Molecular chirality by isotopic substitution. Synthesis, absolute configuration and circular dichroism spectra of 13C-substituted chiral diphenylmethanol

Article abstract of DOI:10.1002/1099-1395(200007)13:7<422::AID-POC256>3.0.CO;2-9

¹³C-Substituted chiral diphenylmethanol, α-phenylbenzene[1,2,3,4,5,6-¹³C₆]methanol, [CD(-)270]-(S)-3, was synthesized from 4-bromo-α-(phenyl[1,2,3,4,5,6-¹³C₆])benzenemethanol (4), which was enantiores

Full text of DOI:10.1002/1099-1395(200007)13:7<422::AID-POC256>3.0.CO;2-9

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2000; 13: 422–425
Short Communication
Molecular chirality by isotopic substitution. Synthesis,
absolute con®guration and circular dichroism spectra of
13C-substituted chiral diphenylmethanol
Nobuyuki Harada,* Kaori Fujita and Masataka Watanabe
Institute for Chemical Reaction Science, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
Received 31 January; revised 21 February
ABSTRACT: 13C-Substituted chiral diphenylmethanol, a-phenylbenzene[1,2,3,4,5,6-13C6]methanol, [CD( )270]-
(S)-3, was synthesized from 4-bromo-a-(phenyl[1,2,3,4,5,6-13C6])benzenemethanol (4), which was enantioresolved
by the chiral phthalic acid method. The S absolute configuration of [CD( )270]-3 was unambiguously determined by
x-ray crystallography of camphanic acid ester of ( )-4. Copyright 2000 John Wiley & Sons, Ltd.
KEYWORDS: molecular chirality by isotopic substitution; 13C-substituted chiral diphenylmethanol; a-phenylben-
zene[1,2,3,4,5,6-13C6]methanol; 4-bromo-a-(phenyl[1,2,3,4,5,6-13C6])benzenemethanol; circular dichroism spectra;
absolute configuration; chiral phthalic acid method; x-ray crystallography
1
INTRODUCTION
the CD Cotton effects of the Lb transition also acquire
their intensities from the coupling with the totally
symmetrical vibration, showing the corresponding vibra-
tional structure.1
Chiroptical activity is attributable to the dissymmetric
molecular structure, which is not superimposable with
its mirror image. As a unique case of molecular
asymmetry, there is the category of chirality generated
by isotopic substitution. For example, recently we
The vibrational frequency depends on the mass of an
oscillator, i.e. carbon and hydrogen atoms in a benzene
ring in the case of alcohols 1 and 2. Therefore, the CD
spectra of isotopically substituted compounds 1 and 2
reflect the mass difference between oscillators. In the
case of 1 and 2, the mass difference, Dm = 1, between
12C–1H (m = 13) and 12C–12H (m = 14) is essential for
generating the CD activity. Chiral alcohols 1 and 2 show
very weak but distinct Cotton effects with vibrational
structure.1 There is another class of isotopic chirality in
diphenylmethanol. As shown in formula 3 (Fig. 1), 13C
2
reported the synthesis of H-substituted chiral diphenyl-
methanols,
a-phenylbenzene[2,3,4,5,6-2H5]methanol,
[CD( )270.4]-(S)-1 and a-phenylbenzene[4-2H]metha-
nol, [CD(‡)270.6]-(R)-2 (Fig. 1), which exhibited very
weak circular dichroism (CD) Cotton effects character-
1
istic to the vibronic structure of the Lb transition of a
benzene chromophore around 250–280 nm.1 The Lb
1
transition of benzene, which appears as eight or nine
weak UV peaks around 220–280 nm, is essentially
forbidden, but it becomes slightly allowed by coupling
with the vibration of the benzene skeleton. The major
vibration mode responsible for the 1Lb transition has been
assigned to the totally symmetrical vibration of a benzene
ring: peak interval of progression, 923 cm 1.2 Therefore,
*Correspondence to: N. Harada, Institute for Chemical Reaction
Science, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577,
Japan.
E-mail: n-harada@icrs.tohoku.ac.jp
Contract/grant sponsor: Ministry of Education, Science, Sports and
Culture; Contract/grant number: 07408032; Contract/grant number:
10554035; Contract/grant number: 11480159; Contract/grant num-
ber: 10146205; Contract/grant number: 10208202; Contract/grant
number: 10045022; Contract/grant number: 09874129.
Contract/grant sponsor: NOVARTIS Foundation (Japan) for the
Promotion of Science.
2
Figure 1. H-and 13C-substituted chiral diphenylmethanols
and derivative
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 422–425

MOLECULAR CHIRALITY BY ISOTOPIC SUBSTITUTION
423
Scheme 2. (a) LiAlH4±THF; (b) (1S)-( )-camphanic acid,
DCC, DMAP±CH2Cl2
7b crystallized as fine needles. From our previous
2
experience with the H-substituted analogues, we had
Scheme 1. (a) Mg±THF; (b) DCC, DMAP±CH2Cl2
expected that ( )-camphanic acid esters would form
good single crystals, the x-ray analysis of which would
lead to the unambiguous determination of absolute
configuration.1 Therefore, to synthesize camphanate
substitution also forms molecular chirality. In this case,
the mass difference, Dm = 1, between 12C–1H (m = 13)
and 13C–1H (m = 14) is intrinsic to chiroptical activity,
and it is similar to the cases of 1 and 2. Therefore, it is
intriguing to compare the CD spectrum of 3 with those of
1 and 2. In this paper we report the enantioresolution,
synthesis and absolute configurations of new 13C-
substituted chiral diphenylmethanol 3 and related com-
pounds.
esters, 7a was treated with LiAlH4 in THF affording
25
the enantiopure alcohol ( )-4 (84%): [a]D
15.9° (c
0.73, CHCl3) (Scheme 2). Esterification with camphanic
acid was carried out as usual; a mixture of alcohol ( )-4,
( )-camphanic acid, DCC and DMAP in CH2Cl2 was
stirred at room temperature overnight yielding ester 8
(96%).
When recrystallized from MeOH, ester 8 appeared as
colorless prisms suitable for x-ray diffraction. A single
crystal of 8 was subjected to x-ray analysis: crystal data
12
for ester (S)-8, 13C6 C17H23BrO4; Mr = 449.10; colorless
EXPERIMENTAL AND RESULTS
prism (0.44 Â 0.41 Â 0.30 mm); monoclinic; space group
4-Bromo-a-(phenyl[1,2,3,4,5,6-13C6])benzenemethanol-
(4) was prepared from bromobenzene[13C6] (5, >99
atom% 13C, purchased from Isotec) and 4-bromobenzal-
dehyde by the Grignard reaction: 90% yield from 5
(Scheme 1). Racemic alcohol (Æ)-4 was enantioresolved
by the chiral phthalic acid method:3–5 a mixture of
alcohol (Æ)-4, chiral dichlorophthalic acid ( )-6, 4-
dimethylaminopyridine (DMAP) and 1,3-dicyclohexyl-
carbodiimide (DCC) in CH2Cl2 was stirred at room
temperature overnight, yielding a diastereomeric mixture
of esters 7a and 7b. The mixture was easily separated by
HPLC on silica gel [hexane–EtOAc (8:1)], separation
factor a = 1.1; resolution factor RS = 1.5. The first-eluted
ester 7a (48%) and the second one 7b (48%) were
obtained.
P21
(#4);
a = 12.520(3),
b = 6.685(2),
c =
3
˚
˚
12.514(2) A, b = 93.04(2)°; V = 1045.9(4) A ; Z = 2;
Dx = 1.426 g cm 3; Dm = 1.420 g cm 3 by flotation using
a CCl4–hexane solution; radiation, Cu Ka (1.54178 A);
˚
unique data Fo > 3ꢀ(Fo), 1952. The skeletal structure
was solved by the direct method and successive Fourier
syntheses. Absorption correction and full matrix least-
squares refinement of positional and thermal parameters,
including anomalous scattering factors of bromine,
oxygen and carbon atoms, led to the final convergence
with R = 0.0288 and Rw = 0.0494, while R = 0.0338 and
Rw = 0.0565 for the mirror image structure. The absolute
stereochemistry of ester 8 was thus determined as S by
the heavy atom effect as shown in Fig. 2. The S
configuration of 8 was confirmed by the internal
reference method using the known absolute configuration
of the camphanate part. The S absolute configuration of
alcohol ( )-4 was thus established.
In the application of the chiral phthalic acid method,
large single crystals of esters suitable for x-ray diffraction
have been obtained in most cases. However, esters 7a and
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 422–425

424
A. HARADA, K. FUJITA AND M. WATANABE
Figure 2. ORTEP drawing of ester (S)-8. The atoms are drawn
as 50% probability ellipsoids
Alcohol (S)-( )-4 was reduced with H2NNH2–H2O
and Pd–C in EtOH yielding enantiopure a-phenyl-
benzene[1,2,3,4,5,6-13C6]methanol, (S)-3, in 98% yield
(Scheme 3). The CD spectrum of (S)-3 showed weak and
complex, but distinct, Cotton effects around 250–270 nm
due to the molecular chirality by the 13C isotopic
substitution (Fig. 3). These Cotton effects are assigned
Figure 3. CD and UV spectra of a-phenylbenzene-
[1,2,3,4,5,6-13C6]methanol, [CD( )270]-(S)-3, in EtOH
1
to the vibronic Lb transition of the benzene chromo-
phore. Since 13C-substituted alcohol (S)-3 shows a
negative Cotton effect at 270 nm, the chiroptical property
and absolute configuration of a-phenylbenzene-
[CD( )270.4]-(S)-1, having a heavier 2H-substituted
phenyl group at the left side and a lighter regular phenyl
group at the right side, shows a negative CD Cotton effect
at 270 nm (Fig. 1).1 On the other hand, in the case of
monodeutserated alcohol [CD(‡)270.6]-(R)-2, a heavier
group at the right side and a lighter one at the left side
brings a positive CD at 270 nm. The correlation between
[1,2,3,4,5,6-13C6]methanol
were
designated
as
[CD( )270]-(S)-3 (see the definition of enantiomers by
CD data6).
As discussed above, we have succeeded in the
synthesis and unequivocal determination of the absolute
configurations of 13C-substituted chiral diphenylmetha-
nol, the CD spectrum of which correlates with the
absolute configuration as follows. When the molecule
(S)-3 is placed as shown in Fig. 1, i.e. the hydroxyl group
is oriented top and front, the 13C-substituted phenyl group
is located at the left side and the regular phenyl group at
the right side. This arrangement, i.e. a heavier phenyl
group at the left side and a lighter one at the right side,
leads to a negative CD Cotton effect at 270 nm (Fig. 3).
The present correlation holds for the cases of deuterium-
substituted chiral diphenylmethanols 1 and 2. Alcohol
1
the CD in the Lb transition region and the absolute
configuration of chiral diphenylmethanol is thus rationa-
lized.
The CD Cotton effects of [CD( )270]-(S)-3 are much
weaker than those of [CD( )270.4]-(S)-1: CD of (S)-3,
ꢁext 270.0 nm, Dꢂ 0.016; CD of (S)-1, ꢁext 270.4 nm,
Dꢂ 0.073. The CD intensity of 13C-substituted di-
phenylmethanol (S)-3 is ca one fifth of that of the
2H-substituted (S)-1, and almost comparable to that
of [CD(‡)270.6]-(R)-2: CD of (R)-2, ꢁext 270.6 nm,
Dꢂ ‡ 0.011.1 As discussed in the Introduction, the mass
difference in [CD( )270]-(S)-3 is the same as that in
[CD( )270.4]-(S)-1, and therefore we had expected a
similar CD intensity for them. However, the observed CD
intensities are very different. This observation indicates
that hydrogen atoms in the totally symmetrical vibration
of the benzene skeleton contribute much more to the CD
intensity than do carbon atoms. The CD intensity is
sensitive to the vibration of the C—H part rather than the
C—C part. Further studies of the molecular chirality
generated by isotopic substitution are in progress.
Scheme 3. (a) H2NNH2±H2O, Pd±C, EtOH, re¯ux
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 422–425

MOLECULAR CHIRALITY BY ISOTOPIC SUBSTITUTION
425
3. (a) Harada N, Soutome T, Nehira T, Uda H, Oi S, Okamura A,
Miyano S. J. Am. Chem. Soc. 1993; 115: 7547–7548; (b) Harada N,
Nehira T, Soutome T, Hiyoshi N, Kido F. Enantiomer 1996; 1: 35–
39.
Acknowledgements
This work was supported in part by grants from the
Ministry of Education, Science, Sports and Culture,
Japan [Scientific Research (A) No. 07408032, (B) No.
10554035, (B) No. 11480159, Priority Areas (A) No.
10146205, (B) No. 10208202, and International Joint No.
10045022 to N.H.; Exploratory Research No. 09874129
to M.W.] and the NOVARTIS Foundation (Japan) for the
Promotion of Science (to N.H.).
4. (a) Harada N, Koumura N, Robillard M. Enantiomer 1997; 2: 303–
309; (b) Harada N, Hiyoshi N, Vassilev VP, Hayashi T. Chirality
1997; 9: 623–625; (c) Harada N, Vassilev VP, Hiyoshi N.
Enantiomer 1997; 2: 123–126; (d) Nemoto H, Miyata J, Fukumoto
K, Ehara H, Harada N, Uekusa H, Ohashi Y. Enantiomer 1997; 2:
127–131; (e) Harada N, Koumura N, Feringa BL. J. Am. Chem. Soc.
1997; 119: 7256–7264; (f) Harada N, Fujita K, Watanabe M.
Enantiomer 1997; 2: 359–366; (g) Kuwahara S, Fujita K, Watanabe
M, Harada N, Ishida T. Enantiomer 1999; 4: 141–145.
5. (a) Watanabe M, Kuwahara S, Harada N, Koizumi M, Ohkuma T.
Tetrahedron: Asymmetry 1999; 10: 2075–2078; (b) Kuwahara S,
Watanabe M, Harada N, Koizumi M, Ohkuma T. Enantiomer 2000;
5: 109–114.
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Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 422–425