determined by X-ray analysis. Noncrystalline threo-3b was
derivatized to the crystalline p-bromobenzoate whose structure
was analyzed by X-ray diffraction. Single crystals of threo-1a,
erythro-1a, threo-1b, erythro-1b, threo-2a, erythro-2a, threo-
2b, erythro-2b, threo-3a, and erythro-3b were obtained by
recrystallization, while threo-3b did not crystallize. These
crystallographic data are summarized in Table 1. Figure 5 shows
the molecular structures with selected interatomic distances,
bond angles, dihedral angles, and the position of the hydroxy
proton.
The simple cyclohexanone-derived aldols 1 crystallized in
the monoclinic system with a P21/a, P21/c, or P21/n space group.
The compounds threo-1a, erythro-1a, and threo-1b contain an
intramolecular hydrogen bond forming a six-membered cyclic
framework with OH‚‚‚OdC bond distances of 1.81, 2.48, and
2.15 Å and the O‚‚‚HsO bond angles of 133.36, 132.0, and
133.03°, respectively. The hydroxy protons are located at the
point of θ ) 55.2-69.7° and φ ) -5.7-10°, in good agreement
with the calculated values for 3-hydroxypropanal (Figure 4).
In erythro-1a, the OH proton interacted not only with the Cd
O oxygen in the same molecule but also with the CdO of the
other enantiomeric aldol, and as a result, the aldol formed a
heterochiral dimer. The erythro-1b crystal has no intramolecular
hydrogen bond, but instead, a pair of the enantiomeric aldol
molecules form a heterochiral dimer with the R22(12) graph
set20 via an intermolecular OH‚‚‚OdC interaction. These dimeric
aldols have θ and φ values of 77.6-89° and 65.2-82.1°,
respectively, giving a near-linear OH‚‚‚OdC bond. The dis-
tances between one of the C(3)sH protons and the cyclohexyl
methine carbon in threo-1a and erythro-1a are 2.22-2.65 and
2.60-2.63 Å, respectively. These values are close to the sum
of the van der Waals radii of two hydrogen atoms, 2.4 Å.
Notably, replacement of the cyclohexyl with a phenyl group
shortened the H‚‚‚C distances to 2.71 (threo-1b) and 2.69 (2.76)
Å (erythro-1b), which were 5-8% shorter than the distance of
2.9 Å, indicating the existence of a CH/π interaction between
the C(3)-H and the phenyl carbon.21 As expected, all four of
these aldols have an equatorially oriented C(2) substituent, with
respect to the chairlike cyclohexanone framework possessing
staggered C(sp3)sC(sp3) linkages and a small OdCsC(R)s
C(â) dihedral angle (ω1), 2.7-7.6°, close to the standard 0°.
The presence of an ethyl substituent at C(3) totally changes
the crystalline structures. The crystals of aldols 2 were mono-
clinic or tetragonal with a P21/c, P21/a, P4/n, or Cc space group.
None of these crystals had an intramolecular hydrogen bond;
rather, the aldol molecules interacted intermolecularly to result
in polymeric structures. Among them, threo-2a, erythro-2a, and
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°). The ω1 dihedral angle ranges from
-102.4 to -111.3°, which is to be compared to the standard
value of -120°, while the C(sp3)sC(sp3) linkages have a normal
staggered geometry. The cyclohexanone skeletons are character-
ized by the trans diaxial substituents at C(2) and C(3), with the
dihedral angles ranging from 152 to 168.8°. Such unusual
conformations were due to the substantial repulsion of the vicinal
large substituents, but the local energetic penalty was compen-
sated for by forming multiple intermolecular hydrogen bonds
and by improving the packing efficiency into the unit cell.
The cyclopentanone aldol threo-3a crystallized in a mono-
clinic system with a P21/a space group, while erythro-3b crystals
had an orthorhombic system with a Pbca space group. Both
threo-3a and erythro-3b form polymeric structures by intermo-
lecular OH‚‚‚OdC hydrogen bonds. The hydroxy protons are
directed toward the oxygen sp2 lone pair, though not in the Cd
O plane (θ ) 54.6-70.4°, φ ) 21.4-41.3°). The cyclopen-
tanone ring of threo-3a has an envelope conformation with an
ω1 dihedral angle of -56.4°. In 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 to -111° angles for cyclohexanone derivatives 2.
Furthermore, the CsC(2)sC(3)sC dihedral angles involving
the C(2) and C(3) substituents, 86.6 and 89.6°, respectively,
are much smaller than the values of the trans disubstituted
cyclohexanones 2, 152-169°. In erythro-3b, a CH/π attraction21
is present between one of the C(3)sethyl methylene protons
(unlike C(3)sH in threo- and erythro-1b) and the phenyl carbon,
as judged by the short H‚‚‚C distance, 2.69 Å.
Such unique crystalline structures would already recommend
the careful use of the Stiles-House structural analysis in
solution.
Figure 6 illustrates the statistic lone pair directionality in the
OH‚‚‚OdC interaction in aldols. The data were collected from
the present study and the Cambridge Structural Database.22 The
result indicates that the position of the hydroxy proton is highly
flexible, depending on the structures. Owing to the skeletal
restriction, intramolecularly hydrogen-bonded monomers gave
small φ values (∼0°), whereas the cyclic dimers gave values
larger than 60°. Such skeletal constraints were relieved in the
polymeric aldols, which formed intermolecular hydrogen bonds
largely along the direction of the CdO sp2 lone pairs. Such
hydrogen bonds are enthalpically more favored. In fact, 21
(16) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56,
2098-2106.
(17) Noyori, R.; Yokoyama, K.; Sakata, J.; Kuwajima, I.; Nakamura,
E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99, 1265-1267.
(18) Billimoria, J. D. J. Chem. Soc. 1955, 1126-1129.
(19) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141-5144. Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R.
Bull. Chem. Soc. Jpn. 2000, 73, 999-1014.
(21) Nishio, M.; Hirota, M.; Umezawa, Y. The CH/π Interaction; Wiley-
VCH: New York, 1998; p 66.
(20) Bernstein, J.; Davis, R.; Shimoni, L.; Chang, N.-L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1555-1573. Etter, M. C. Acc. Chem. Res. 1990,
23, 120-126. Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr.
1990, B46, 256-262. Etter, M. C. J. Phys. Chem. 1991, 95, 4601-4610.
(22) Allen, F. H.; Bellard, S.; Brice, M. D.; Cartwright, B. A.; Doubleday,
A.; Higgs, H.; Hummelink, T.; Hummelink-Peters, B. G.; Kennard, O.;
Motherwell, W. D. S.; Rodgers, J. R.; Watson, D. G. Acta Crystallogr.
1979, B35, 2331-2339.

Stereochemistry of Aldols
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8943
Table 1. Crystallographic Data for 1, 2, and 3a
Compunds 1
erythro-1a
C13H22O2
compound
mol formula
mol wt
threo-1a
C13H22O2
210.31
threo-1b
C13H16O2
204.27
erythro-1b
C13H16O2
204.27
210.31
cryst color, habit
cryst size/mm3
cryst syst
lattice type
space group
a/Å
colorless, prismatic
0.20 × 0.10 × 0.20
monoclinic
primitive
P21/a
10.5975(5)
10.1387(7)
11.5644(5)
90
100.719(3)
90
1220.8(1)
4
colorless, prismatic
0.20 × 0.20 × 0.20
monoclinic
primitive
colorless, prismatic
0.20 × 0.20 × 0.50
monoclinic
primitive
colorless, prismatic
0.05 × 0.10 × 0.50
monoclinic
primitive
P21/a
15.577(4)
5.714(5)
26.195(3)
90
106.31(1)
90
2237(2)
8
P21/c
P21/n
11.465(2)
10.190(1)
11.667(1)
90
114.924(10)
90
1236.1(3)
4
1.130
10.252(3)
11.273(3)
10.421(2)
90
112.67(2)
90
1111.3(5)
4
1.215
b/Å
c/Å
R/deg
â/deg
γ/deg
vol/Å3
Z
F
calcd/g cm-3
1.140
2054
1940 (Rint ) 0.022)
Lorentz polarization
1.213
3884
total reflections
unique reflections
corrections
1606
1861
1523 (Rint ) 0.041)
Lorentz polarization
absorption
(trans. factors:
0.7677-1.0000)
1755 (Rint ) 0.043)
Lorentz polarization
secondary extinction
(coefficient:
3731 (Rint ) 0.105)
Lorentz polarization
absorption
(trans. factors:
0.6721-1.0000)
secondary extinction
(coefficient:
2.05553 × 10-5
)
3.23304 × 10-6
direct methodsc
1709
)
structure solution
no. of observations
direct methodsb
1276
direct methodsb
1337
direct methodsc
1058
(I > 3.00σ(I))
R
Rw
0.070
0.074
0.085
0.107
0.058
0.044
0.055
0.039
Compounds 2
erythro-2a
C15H26O2
compound
mol formula
mol wt
threo-2a
C15H26O2
238.37
threo-2b
C15H20O2
232.32
erythro-2b
C15H20O2
232.32
238.37
cryst color, habit
cryst size/mm3
cryst syst
lattice type
space group
a/Å
colorless, prismatic
0.20 × 0.30 × 0.40
monoclinic
primitive
P21/c
9.456(2)
5.989(1)
25.338(1)
90
100.40(1)
90
1411.4(5)
4
1.122
2498
colorless, prismatic
0.10 × 0.20 × 0.50
monoclinic
primitive
P21/a
9.654(1)
13.835(2)
10.6001(8)
90
98.179(8)
90
1401.3(2)
4
1.130
colorless, prismatic
colorless, prismatic
0.50 × 0.10 × 0.10
monoclinic
C-centered
Cc
22.200(7)
11.977(4)
10.360(7)
90
102.61(4)
90
0.50 × 0.50 × 0.30
tetragonal
primitive
P4/n
18.217(3)
18.217(3)
8.387(3)
90
90
90
2782.3(8)
8
1.109
b/Å
c/Å
R/deg
â/deg
γ/deg
vol/Å3
2688(1)
8
1.148
1844
Z
F
calcd/g cm-3
total reflections
unique reflections
corrections
2330
2404
2341 (Rint ) 0.066)
Lorentz polarization
absorption
(trans. factors:
0.6915-1.0000)
decay (-14.54% decline)
secondary extinction
(coefficient:
2187 (Rint ) 0.027)
Lorentz polarization
1788 (Rint ) 0.067)
Lorentz polarization
absorption
(trans. factors:
0.4504-1.0000)
secondary extinction
(coefficient:
Lorentz polarization
secondary extinction
(coefficient:
4.06736 × 10-6
)
1.73621 × 10-6
)
2.64278 × 10-6
direct methodsd
1734
)
structure solution
no. of observations
direct methodsb
1120
direct methodsd
1609
direct methodsc
1179
(I > 3.00σ(I))
R
Rw
0.078
0.089
0.051
0.046
0.082
0.077
0.070
0.053
Compounds 3
erythro-3b
C14H18O2
compound
mol formula
mol wt
threo-3a
C14H24O2
224.34
p-bromobenzoate of threo-3b
C21H21O3Br
401.30
218.29
cryst color, habit
cryst size/mm3
cryst syst
lattice type
space group
colorless, prismatic
0.20 × 0.20 × 0.30
monoclinic
primitive
P21/a
colorless, prismatic
0.50 × 0.30 × 0.10
orthorhombic
primitive
colorless, prismatic
0.30 × 0.30 × 0.30
monoclinic
primitive
P21/n
Pbca

8944 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Table 1. (Continued)
Kitamura et al.
Compounds 3 continued
a/Å
b/Å
c/Å
9.249(6)
14.702(7)
10.628(6)
90
110.08(4)
90
1357(1)
4
23.425(4)
14.245(3)
7.318(2)
90
90
90
2442(1)
8
1.187
2126
10.083(2)
14.058(1)
13.804(2)
90
98.99(1)
90
1932.7(4)
4
1.379
R/deg
â/deg
γ/deg
vol/Å3
Z
F
calcd/g cm-3
1.098
2261
total reflections
unique reflections
corrections
3217
2117 (Rint ) 0.079)
Lorentz polarization
secondary extinction
(coefficient:
3028 (Rint ) 0.224)
Lorentz polarization
absorption
Lorentz polarization
secondary extinction
(coefficient:
(trans. factors:
1.58036 × 10-5
)
9.16900 × 10-6
)
0.4496-1.0000)
secondary extinction
(coefficient: 2.05595 × 10-7
direct methodsd
2292
)
structure solution
no. of observations
direct methodse
1158
direct methodsc
1300
(I > 3.00σ(I))
R
Rw
0.065
0.074
0.068
0.066
0.125
0.134
a Function minimized by ∑ω(|Fo| - |Fc|)2. b SIR92: Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, M.; Giacovazzo, C.; Guagliardi, A.;
Polidori, G. J. Appl. Crystallogr. 1994, 435. c SAPI91: Fan, H.-F. Structure Analysis Program with Intelligent Control; Rigaku Corporation:
Tokyo, Japan, 1991. d SIR88: Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Polidori, G.; Spagna, R.; Viterbo, D. J.
Appl. Crystallogr. 1989, 389. e SAPI90: Fan, H.-F. Structure Analysis Program with Intelligent Control; Rigaku Corporation: Tokyo, Japan, 1990.
compounds among the total of 36 crystalline aldols were
polymeric, indicating that intermolecular hydrogen bonds
facilitate crystal lattice formation.
Infrared Spectroscopy. To suitably evaluate the solution
structures of aldols 1-3, the patterns of hydrogen bonds must
be clarified. To detect the presence and define the nature of
these aldols, whether hydrogen-bonded intramolecularly or
intermolecularly, their IR spectra were taken by changing the
concentration from 100 to 500 mM in benzene. Table 3 shows
the observed stretching vibration absorption bands of the
hydroxy and carbonyl groups. Although a similar aggregation
state is accessible in cyclohexane at a concentration of lower
than ∼15 mM, reliable spectra with a reasonable signal-to-noise
ratio could not be obtained.
Molecular Weight Determination. The conformational
analysis in solution (Figure 1) assumes the monomeric structures
for aldols. The aggregation states of the aldols 1-3 in
hydrocarbons were determined by a cryoscopic molecular weight
measurement using a 100-500 mM benzene solution or a ∼10
mM cyclohexane solution. The number-average molecular
weight (MWobs) and the aggregation state (MWobs/MWcalcd) were
calculated on the basis of the molar depression values of 5.1623
(benzene) and 22.3 (cyclohexane) and the monomeric molecular
weights of 210.32 (1a), 204.27 (1b), 238.37 (2a), 232.32 (2b),
224.34 (3a), and 218.29 (3b). The results are listed in Table 2.
In all cases, the MWobs/MWcalcd ratio ranged between 1 and 2,
indicating that the aldols exist as an equilibrium mixture of the
monomer and some aggregates. In a 10-13 mM cyclohexane
solution at ∼6 °C, threo-1a, erythro-1a, threo-1b, erythro-1b,
Because the frequency is proportional to the square root of
the reduced mass, OsH bands are more sensitive to hydrogen
bonding than CdO bands. At a concentration of 100 mM in
benzene, threo-1a, erythro-1a, threo-1b, erythro-1b, threo-2a,
threo-3a, and threo-3b exhibited broad OsH bands at 3477-
3577 cm-1, and in the range 100-500 mM, virtually no band
shifts were observed. The broad shape of signals with no
concentration effect indicates the presence of intramolecular
hydrogen bonds in these aldols. On the other hand, one sharp
and one broad band were observed in a ∼3:1 ratio at 3604 and
3475 cm-1 for erythro-2a, and at 3576 and 3483 cm-1 for
erythro-2b in 100 mM benzene solutions. The ratio of the two
bands was changed to ∼1:1 as the concentration was increased
to 500 mM. A 100 mM benzene solution of erythro-3b also
exhibited a sharp band at 3581 cm-1 and a broad one at 3491
cm-1; a good spectrum could not be obtained at concentrations
greater than 300 mM, owing to the solubility problem. The sharp
and broad bands are assignable to the stretching vibrations of a
free hydroxy and intermolecularly hydrogen-bonded hydroxy
group, respectively. A 100 mM solution of threo-2b exhibited
one sharp and two broad bands in a ∼2:2:1 ratio at 3567, 3512,
and 3424 cm-1, respectively. In a 500 mM solution, the intensity
of the 3567 cm-1 band was halved, while the strength of the
3424 cm-1 band was doubled, with the 3512 cm-1 band
remaining unchanged. These bands can be assigned to free,
intramolecularly hydrogen-bonded and intermolecularly hydrogen-
bonded hydroxy groups, respectively. These IR observations
are consistent with the cryoscopic experiments. The compounds
threo-2a, erythro-2a, threo-3a, and threo-3b gave an MWobs
/
MWcalcd value of 0.95-1.25, suggesting the preference for the
monomeric form. With threo-2b and erythro-2b under similar
conditions, however, the values were increased to 1.47-1.62
and 1.72-1.96, respectively. Assuming a monomer-dimer
equilibrium, 63-77% of threo-2b and 84-98% of erythro-2b
exist in the dimeric form, although the participation of higher
aggregates is also conceivable. The high crystallinity of erythro-
3b did not allow a molecular weight measurement. In more polar
benzene, the MWobs/MWcalcd value of all aldols never exceeded
1.13, even in a solution with a concentration that was 10 times
higher. However, when the concentration was increased from
100 mM to 300 or 500 mM, the aldols behaved similarly to
those in a 10 mM cyclohexane solution. Thus, the aggregation
states of threo- and erythro-1a, threo- and erythro-1b, and threo-
2a were in the range 1.05-1.24, while the values of erythro-
2a, threo-2b, and erythro-2b were higher, from 1.44 to 1.66.
Thus, 61-80% of these aldols exist as dimers in solutions with
concentrations greater than 300 mM.
(23) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028-4036.

Stereochemistry of Aldols
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8945
Figure 5. Molecular structures of the aldols 1-3 in the crystalline state. The interatomic distances are in angstroms, and the angles are in degrees.
The dotted and broken lines indicate hydrogen bonds and CH/π interactions, respectively. For definitions of ω1, ω2, θ, and φ, see Figure 3. The IR
data were taken by a KBr method.
forming intermolecular hydrogen bonds tended to show higher
aggregation states.
intermolecular hydrogen bonds, however, tended to give signals
at a higher magnetic field as concentrations were lowered,
because the degree of the magnetic shielding effect was
increased as the hydrogen bond became weak.
NMR Spectroscopy. NMR spectra provide various informa-
1
tion about the aldol structures in solution. H and 13C NMR
1
experiments were conducted in 10 and 2 mM cyclohexane-d12
solutions at 23 °C to investigate the presence of hydrogen bonds
and to obtain conformational information on the aldol molecules
in solution. The results are shown in Table 4.
The H chemical shifts of OH were little affected by the
concentration of threo-1a, erythro-1a, threo-1b, erythro-1b,
threo-2a, threo-3a, or threo-3b. This phenomenon was attributed
to the absence of an intermolecular hydrogen bond and probably
to the formation of an intramolecular hydrogen bond. In the
cases of erythro-2a, threo-2b, and erythro-2b, the OH signal
1
The H and 13C chemical shifts of C(R)H and C(â)H were
insensitive to concentration. The hydroxy protons involved in

8946 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Kitamura et al.
Table 2. Molecular Weights and Aggregation States of Aldols 1-3
aggregation
state in crystal
a
compound
solvent
conc, mM
MWobs
MWobs/MWcalcd
threo-1a
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
benzene
benzene
benzene
cyclohexane
cyclohexane
cyclohexane
cyclohexane
300
200
100
13
300
200
100
13
300
200
100
13
300
200
100
13
500
300
100
13
500
300
100
13
500
300
100
11
500
300
100
10
221-229
204-229
192-201
253
1.05-1.09
0.97-1.09
0.91-0.96
1.20
monomer
erythro-1a
threo-1b
223-226
228-230
222-226
245-261
217-230
230-242
210-226
223-230
241-243
226-228
190-210
193-215
291-296
274-282
247-270
245-259
344-352
302-308
246-255
271-298
379-385
332-340
237-241
341-377
340-345
303-310
245-250
399-456
232-246
239-261
-
1.06-1.07
1.08-1.09
1.05-1.07
1.17-1.25
1.06-1.13
1.13-1.19
1.03-1.11
1.09-1.12
1.18-1.19
1.11-1.12
0.93-1.03
0.95-1.05
1.22-1.24
1.15-1.18
1.03-1.13
1.03-1.09
1.44-1.48
1.26-1.29
1.03-1.07
1.14-1.25
1.63-1.66
1.43-1.46
1.02-1.04
1.47-1.62
1.46-1.48
1.30-1.33
1.05-1.07
1.72-1.96
1.04-1.10
1.10-1.20
-
dimer
monomer
dimer
erythro-1b
threo-2a
polymer
polymer
tetramer
polymer
erythro-2a
threo-2b
erythro-2b
threo-3a
threo-3b
erythro-3b
13
13
polymer
-
polymer
5-13b
a MWcalcd: 1a (210.32), 1b (204.27), 2a (238.37), 2b (232.32), 3a (224.34), 3b (218.29). b Crystallization occurred during measurement.
frequently been used for the configurational assignment of aldols
(Stiles-House rule). For such an assignment, the aldol must
have a monomeric, intramolecularly hydrogen-bonded, six-
membered structure for the conformational arguments of Figure
1. Judging from the cryoscopic, IR, and NMR study, the four
aldols of series 1, threo-2a, threo-3a, and threo-3b are suitable
for the NMR analysis, because they satisfy the prerequisite in
a hydrocarbon solution. If applied rigorously, only series 1
fulfills Stiles’ original criteria,9 where both threo and erythro
diastereomers have equally monomeric, hydrogen-bonded struc-
tures in solution. Great care must be taken for the other aldols
with intermolecular hydrogen bonds. In the case of 2a, 3a, and
3b, only one of these diastereomers satisfies the conditions for
analysis.
Figure 6. Plots of the lone pair directionality in OH‚‚‚OdC bonds.
The filled symbols refer to the results obtained in our laboratories
(unpublished data included). The open symbols refer to the values taken
from the Cambridge Structural Database.
The JR,â values of the simple cyclohexanone-derived aldols
1 are fully consistent with the Stiles-House empirical rule that
a threo isomer exhibits the vicinal coupling constant of 6-9
Hz, and an erythro isomer 2-4 Hz.10 In fact, threo-1a, erythro-
1a, threo-1b, and erythro-1b gave the JR,â values 7.3, 2.7, 8.8,
and 2.4 Hz, respectively. These aldols are thought to have the
Tap or E-sc conformations, shown in Figure 1 (also Figure 3a)
with an equatorial C(â) substituent. The crystalline state
structures of Figure 5 also fit with this view, with the exception
of erythro-1b, which forms intermolecular hydrogen bonds
(Figure 3b).
shifted from δ 1.65 to 1.60, from δ 3.37 to 3.31, and from δ
2.87 to 2.78, respectively, upon decreasing the concentration
from 10 to 2 mM. The higher-field shift by 0.05-0.09 ppm
revealed the presence of an intermolecular hydrogen bond. This
interpretation is in full accord with the cryoscopic and IR
analyses. The presence of an intermolecular hydrogen bond in
erythro-3b was suggested by the IR and molecular weight
measurement but remained unclear. However, the presence of
such a bond was verified by NMR analysis, which showed the
OH signal at δ 2.77 in a 10 mM solution and δ 2.69 in a 2 mM
solution, both at 50 °C.
The Stiles-House rule does not apply for aldols 2 having an
ethyl substituent at C(3). Instead, the forcing application leads
to an erroneous, opposite assignment for threo-2a and erythro-
2a. Thus, the threo isomer is monomeric and does form an
intramolecular hydrogen bond, but the observed JR,â value of
Validity of the Stiles-House Rule. Thanks to their high
sensitivity to conformations, NMR coupling constants have

Stereochemistry of Aldols
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8947
Table 3. Infrared Stretching Absorption Bands of Hydroxy and
Carbonyl Groups of Aldols 1-3 in Benzenea
The vicinal coupling constants of cyclopentanone aldols
threo- and erythro-3b (7.8 and 3.0 Hz) seem consistent with
the empirical rule. However, no intramolecular hydrogen bond
is observed in the erythro isomer.
frequency, cm-1
compound conc, mM
OsH
CdO
Origin of Conformational Preference. The conformational
issue is twofold, involving both the cycloalkanone geometry
and the aldol structure, and these two are interrelated. The
structures of 1-3 in solution, inferred from NMR, do not always
follow those in crystals, which are determined by the total
balance of a variety of weak forces working in an intra- or
intermolecular way. Many of the aldols are flexible and are in
an equilibrium of various conformers in solution. Figure 7
depicts six staggered conformations possible for each threo and
erythro isomer of cyclohexanone aldols 1 and 2. The prefixes
eq and ax refer to the diequatorial and diaxial orientations,
regarding the C(2) and C(3) substituents in the ring. As noted
earlier, T and E represent threo and erythro relative configura-
tions, while ap, +sc, and -sc express antiperiplanar, (+)-
synclinal, and (-)-synclinal staggered conformations in terms
of HR and Hâ, respectively. Among various conformers, only
eq-Tap, eq-T+sc, eq-E+sc, and eq-E-sc involve an intramolecular
hydrogen bond. The reported J values of the rigidly fixed
steroidal aldols24 suggest that the vicinal coupling in Tap and
Eap with an HR-C-C-Hâ dihedral angle of 180° is 10 Hz,
and the values of other synclinal conformers with the dihedral
angle of 60° are 2 Hz. Table 5 summarizes the distribution of
conformers of the aldols inferred from the NMR coupling
constants.
threo-1a
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
500
300
100
300b
100
3553
3553
3553
3574
3575
3577
3573
3573
3573
3573
3573
3573
3541
3542
3542
1697
1697
1697
1701
1701
1701
1698
1698
1698
1701
1701
1701
1698
1698
1698
1705
1705
1706
erythro-1a
threo-1b
erythro-1b
threo-2a
erythro-2a
threo-2b
3604 (s), 3475 (br) (∼1:1)
3604 (s), 3475 (br) (∼2:1)
3604 (s), 3475 (br) (∼3:1)
3567 (s), 3506 (br), 3424 (br) (∼1:2:2) 1702
3567 (s), 3512 (br), 3424 (br) (∼3:4:3) 1702
3567 (s), 3512 (br), 3424 (br) (∼2:2:1) 1701
erythro-2b
threo-3a
3571 (s), 3464 (br) (∼1:1)
1702
1702
1703
1726
1726
1726
1722
1722
1722
-
3575 (s), 3474 (br) (∼2:1)
3576 (s), 3483 (br) (∼3:1)
3492
3492
3492
threo-3b
3477
3477
3477
erythro-3b
-
The substituents of cyclohexanone rings tend to take an
equatorial orientation, but the geometry of 1 and 2 is influenced
by the aldol moiety that forms intramolecular or intermolecular
hydrogen bonds. The conformation of the six-membered ring
is largely affected by the substituents (Figure 8) and various
intermolecular interactions. Notably, threo-2a, threo-2b, and
erythro-2b gave a large coupling constant between C(2)H and
C(3)H (8-9.3 Hz), indicating the chairlike cyclohexanone
structure with two equatorial substituents (Figure 8). In contrast,
in all of the crystals of 2, the cyclohexanone ring has a diaxial
conformer (Figure 5). The smaller J2,3 value (4.9-5.4 Hz) for
erythro-2a suggests the contribution of such a diaxial conforma-
3581 (s), 3491 (br) (∼2:1)
1741
a Measured at 23 °C using an optical path length of 0.025 mm.
b Unmeasurable because of the low solubility.
2.3 Hz nevertheless disagrees with the expected 6-9 Hz value.
Furthermore, the erythro isomer equilibrating with the dimer
gave a value of 7.3 Hz, rather than the expected 2-4 Hz. Thus,
the relative magnitudes were reversed. In a similar manner,
threo-2b and erythro-2b, which exist as an equilibrium mixture
of the monomer and aggregates, gave JR,â values 3.9 and 4.4
Hz, values totally different from the 6-9 and 2-4 Hz values
predicted from the empirical rule, respectively.
1
Table 4. Selected H and 13C NMR Data for 1, 2, and 3 in Cyclohexane-d12 at 23 °C
1H NMR
13C NMR
δ, ppm
C(R)
δ, ppm
C(â)H
coupling constant, Hz
compound
conc, mM
OH
C(R)H
JR,â
J2,3
C(CdO)
C(â)
threo-1a
10
2
10
2
10
2
10
2
10
2
10
2
10
2
10
2
3.04
3.03
2.43
2.42
3.69
3.68
2.87
2.86
2.36
2.35
1.65
1.60
3.37
3.31
2.87
2.78
2.56
2.55
3.94
3.93
2.77
2.69
3.40
3.39
3.69
3.69
4.63
4.63
5.30
5.30
3.15
3.15
3.72
3.72
4.81
4.79
5.14
5.14
3.24
3.25
4.62
4.62
5.11
5.11
2.36
2.36
2.32
2.32
2.38
2.38
2.45
2.45
2.29
2.29
2.33
2.32
2.57
2.58
2.53
2.53
1.84
1.84
1.95
1.95
2.06
2.06
7.3
7.3
2.7
2.7
8.8
8.8
2.4
2.4
2.3
2.3
7.3
7.3
3.9
3.9
4.4
4.4
5.4
5.4
7.8
7.8
3.0
3.0
-
-
213.0
213.0
212.2
212.2
212.6
212.6
212.2
212.2
213.5
213.5
210.3
210.2
212.2
212.2
211.9
211.9
219.2
b
53.7
53.7
53.0
53.0
58.9
58.9
58.3
58.3
56.2
56.2
59.4
59.4
61.7
61.7
61.6
61.6
56.4
56.4
60.8
60.8
61.0
b
75.8
75.8
73.3
73.3
75.3
75.3
70.9
70.9
74.6
74.6
75.0
75.0
72.0
72.0
72.8
72.8
76.3
76.4
76.0
76.0
73.3
b
erythro-1a
threo-1b
-
-
-
-
erythro-1b
threo-2a
-
-
9.3
9.3
5.4
4.9
9.3
9.3
8.1
8.0
a
erythro-2a
threo-2b
erythro-2b
threo-3a
10
2
10
2
10
2
a
threo-3b
a
220.1
220.0
218.8
b
a
erythro-3bc
a
a
a Unassignable because of signal overlapping. b Data could not be obtained with an acceptable signal-to-noise ratio. c At 50 °C.

8948 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Kitamura et al.
Figure 8. Diequatorial (eq) and diaxial (ax) conformations of 2,3-
disubstituted cyclohexanones.
This geometry is further stabilized by the presence of the aldol
moiety forming an intramolecular OH‚‚‚OdC hydrogen bond.
The monomeric threo-1a existed in an equilibrium between eq-
Tap and eq-T+sc in favor of the former, as judged from the JR,â
of 7.3 Hz. The phenyl substituted threo-1b also showed the same
trend. The major eq-Tap conformers were seen in crystalline
structures (Figure 5).
Compounds erythro-1a and erythro-1b are also monomeric
and intramolecularly hydrogen-bonded. The small JR,â values
< 3 Hz suggest the preference of eq-E+sc or eq-E-sc. These
aldols would exist largely (∼100%) as eq-E-sc in solution, just
as in the crystalline state (Figure 5). In fact, erythro-1a in a 10
mM cyclohexane-d12 solution at 25 °C showed a 2.5% NOE
between C(R)H and the cyclohexyl methine proton. Similarly,
with erythro-1b, a 1.2% NOE was seen between C(R)H and
the ortho protons in the phenyl substituent. The 1H NMR spectra
of these aldols taken as a 300 mM toluene-d8 solution gave a
single set of signals with the same line shapes at both 25 °C
and a low temperature (-78 °C for erythro-1a and -20 °C for
erythro-1b), although the chemical shifts varied considerably.
The stability of the eq-E-sc would be partially ascribed to the
σC(R)-H/σ*C(â)-OH orbital interaction.
The effects caused by intermolecular hydrogen bonds are
unpredictable. Notably, however, erythro-2a showed J2,3 values
of 5.4 and 4.9 Hz in 10 and 2 mM cyclohexane solutions,
respectively. The higher concentration increased the number of
intermolecular hydrogen bonds, which in turn enhanced the
contribution of the ax-Eap conformer. A similar trend was seen
in erythro-2b.
Figure 7. Staggered conformations of (a) threo and (b) erythro
cyclohexanone aldols 1 and 2 (Râ ) C6H5 or c-C6H11; R′ ) H or C2H5).
In the diaxial conformers, R′ is behind C(3) of cyclohexanone.
Table 5. Distribution of Conformers of Aldols 1-3 in
B. Steric Effects of the C(3) Substituents. The C(3)-
ethylated aldol, threo-2a, is a monomer with an intramolecular
hydrogen bond in cyclohexane. Unlike threo-1a favoring eq-
a
Cyclohexane-d12
conformers
cryst
eq-Tap eq-T+sc eq-T-sc ax-Tap ax-T+sc ax-T-sc struct
Tap (JR,â ) 7.3 Hz), it existed mostly (95%) as eq-T+sc (JR,â
)
2.3 Hz), owing to the gauche interaction between the C(2) and
C(3) substituents. This aldol still prefers a diequatorial conformer
in solution, but the repulsive interaction becomes prominent in
the crystalline state, to result in the diaxial conformer ax-Tap.
In the erythro isomers, the gauche interaction destabilizes both
eq-E+sc and eq-E-sc. Consequently, the intramolecular hydrogen
bond is removed to result in eq-Eap and ax-Eap, which in turn
are stabilized by intermolecular hydrogen bonds. Such an effect
is also seen in erythro-2a with JR,â ) 7.3 and J2,3 ) 5 Hz.
C. CH/π Attraction. The cyclohexyl (a series) and phenyl
compounds (b series) have similar structures. However, in
certain b compounds, the phenyl ipso carbon has an attractive
interaction with the C(3)H or C(3)CH2CH3 proton, as clearly
seen in the eq-Tap conformer of threo-1b as well as in the eq-
E-sc form of erythro-1b and erythro-3b (Figure 5). Such a CH/π
interaction21 subtly influences the conformer of aldols in
solution. For example, the JR,â value of 8.8 Hz in threo-1b
dictates an eq-Tap/eq-T+sc ratio of 85:15. The preference for the
eq-Tap geometry is decreased to 65:35 (JR,â ) 7.3 Hz) in the
cyclohexyl analogue threo-1a, which lacks the CH/π stabiliza-
tion. This is also the case with the cyclopentanone aldols: threo-
3b, eq-Tap/eq-T+sc ) 75:25 (JR,â ) 7.8 Hz), versus threo-3a,
eq-Tap/eq-T+sc ) 50:50 (JR,â ) 5.4 Hz).
threo-1a
threo-1b 85
threo-2a
threo-2b 85
threo-3a 50
threo-3b 75
65
35
15
95
15
50
25
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
eq-Tap
eq-Tap
ax-Tap
ax-Tap
eq-T+sc
-
5
cryst
eq-Eap eq-E+sc eq-E-sc ax-Eap ax-E+sc ax-E-sc struct
erythro-1a
erythro-1b
0
0
0
0
∼100
0
0
0
0
0
0
0
0
0
0
0
0
eq-E-sc
eq-E-sc
ax-Eap
ax-Eap
eq-E-sc
∼100
erythro-2a 30
erythro-2b 25
(35)b
(70)b
(35)b 35
(70)b
(90)b (10)c
5
erythro-3b (10)c (90)b
a Distributions in percentage inferred from coupling constant. b Con-
former could not be specified by NMR. Sum of eq-E+sc and eq-E-sc
.
c Preference could not be specified. Sum of eq-Eap and ax-Eap.
tion or a deformed chair structure in solution as well. Major
factors which affect the aldol structures will be discussed by
taking typical examples.
A. Hydrogen Bonds. 2-Substituted cyclohexanones take a
chair conformer possessing an equatorially oriented substituent.
(24) Morrison, G. A.; Wilkinson, J. B. J. Chem. Soc., Perkin Trans. 1
1990, 345-351.

Stereochemistry of Aldols
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 8949
hexyl(hydroxy)methyl]cyclohexanone (erythro-1a) was synthesized by
reaction of 1-(trimethylsiloxy)cyclohexene (1.8 g, 1.0 mmol) and
cyclohexanecarbaldehyde (1.1 g, 1.0 mmol) in the presence of tetrabu-
tylammonium fluoride (1.0 mL of a 1.0 M THF solution, 1.0 mmol) in
THF at -78 °C for 5 min.17 After workup, the crude products were
purified by silica gel column chromatography (70 g; eluent, 10:1
hexane-ethyl acetate mixture), followed by recrystallization from
hexane to give erythro-1a in 37% yield. The physical properties were
consistent with the reported ones.27 A 1:2 mixture of (2R*)-2-[(R*)-
hydroxy(phenyl)methyl]cyclohexanone (threo-1b) and (2R*)-2-[(S*)-
hydroxy(phenyl)methyl]cyclohexanone (erythro-1b) was obtained by
reaction of cyclohexanone (5.0 mL, 50 mmol) and benzaldehyde (5.0
mL, 50 mmol) in a 0.2 M aq NaOH solution (55 mL) at 23 °C for 24
h.18 Purification on silica gel column chromatography (500 g; eluent,
10:1 to 7:1 hexane-ethyl acetate mixture) afforded threo-1b (1.3 g,
13% yield) and erythro-1b (2.7 g, 26% yield), whose physical properties
were consistent with those reported previously.10 Cu(I)-catalyzed 1,4-
addition of diethylzinc to 2-cyclohexenone19 was applied to the synthesis
of 3-ethyl-cycloalkanone aldols, (2R*,3R*)-2-[(R*)-cyclohexyl(hy-
droxy)methyl]-3-ethylcyclohexanone (threo-2a), (2R*,3R*)-3-ethyl-2-
[(R*)-hydroxy(phenyl)methyl]cyclohexanone (threo-2b), (2R*,3R*)-3-
ethyl-2-[(S*)-hydroxy(phenyl)methyl]cyclohexanone (erythro-2b),
(2R*,3R*)-2-[(R*)-cyclohexyl(hydroxy)methyl]-3-ethylcyclopen-
tanone (threo-3a), (2R*,3R*)-3-ethyl-2-[(R*)-hydroxy(phenyl)methyl]-
cyclopentanone (threo-3b), and (2R*,3R*)-3-ethyl-2-[(S*)-hydroxy-
(phenyl)methyl]cyclopentanone (erythro-3b). The detailed procedure
as well as the physical properties have been previously reported.19
(2R*,3R*)-2-[(S*)-Cyclohexyl(hydroxy)methyl]-3-ethylcyclohex-
anone (erythro-2a) was obtained by a modified procedure as follows.
Ethylzinc enolate, generated by the Cu(I)-catalyzed 1,4-addition of
diethylzinc (6.6 mL of a 4.98 M toluene solution, 33 mmol) to
2-cyclohexenone (2.9 g, 30 mmol), was cooled to -78 °C, and a boron
trifluoride ether complex (4.3 g, 30 mmol) was added. After the solution
was stirred for 10 min at the same temperature, cyclohexanecarbalde-
hyde (3.6 mL, 30 mmol) was added. The resulting solution was stirred
for 6 h at the same temperature and then poured into saturated aq NH4-
Cl solution (40 mL). The usual extractive workup afforded a 1:1 mixture
of threo-2a and erythro-2a. This was chromatographed on silica gel
(BW 300S, 400 g; eluent, 50:100:1 hexane-dichloromethane-ethanol
mixture) to give threo-2a (1.48 g, 20.7%), erythro-2a (1.36 g, 19.0%),
and a threo/erythro mixture (4.31 g, 60.3%). erythro-2a: mp 77-78
°C; IR (KBr, cm-1) 3415, 2927, 2855, 1692; 1H NMR (400 MHz,
C6D12) δ 0.90 (t, 3H, J ) 7.3 Hz, CH3), 1.99-1.48 (m, 8H), 1.51-
1.58 (m, 2H), 1.60-1.67 (m, 1H), 1.70-2.22 (m, 6H), 1.90 (d, 1H, J
) 7.3 Hz, OH), 2.08-2.16 (m, 1H), 2.22-2.38 (m, 2H), 2.41 (dd, 1H,
J ) 4.4 and 7.3 Hz, COCHCHOH), 3.72 (ddd, 1H, J ) 4.4, 7.3, and
7.3 Hz, CHOH); 13C NMR (100 MHz, CDCl3) δ 11.50, 22.80, 25.05,
25.61, 25.89, 25.99, 26.31, 26.40, 30.77, 39.17, 41.06, 41.15, 59.23,
74.61, 214.56. Anal. Calcd for C15H26O2: C, 75.58; H, 11.0. Found:
C, 75.20; H, 11.38.
Conclusion
Single crystal X-ray analysis is the only spectroscopic method
to unambiguously determine the relative configurations of the
cycloalkanone-based aldols 1-3. The structural assignment
using NMR analysis in solution must be combined with IR
spectroscopy and molecular weight measurement. The Stiles-
House empirical method can be safely applied in only limited
cases. The solution-phase structures are often different from the
crystalline-state geometries. Many of the aldols exist as the
monomer, having an intramolecular OH‚‚‚OdC hydrogen bond
in hydrocarbons. Some aldols, however, possess free hydroxy
groups prone to form intermolecular hydrogen bonds at higher
concentrations, where the dimer or higher aggregates form
without significant conformational change. Skeletally unre-
stricted aldols tend to have a CdO/C(R)sC(â)-eclipsed geom-
etry rather than a half-chair conformation. The cycloalkanone
aldols normally are in an equilibrium of several conformers,
where the relative importance is controlled largely by torsional
strain. Their stability is further delicately affected by various
intramolecular interactions, such as the gauche interactions
between the C(2) and C(3) substituents in 2 and 3 and the CH/π
attraction between the cycloalkanone skeleton and phenyl
substituent in the b series compounds.
Experimental Section
General. Melting points were measured on a YANAKO micro
melting point apparatus and were uncorrected. The number-average
molecular weights (MWobs) of the aldols were determined using a
cryoscopic apparatus consisting of an inner cell with an inside diameter
of 3 cm and an outer air jacket with an inside diameter of 4.5 cm,
which prevents overcooling of the solution. The inner sample cell was
equipped with a Beckmann thermometer and a side arm connected to
the vacuum-argon line.23 Infrared spectra were obtained on a Perkin-
Elmer 2000 or Shimadzu 8100M Fourier transform spectrophotometer.
Sample cells made of KBr were used. NMR spectra were recorded on
a JEOL R-400 (1H NMR at 400 MHz, 13C NMR at 100 MHz), ECP-
500 (1H NMR at 500 MHz, 13C NMR at 125 MHz), or ECP-800 (1H
NMR at 800 MHz, 13C NMR at 200 MHz) spectrometer with a
deuterated solvent as an internal lock. 1H NMR spectra were referenced
to the chemical shift of the residual proton signal of the deuterated
solvent (δ 1.38 for cyclohexane-d12) or tetramethylsilane (TMS) as the
internal reference. 13C NMR spectra were referenced to solvent signals
(δ 26.4 for cyclohexane-d12). All spectra are proton decoupled. 1H and
13C resonances are reported in units of ppm downfield from TMS, and
proton signal patterns are indicated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; or br, broad signal. X-ray crystallographic
analyses were conducted on a Rigaku automated four-circle diffracto-
meter AFC-7R, and the structures were solved by direct methods using
the teXsan crystallographic software package from the Molecular
Structure Corporation. Analytical thin-layer chromatography was
performed using Merck 5715 plates precoated with silica gel 60 F254
of 0.25-mm layer thickness. The product spots were visualized with a
solution of anisaldehyde. Liquid chromatographic purifications were
performed by flash column chromatography, using glass columns
packed with Fuji Davison silica gel BW300 (240-400 meshes).
Method of Theoretical Calculations. The gas-phase geometries of
four conformers of 3-hydroxypropanal were fully optimized using the
B3LYP hybrid density functional method using the 6-311++G(d,p)
basis set (B3LYP/6-311++G(d,p)).25,26 Relative energies are corrected
with unscaled zero-point energy.
Preparation of Aldols. (2R*)-2-[(R*)-Cyclohexyl(hydroxy)methyl]
cyclohexanone (threo-1a) was prepared in 92% yield by reaction of
lithium enolate, generated from 1-(trimethylsiloxy)cyclohexene (1.5 g,
8.8 mmol) and n-butyllithium (5.5 mL of a 1.6 M hexane solution, 8.8
mmol) in THF, and cyclohexanecarbaldehyde (1.0 g, 8.8 mmol) at -78
°C for 5 min followed by the standard workup and purification by
Kugelrohr distillation (120 °C at 0.2 mmHg).16 (2R*)-2-[(S*)-Cyclo-
X-ray Diffraction Studies. Single X-ray quality crystals of threo-
1a, erythro-1a, threo-1b, erythro-1b, threo-2a, erythro-2a, threo-2b,
erythro-2b, threo-3a, and erythro-3b were obtained by recrystallization
from ether, pentane, or hexane solution maintained at 23 or 0 °C for
several days. Their mps were 28, 58-61.5, 78-79, 102-104, 68-69,
77-78, 106-108, 86-86.5, 64-67, and 84-86 °C, respectively. The
(25) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9;
Gaussian, Inc.: Pittsburgh, PA, 1998.
(26) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. 1988, B37, 785-789.
Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(27) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem.
Soc. 1999, 121, 4982-4991.

8950 J. Am. Chem. Soc., Vol. 123, No. 37, 2001
Kitamura et al.
oily threo-3b was converted to the p-bromobenzoate derivative (pyri-
dine, 25 °C, 12 h), whose crystals were obtained by recrystallization
from hexane at 25 °C, mp 90-91 °C. The X-ray irradiation to the aldol
crystals except for threo-1a were conducted at 25 °C with graphite-
monochromated Cu KR. For threo-1a, the diffraction data were
corrected at 0 °C. The orientation matrix and best cell dimensions were
calculated by using 22-25 carefully centered reflections. The assigned
crystal system and space group were uniquely determined by systematic
absences in the diffraction data. Intensities of three standard reflections
were recorded after every 150 reflections. Carbon, oxygen, hydroxy
hydrogen, and some other hydrogen atoms were found in the difference
electron density maps. All non-hydrogen atoms were anisotropically
refined. The remaining hydrogen atoms were calculated and treated as
idealized riding model contributions. For threo-1a, threo-1b, erythro-
2a, threo-2b, threo-3a, and erythro-3b, no absorption correction was
applied. Final difference electron density maps showed no features
MWobs 242, 238, 230. threo-1b (791.7 mg): benzene (13 mL); 300
mM (ω ) 69.8); ∆T 1.56, 1.66, 1.61; MWobs 230, 217, 223. threo-1b
(34.4 mg): cyclohexane (13 mL); 13 mM (ω ) 3.37); ∆T 0.33, 0.33,
0.34; MWobs 230, 230, 223. erythro-1b (263.8 mg): benzene (13 mL);
100 mM (ω ) 23.2); ∆T 0.62, 0.57, 0.63; MWobs 193, 210, 190.
erythro-1b (527.8 mg): benzene (13 mL); 200 mM (ω ) 46.5); ∆T
1.06, 1.05, 1.05; MWobs 226, 228, 228. erythro-1b (791.7 mg): benzene
(13 mL); 300 mM (ω ) 69.8); ∆T 1.49, 1.48, 1.49; MWobs 241, 243,
241. erythro-1b (34.2 mg): cyclohexane (13 mL); 13 mM (ω ) 3.38);
∆T 0.39, 0.35, 0.35; MWobs 193, 215, 215. threo-2a (309.5 mg):
benzene (13 mL); 100 mM (ω ) 27.2); ∆T 0.54, 0.57, 0.52; MWobs
260, 247, 270. threo-2a (930.0 mg): benzene (13 mL); 300 mM (ω )
81.9); ∆T 1.52, 1.54, 1.50; MWobs 278, 274, 282. threo-2a (1550.2
mg): benzene (13 mL); 500 mM (ω ) 136.4); ∆T 2.42, 2.39, 2.38;
MWobs 291, 295, 296. threo-2a (40.0 mg): cyclohexane (13 mL); 13
mM (ω ) 3.95); ∆T 0.34, 0.35, 0.36; MWobs 259, 252, 245. erythro-
2a (309.3 mg): benzene (13 mL); 100 mM (ω ) 27.2); ∆T 0.57, 0.55,
0.55; MWobs 246, 255, 255. erythro-2a (929.5 mg): benzene (13 mL);
300 mM (ω ) 81.8); ∆T 1.40, 1.39, 1.37; MWobs 302, 304, 308.
erythro-2a (1551.0 mg): benzene (13 mL); 500 mM (ω ) 136.5); ∆T
2.05, 2.05, 2.00; MWobs 344, 344, 352. erythro-2a (40.6 mg):
cyclohexane (13 mL); 13 mM (ω ) 3.95); ∆T 0.33, 0.30, 0.31; MWobs
271, 298, 288. threo-2b (302.6 mg): benzene (13 mL); 100 mM (ω )
26.6); ∆T 0.58, 0.57, 0.57; MWobs 237, 241, 241. threo-2b (906.7
mg): benzene (13 mL); 300 mM (ω ) 79.8); ∆T 1.24, 1.21, 1.23;
MWobs 332, 340, 335. threo-2b (1510.2 mg): benzene (13 mL); 500
mM (ω ) 132.9); ∆T 1.81, 1.79, 1.78; MWobs 379, 383, 385. threo-2b
(50.0 mg): cyclohexane (20 mL); 11 mM (ω ) 3.21); ∆T 0.21, 0.19,
0.19; MWobs 341, 377, 377. erythro-2b (302.2 mg): benzene (13 mL);
100 mM (ω ) 26.6); ∆T 0.55, 0.55, 0.56; MWobs 250, 250, 245.
erythro-2b (906.7 mg): benzene (13 mL); 300 mM (ω ) 79.8); ∆T
1.33, 1.36, 1.33; MWobs 310, 303, 310. erythro-2b (1511.1 mg):
benzene (13 mL); 500 mM (ω ) 133.0); ∆T 2.02, 2.00, 1.99; MWobs
340, 343, 345. erythro-2b (29.0 mg): cyclohexane (13 mL); 10 mM
(ω ) 2.86); ∆T 0.16, 0.14, 0.14; MWobs 399, 456, 456. threo-3a (38.0
mg): cyclohexane (13 mL); 13 mM (ω ) 3.75); ∆T 0.34, 0.34, 0.36;
MWobs 246, 246, 232. threo-3b (38.0 mg): cyclohexane (13 mL); 13
mM (ω ) 3.75); ∆T 0.32, 0.35, 0.34; MWobs 261, 239, 246.
outside the range from 0.12 to -0.18 eÅ-3, from 0.14 to -0.13 eÅ-3
,
from 0.09 to -0.14 eÅ-3, from 0.18 to -0.21 eÅ-3, from 0.13 to -0.13
eÅ-3, and from 0.22 to -0.20 eÅ-3, respectively. An empirical
absorption correction based on an azimuthal scan of several reflections
was applied for erythro-1a, erythro-1b, threo-2a, erythro-2b, and the
p-bromobenzoate derivative of threo-3b, whose transmission factors
ranged from 0.77 to 1.00, 0.67 to 1.00, 0.69 to 1.00, 0.45 to 1.00, and
0.45 to 1.00, respectively. In each case, the final difference electron
density maps showed no features outside the range from 0.25 to -0.39
eÅ-3, from 0.15 to -0.20 eÅ-3, from 0.25 to -0.25 eÅ-3, from 0.18
to -0.21 eÅ-3, and from 0.18 to -0.20 eÅ-3. The crystallographic
data are listed in Table 1 for all the crystalline aldols and the
p-bromobenzoate of threo-3b.
Molecular Weight Determination. Cryoscopic measurement was
used to determine the aldol molecular weight averages. The procedures
are the same as those described previously.23 The molecular weights
were calculated using the equation ∆T ) Kfω/MWobs (∆T ) freezing
point depression (deg), Kf ) molar depression of the solvent, ω )
weight (g) of solute in 1000 g of solvent, and MWobs ) number-average
molecular weight). The Kf values of benzene and cyclohexane were
calculated to be 5.16 and 22.3 on the basis of the depression of a
benzene (10.53 g) solution and a cyclohexane (10.13 g) solution by
naphthalene (118.6-566.6 mg and 17.0-67.6 mg, respectively). The
experimental parameters are listed below in the order of sample (g),
solvent (mL), concentration (ω), ∆T, and MWobs. threo-1a (274.5
mg): benzene (13 mL); 100 mM (ω ) 24.2); ∆T 0.65, 0.62, 0.62;
MWobs 192, 201, 201. threo-1a (548.9 mg): benzene (13 mL); 200
mM (ω ) 48.3); ∆T 1.22, 1.11, 1.09; MWobs 204, 225, 229. threo-1a
(823.4 mg): benzene (13 mL); 300 mM (ω ) 72.5); ∆T 1.69, 1.63,
1.66; MWobs 221, 229, 226. threo-1a (35.5 mg): cyclohexane (13 mL);
13 mM (ω ) 3.51); ∆T 0.31, 0.31, 0.31; MWobs 253, 253, 253. erythro-
1a (273.4 mg): benzene (13 mL); 100 mM (ω ) 24.1); ∆T 0.55, 0.56,
0.56; MWobs 226, 222, 222. erythro-1a (546.8 mg): benzene (13 mL);
200 mM (ω ) 48.1); ∆T 1.09, 1.08, 1.09; MWobs 228, 230, 228.
erythro-1a (820.2 mg): benzene (13 mL); 300 mM (ω ) 72.2); ∆T
1.67, 1.65, 1.66; MWobs 223, 226, 224. erythro-1a (35.5 mg):
cyclohexane (13 mL); 13 mM (ω ) 3.51); ∆T 0.32, 0.32, 0.30; MWobs
245, 245, 261. threo-1b (263.8 mg): benzene (13 mL); 100 mM (ω )
23.2); ∆T 0.53, 0.57, 0.53; MWobs 226, 210, 226. threo-1b (527.8
mg): benzene (13 mL); 200 mM (ω ) 46.5); ∆T 0.99, 1.01, 1.04;
Acknowledgment. This work was supported by a Grant-
in-Aid for COE Research (No. 07CE2004) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
Authors thank Mr. T. Noda for making the cryoscopic measure-
ment apparatus.
Supporting Information Available: ORTEP drawings with
numbering schemes, tables of atomic parameters, anisotropic
temperature factors, and complete listings of bond angles and
interatomic distances for threo-1a, erythro-1a, threo-1b, erythro-
1b, threo-2a, erythro-2a, threo-2b, erythro-2b, threo-3a, erythro-
3b, and the p-bromobenzoate derivative of threo-3b as well as
the result of DFT calculations for 3-hydroxypropanal (51 Pages).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0110978