Wedekind-Fock-Havinga salt Me(Et)N+(All)PhI- · CHCl3 as historically the first object for absolute asymmetric synthesis: Spontaneous resolution, structure and absolute configuration

Article abstract of DOI:10.1070/MC2001v011n01ABEH001420

The title salt crystallises as a conglomerate (space group P2₁2₁2₁, Z = 4) with one solvate CHCl₃ molecule forming strong shortened contact with I^- [Cl···I^- 3.599(2) A?]. Therefore, it unde

Full text of DOI:10.1070/MC2001v011n01ABEH001420

, 2001, 11(1), 1–6
Wedekind–Fock–Havinga salt Me(Et)N+(All)PhI– ·CHCl3 as historically the first
object for absolute asymmetric synthesis: spontaneous resolution, structure and
absolute configuration†
Remir G. Kostyanovsky,*a Vasilii R. Kostyanovsky,a Gul’nara K. Kadorkinaa and Konstantin A. Lyssenkob
a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation.
Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation.
Fax: +7 095 135 5085; e-mail: kostya@xlab.ineos.ac.ru
10.1070/MC2001v011n01ABEH001420
The title salt crystallises as a conglomerate (space group P212121, Z = 4) with one solvate CHCl3 molecule forming strong short-
ened contact with I– [Cl···I– 3.599(2) Å]. Therefore, it undergoes spontaneous resolution by simple crystallisation with a deficiency
of the conglomerator CHCl3 or by an internal entrainment procedure. It exhibits the (S)-(+) absolute configuration and racemises
in solution (∆G#rac = 26.5 kcal mol–1). The salt was almost completely converted into one enantiomer by stirred crystallisation from
solution (with full evaporation) or from a melt under conditions of enantiomerisation. The contribution of autocatalysis to this
process is discussed.
Chiral ammonium salt Me(Et)N+(All)PhI– ·CHCl3 1 has at-
(a)
tracted the attention of several generations of chemists and
H
H
∆
I
I
remains to be of much current interest because “...mental adjust-
ments are required in order to deal intuitively with ‘improbable’
solid-state phenomena.”3 Salt 1 by right should be named for
three outstanding persons who are responsible for its highly
important place in the history of stereochemistry (see photos on
the back cover and historical outlook‡).
N
Pr
N
Pr
Ph
Ph
Et
Et
B, mp 179 °C
[a]D = –21.2°
C, mp 208 °C
[a]D = +31.2°
E. Wedekind was the first to synthesise5(a),(g) salt 1 and to
find that it incorporates crystallisation CHCl3. He examined
spontaneous racemisation of 1 and similar salts in solutions (its
(b)
I
20 °C
EtOH
Pri
CH2CO2- -menthyl
N
†
L
Asymmetric Nitrogen. Part 84. Previous communication see ref. 1.
Preliminary results of this work have been published.2
D, mp 146–148 °C
[a]D = –12.5°
‡
E. Wedekind, born on December 31, 1870, in Altona on Elbe, studied
in Tübingen and Munich (thesis). In 1897–1899, he worked at the
Polytechnical Institute in Riga (Russia); in 1904, he became a Professor
at the Chemical Institute of Tübingen University. Over decades, he was
elaborating the problems of asymmetric four-coordinated nitrogen4 (which
was earlier considered as five-coordinated). The related results obtained in
Riga, Tübingen, and Strasbourg were published in 2 monographs and 60
communications in 1899–1934 (see ref. 5).
I
Pri
CH2CO2-L-menthyl
N
mp 163–164 °C
[a]D = –40.1°
The question as to whether the four-coordinated nitrogen exists has
been raised first by J. Wislicenus in 1877 [ref. 5(a), p. 1], and those as to
three-coordinated nitrogen by A. Hantzsch and A. Werner in 1890.6
Described in the next year by J. A. Le Bel, the optical activation of
Me(Et)N+(Prn)BuiCl– under the action of microorganisms7(a) was not
confirmed later (1899).7(b),(c) Despite the unsuccessful attempts to resolve
the Le Bel salt using the optically active acids such as tartaric, cam-
phoric, and mandelic ones,7(b) Wedekind, in the same year, has launched
an attack on solving the problem. One of the major arguments in support
of the stereoisomerism of ammonium salts that Wedekind kept in mind5(c)
was identity of the Menshutkin salts prepared by means of three pos-
sible ways from the corresponding N,N-dialkylaniline and alkyl iodide.8
Studies by Wedekind of 1899 initiated the German9 and three groups of
British chemists10 to be involved in the solution of this problem. These
data on the synthesis, crystallographic characterisation, and unsuccess-
ful attempts to resolve salts Me(All)N+(CH2Ph)PhHal– A using optically
active tartaric and camphoric acids in aqueous solutions have been
reported5(d),(e) followed by the publication of W. J. Pope et al.10(a),(b) on the
resolution of salt A via camphorsulfonates in non-aqueous solutions. In
1905, M. B. Thomas and H. O. Jones first observed10(c) apparently asym-
metric transformation of diastereomeric salts such as (+)-camphorsulfo-
nate obtained from Wedekind salt 1; when heated the latter above 50 °C
in H2O, its optical activity was changed to the sign reversal. However,
the authors could not make the important fact out, and just expressed
their astonishment: “It is curious that the rotatory power . . . vanish at
some temperature above 50 °C and then become levorotatory...”. Asym-
metric transformation of a covalent diastereomeric salt was precisely
detected9 at the first time in 1905 by M. Scholtz who has synthesised
derivatives of the alkaloid coniine for biological tests. In response to the
Wedekind works, he has isolated diastereomerically pure salts B and C
and carried out their intertransformations under short heating up to the
melting [Scheme 1 (a)].
Scheme 1 Asymmetric diastereomeric transformations of the chiral ammo-
nium salts.
Similar transformations were observed by Wedekind under mild con-
ditions5(j),(k) [D, Scheme 1(b)]. It is amazing that till now the discovery
of such phenomena important both in principle and in terms of tech-
nology, as asymmetric diastereomeric transformation was ascribed to
H. Leuhs and J. Wutke (1913), and a well-known list of conglomerates11
does not include many of hemihedral crystals found by Wedekind and
A. L. Fock.5,13
A. L. Fock, born on April 28, 1856, in Böbs near Lübeck (Germany),
studied (1876–1880) in Strasbourg (thesis). Since 1881, he worked with
H. H. Landolt as his assistant and, since 1885, as an assistant professor
at the Berlin University. Famous crystallographer, the author of the
monograph “Introduction in Chemical Crystallography”12 (translated and
edited by W. J. Pope, one of the most prominent chemist of that time),
Fock has performed all crystallographic studies of the Wedekind salts.5,13
Both scientists were mad about hunting for conglomerates, and trium-
phed over each new find of the hemihedral crystal, in particular, of A5(d)
and 1.5(g) It is interesting to mention a microgoniometric study when hemi-
hedrism was observed only for the enantiomer (–)-Me(Pri)N+(CH2Ph)PhI–
(mp 132 °C) but not for the racemate (mp 133 °C).10(c) The priority in
obtaining an optically active compound containing a stereogenic hetero-
atom is attributed to Pope and co-workers;4,14 however, before them
Wedekind and Fock have found hemihedrism (i.e., homochirality) of the
crystals of iodide A5(d) and then isomorphism of halides A.5(c) This fact
was confirmed by Pope himself. He wrote [ref. 10(a), p. 1130]: “...Fock
actually measured crystals of the optically active iodides”, and empha-
sizing identity of the crystallographic parameters found by Fock for
bromide ( )-A5(c) with those for enantiomers found by himself, he con-
– 1 –

, 2001, 11(1), 1–6
rate depends on the type of anion: I > Br > Cl) and explained
the racemisation by reversible dissociation into an amine and an
allyl halide.5( f )
All–I
CHCl3
PhN(Me)Et
1
A. L. Fock pioneered microgoniometric studies of salt 1 and
found the hemihedrism of its crystals;5(a),7 i.e., he found that it
crystallises as a conglomerate (a mixture of homochiral crystals
of the enantiomers) and hence is capable of spontaneous reso-
lution.
EtI
1
PhN(Me)All
+ PhN+(Me)(All)2I– + PhN+(Me)Et2I–
CHCl3
2
3
4
EtI
All = Allyl
2
PhN(Me)Et
E. Havinga was the first to perform spontaneous resolution
of 1 and proposed the idea of spontaneous asymmetric syn-
thesis21 (absolute asymmetric synthesis or crystallisation-induced
the second order asymmetric transformation11). Such a synthesis
takes place under the following conditions: (a) the material
crystallises as homochiral crystals (conglomerate); (b) the char-
acteristic time of formation of the first nucleus is long; and (c)
the rate of spontaneous or catalysed racemisation in a solution
or melt is higher than the rate of crystal growth. Then, crys-
tallisation from a supersaturated solution or a melt gives an
enantiomerically pure product as a result of cloning molecules
on the first nucleus formed (see, e.g., refs. 3, 32 for the
nucleation mechanism) from a mixture of the constant enantio-
meric composition 1:1 (because of rapid racemisation). Thus,
the racemate is converted into a single d- or l-enantiomer. This
idea became universally recognised.11,20,22–28 However, the total
enantiomeric enrichment of the precipitate and the mother
liquor in a particular experiment cannot be quantitatively evalu-
ated from the experimental data by Havinga. It was noted
by himself21 that “...crystals contain CHCl3, tend to liquate
and soon become sticky renders exact quantitative determina-
tions in small-scale experiments somewhat difficult”. Moreover,
∆ solution
Ph
N
(S)-1
or
(R)-1
Me
Et
∆ melt
I
Ph
N
Me
I
Et
0.5 CHCl3
S-(+)-1
Ph
N
Ha
I
Hb
Me
Et
Hc
R-(–)-1
Scheme 2
Havinga’s experiments “...have never been repeated” [ref. 25(a),
p. 185], and it was noted that his results “...may not be repro-
ducible”.24
In his last year, Havinga has described his academic career in the essay
“Enjoying Organic Chemistry, 1927–1987”.19 He was “a pioneer in
optical activity from chiral crystals...” (see ref. 20). In fact, a new epoch
of exploring the chirality phenomena has begun from his studies on salt
1.21 The whole flood of theoretical and experimental researches was
initiated by his precisely formulated idea of spontaneous asymmetric
synthesis and conditions for its accomplishment. The Havinga effect
named the stereospecific autocatalysis by M. Calvin,22 has been thoroughly
investigated in theoretical aspects.23 The ideas of Havinga were success-
fully realised.11,24–27 Over the past decade it was shown that the efficiency
of the crystallisation-induced asymmetric transformation depends critically
on stirring and evaporation rates.3,28 The main test sample is the salt
NaClO3 capable of crystallising in chiral cubic space group P213. Three
years after translation of Fock’s book12(b) Pope has found10(e) optical
activity of the crystal of this salt (a = 3.6° mm–1 at 546 nm) and has
shown that in 3137 crystals obtained by simple crystallisation, the left–
right relation is practically equal to 1:1. After 92 years, D. K. Kondepudi
et al.28 and then J. M. McBride et al.3 have repeated this experiment and
have demonstrated that its result was dramatically changed under condi-
tions of stirred crystallisation (100–1000 rpm) to give either only left or
only right crystals.
cluded: “It follows that the inactive salt is not a racemic compound but
is . . . a mere mechanical mixture of the two component salts” [ref. 10(b),
pp. 835–836]. The components of this mixture are enantiomorphous
crystals (Figure 1)10(b) like in case of the Pasteur salt. Thus, a break-
through in the stereochemistry of asymmetric heteroatoms took place on
the verge of the centuries (1899–1901) due to efforts of Wedekind, Fock,
Pope, S. J. Peachey and A. W. Harvey.
Wedekind has also synthesised5(h) optically active analogues of A, i.e.
salts (+)- and (–)-Me(Pr)N+(CH2Ph)PhI– E, which were later prepared15
by the reductive transformation of iodides (+)-A ® (+)-E. The absolute
configurations of (S)-(–)-E and (S)-(+)-As-analogue were determined16(a)
using the method of quasi-racemates11 by comparison with (S)-(+)-P-
analogue studied16(b) by X-ray diffraction analysis. The salts like (+)-
A
15(a) and other15(b),(c) were used for the transfer of chirality from N to C
by the Stevens reaction15(a),(c) and Hofmann cleavage.15(b)
The really opposite situation was with three-coordinated nitrogen. In
all instances the resolution of compounds ranging from the Tröger base
(V. Prelog, P. Wieland, 1944) to the chiral dialkoxyamine with the open-
chained asymmetric nitrogen (R. G. Kostyanovsky et al., 1979)17(d),(e) and
systems with the sterically hindered nitrogen inversion1 were carried out
using chiral reagents. Only then did we find out the crystallographic
identity of the enantiomers and racemate of a bis-naphtho analogue of the
Tröger base18 (which was found to be a conglomerate like those found
by Fock and Pope!) we succeeded in spontaneous resolution, again at the
verge of the centuries, and obtained the above synthetic product, each
individual crystal of which was optically active, [a]D20 = 1100–1200°
(c 0.1, MeOH).
Ideas presented in the second section of Havinga’s paper21 were almost
not cited. The readers (not exclusive of the authors of this work) seem to
be so stunned when perceiving the first part of the paper that they lose
sight of the second one though it is not less interesting. Havinga assumes
that in the system of molecules interoriented in a certain manner (crystal
or monolayer), an enantiomeric excess may be preferable, in terms of
free energy, than a racemate. It is well known for crystals (existence
of conglomerates) but not for solutions, and Havinga proposes the
following model. It may be that 3D achiral molecules of the type of
HO(CH2)n(X)C(Y)(CH2)nOH are capable of 2D (two-dimensional, or
dipty) chiral self-association to form a mono-layer at the H2O–air
interface. When the molecules are oriented in such a manner that one of
HO group is directed into H2O phase, its oxidation (e.g., with
permanganate) can result in the formation of a 3D chiral product. This
fantasy was partly realised. Remarkable absolute 2D ® 3D asymmetric
synthesis was described29 still in Havinga times. A large monocrystal of
achiral tiglic acid (space group P1) was cut in two along the planes
(2 1 0) and (2 1 0), each part was coated with an epoxide resin (not
touching the edges) and treated with an oxidant (Figure 2). In result both
enantiomeric products were obtained in yields 40–60% with ee > 95%.
By now, numerous data on the homochiral self-association of mole-
cules in monolayers30 and 2D chiral systems31 are obtained. In case of
2D chiral molecule of 1-nitronaphthalene, the formation of decamer clus-
ters of the composition of 8l2d and diptychiral enantiomer 8d2l are
found. Similarly to the 3D chiral enantiomers of the Pasteur salt, they are
sorted out but scanning tunneling microscopy31 was used instead of an
optical microscope and forceps.
It is incomprehensible why either Wedekind or Pope, who realised the
point perfectly well, never measured the optical rotation for the indivi-
dual crystals of the salts under study. Only half a century later it was
done by Havinga.
E. Havinga born on May 7, 1909, in Amersfoort (the Netherlands),
studied theoretical physics at the Utrecht University (with H. A. Kramers)
and organic chemistry (thesis “Monolayers: Structure and Chemical Reac-
tions”, 1939, under the supervision of F. Kögl), worked in the laboratory
of medicinal chemistry at Utrecht, then became full professor and director
of the laboratory of organic chemistry at the University of Leiden (1949–
1979). His scientific interest ranged from physical organic chemistry to
bioorganic chemistry including photochemistry and the chemistry of vita-
min D, conformational analysis and peptide chemistry, catalysis and
enzymatic reactions. He was gifted with incredible capacity for working
and also with versatile talents outside chemistry. An outstanding teacher
of organic chemistry (the number of theses prepared under his super-
vision amounts to 166), he was also an excellent tennis player, art-lover
and masterly pianist who inspired the Dutch composer W. Aerts to write
“Thirteen variations and coda on a theme of E. Havinga in E minor”.
– 2 –

, 2001, 11(1), 1–6
r
o
r
o
s
s
Me
Mp 166–167 °C
[a]D17 = +64.1°
(c 0.49, CHCl3)
Mp 166–168 °C
[a]D17 = –65.0°
(c 0.58, CHCl3)
H
Me
CO2H
n
n
m
m
n
n
m
m
a
b
b
a
Me
H
R-(+)-A
S-(–)-A
Me
CO2H
s
r
s
r
o
o
X–X
X–X
( )-A+Br–
mp 161–163 °C
Me
Me
Me
HO2C
Me
H
CO2H
H
Figure 1 The enantiomorphous crystals of salt A.
Therefore we analysed, reproduced, supplemented and devel-
oped the above results.
We examined two versions of the synthesis of 1 on an 0.1 mol
scale (Scheme 2)§ and found that only iodoallylation at the
final stage [the advantages of this synthesis were noted previ-
ously5(a),(d)] affords pure product 1, which is nonhygroscopic
[in accordance with data from ref. 10(c) and in contrast to data
from refs. 5(a),(d)]. In the second version of the synthesis,
disproportionation by-products3,4 are formed (cf. ref. 33), which
were isolated and identified. Thus, we found that the data by
Wedekind are reproducible; however, the version of synthesis is
of crucial importance. It is likely that this fact is responsible for
discrepant results by Fock concerning studies of α,β,γ-salts
obtained in different manners.5,13 Unfortunately, the procedure
used for the synthesis of 1 was also not specified in refs. 19, 24.
X–X = OsO4,
cat. Ba(ClO3)2
H2O (~0 °C)
HO
Me
OH
HO
OH
Me
Me
CO2H
Me
HO2C
H
H
40–60%
ee > 95%
2R,3S
2S,3R
Figure 2 2D ® 3D Absolute asymmetric synthesis in tiglic acid bis-
hydroxylation.
Well-formed bright transparent crystals of (+)- or (–)-1
(weighing as much as 0.1 g) were prepared by crystallisation
from thoroughly purified dry chloroform at –6 °C. These crystals
were somewhat different in the specific rotation (a crystal was
cut in half to perform these measurements). The chiral space
group P212121 and the absolute configuration S-(+)-1 were
found by X-ray diffraction analysis using a portion of the
crystal with maximum [a]D 28.8° (c 0.8, CHCl3). The barrier
∆G# = 26.5 kcal mol–1 at 25 °C in CHCl3 was found from the
kinetics of racemisation. Thus, we supported the data by Fock
on the crystallisation of compound as a conglomerate, which
are based on the hemihedrism of the crystals, the data by
Wedekind on the spontaneous racemisation of (+)-1 and the
results by Havinga on the spontaneous resolution of 1.
Considering chloroform incorporated in 1 as a conglo-
merator,2 we removed CHCl3 by evacuation (1 torr) (signals of
CHCl3 in the 1H NMR spectra were monitored in [2H6]acetone).
The crystallisation of the sample from EtOH–Et2O with the
addition of a half-molar amount of the conglomerator CHCl3
(at –6 °C) afforded S-(+)-1 in 20–35% yield, ee 61–70%. Next,
we separated 1 by the internal entrainment procedure.2(c) In
essence, this technique is a version of spontaneous resolution
because the single crystal used for seeding was taken from a
starting racemic mixture. A well-formed crystal (1–3 mg) was
taken from the sample of 1 (150 mg). This crystal was used as a
seed in the crystallisation (with self-evaporation) of this sample
from a supersaturated solution in CHCl3 at 20–25 °C. The
crystals of (+)-1 or (–)-1 were separated in 30–35% yields and
ee 70–75% after 3–5 days. In an analogous experiment, the
precipitate contained a small amount of the solvent after two
weeks. After the removal of the solvent in vacuo (10 torr), the
starting material was completely recovered to an optically active
form (ee 21%). This experiment was repeated with crystallisation
for a month at –6 °C followed by the solvent removal in vacuo
(10 torr). Surprisingly, this experiment also afforded optically
active 1 (ee 16%). Hence, it follows that an autocatalytic effect
of enantiomerisation of 1 occurs in the formation of a solid
phase. A similar effect was observed previously17(d),(e) for the
asymmetric diastereomeric transformation of 1-α-carboxyethyl-
3,3-bis(trifluoromethyl)diaziridine (αS, 1S, 2S) ® (αS, 1R, 2R).
At the inversion barrier ∆G# = 22.5 kcal mol–1 (at 25 °C in
acetone), crystallisation even at –80 °C gave only the first
diastereomer. Analogously, the crystallisation (–6 °C) of N,N'-
dinitroso-N,N'-dimethylethylenediamine [an equilibrium 1:1
mixture of syn–syn and syn–anti rotamers (NO with respect
to MeN); the barrier of hindered rotation about the N–N bond
∆G# = 23.3 kcal mol–1] gave only the first rotamer (relevant
§
1H and 13C NMR spectra were measured at 400.13 and 100.61 MHz,
respectively; optical activity was studied on a Polamat A polarimeter.
1 was obtained from PhN(Me)Et and allyl iodide (12 h at 20 °C), yield
82%; from 2 and EtI (1 month at 6 °C, in the dark), yield 36.6%, mp 79–
80 °C (CHCl3); for selected monocrystal [a]D20 = –28.8°, [a]578 = –29.4°,
1
[a]546 = –33.8° (c 0.8, CHCl3). H NMR (400.13 MHz, [2H6]acetone)
d: 1.1 (t, 3H, MeC, 3J 7.0 Hz), 3.85 (s, 3H, MeN), 4.41 (m, 2H,
2
CH2Me, ABX3 spectrum, ∆n 66.0 Hz, J –13.7 Hz, 3J 7.0 Hz), 5.05 (m,
2H, CH2CH, ABX spectrum, ∆n 40.6 Hz, 2J –13.1 Hz, 3JAX 7.7 Hz, 3JBX
3
2
6.4 Hz), 5.49 (dd, 1H, Hb, Jab 10.1 Hz, Jac 2.0 Hz), 5.69 (m, 1H, Ha),
5.80 (dd, 1H, Hc, Jac 16.8 Hz, 2Jbc 2.0 Hz), 7.66 and 8.21 (m, 5H, Ph),
3
8.38 (s, 1H, CHCl3) {for CHCl3 1H NMR ([2H6]acetone) d: 7.95}.
13C NMR ([2H6]acetone) d: 8.17 (qt, MeCH2, J 129.3 Hz, J 2.9 Hz),
1
2
1
1
47.02 (q, MeN, J 143.9 Hz), 63.04 (t, CH2Me, J 143.9 Hz), 69.67 (t,
CH2CH, 1J 146.7 Hz), 79.22 (d, CHCl3, 1J 215.1 Hz), 125.12 (d, CH=CH2,
1J 159.8 Hz), 127.83 (t, CH2=CH, 1J 159.1 Hz), 122.36, 129.9, 130.0 and
141.32 (d, d, d and s, Ph, 1J 162.8, 164.2 and 164.0 Hz). Found (%): N
3.20. Calc. for C12H20NI·CHCl3 (%): N, 3.32.
2 was obtained from N-methylaniline and allyl bromide in abs. MeOH
(boiling for 20 h), yield 80%, bp 80 °C (5 torr). 1H NMR (CDCl3) d:
2.94 (s, 3H, Me), 3.92 (dt, 2H, CH2, 3J 5.0 Hz, 4J 1.7 Hz), 5.14 (dq, 1H,
1
2
3
Hb, Jab 10.1 Hz, Jbc = 4J = 1.7 Hz), 5.18 (dq, 1H, Hc, Jac 17.1 Hz,
2Jbc = 4J = 1.7 Hz), 5.85 (ddt, 1H, Ha, J
5.0 Hz, Jab 10.1 Hz, Jac
3
3
3
HaCH2
17.1 Hz), 6.7, 6.73 and 7.24 (m, 5H, Ph).
3 was identified in the mixture with 1 and 4. 13C NMR ([2H6]acetone)
d: 47.2 (q, MeN, 1J 144.0 Hz), 69.05 (t, CH2CH, 1J 147.0 Hz), 125.0 (d,
CHCH2, 1J 160.0 Hz), 127.8 (t, CH2CH, 1J 159.0 Hz), 122.0, 129.7,
130.4 and 140.9 (d, d, d, and s, Ph, 1J 163.0, 164.0 and 164.1 Hz).
4, mp 102–104 °C (MeOH–Et2O), identified with the sample obtained
from PhNEt2 and MeI. 1H NMR ([2H6]acetone) d: 1.15 (t, 6H, MeC, 3J
7.0 Hz), 3.83 (s, 3H, MeN), 4.37 (m, 4H, 2CH2Me, ABX3 spectrum,
2
3
∆n 47.0 Hz, J –14.1 Hz, J 7.0 Hz), 7.65, 7.70 and 8.12 (m, 5H, Ph).
13C NMR ([2H6]acetone): 8.42 (qt, MeCH2, 1J 127.9 Hz, 2J 2.9 Hz),
1
1
46.95 (q, MeN, J 142.4 Hz), 64.38 (t, CH2Me, J 146.8 Hz), 122.82,
130.36, 130.64 and 141.81 (d, d, d and s, Ph, 1J 162.8, 164.2 and 164.8 Hz).
Asymmetric transformation of ( )-1 by stirred crystallisation from a melt.
The single crystal (4.5 mg) was taken from the sample of ( )-1 (200 mg).
The sample and a teflon-coated magnetic stirring bar (l = 8 mm, 6 mm in
diameter) were put in a molybdenic glass ampoule (l = 10 cm, 1 cm in
diameter), and the single crystal was put in a side arm of the ampoule.
The ampoule was evacuated (1 Torr) and cooled with liquid nitrogen.
Then, the ampoule was heated to room temperature and filled with CHCl3
vapour, then cooled again and sealed. The sample was heated to melting
point, then cooled to 75 °C. The crystal from the arm was transferred to
the ampoule, and stirred (800–1000 rpm). After 2–5 h, full sample crys-
tallisation occurred. The ampoule was opened, the sample dissolved in
CHCl3 and the optical rotation of the solution was measured. The experi-
ment was repeated three times with the following results: [a]D18 = +28.0,
–28.2 and +28.4° (c 0.8, CHCl3), ee 97.2, 97.9 and 98.5%, respectively.
– 3 –

, 2001, 11(1), 1–6
data will be published elsewhere). Nevertheless, an increase in
the degree of asymmetric conversion with temperature should
be expected. W. A. Bonner, commenting the work by Havinga
as early as 1972, wrote:25(a) “...With gradual evaporation of the
solvent, all of the original racemate might in principle crys-
tallise as the (–)-isomer, provided that the (+)-isomer has not
itself undergone chance nucleation in the meantime.” Indeed,
highly enriched (+)-1, ee 31%, can be obtained by crystallisation
from boiling chloroform up to almost complete evaporation.
In stirred crystallisation3,28 (500–600 rpm), ee increased up to
51% and became even higher, up to 95%, on the addition of a
single crystal from the starting mixture at the step of semi-
evaporation. Stirred crystallisation from a melt (in a sealed
ampoule with CHCl3 vapour) with the addition of a single
crystal to the melt cooled to 75 °C gave a somewhat greater
effect (ee 98.5%). Thus, the racemic mixture of 1 was almost
fully converted into one enantiomer, and the idea proposed by
Havinga was completely supported.
(QTAM)36(a) have shown that such a type of the halogen···
halogen shortened contacts can be described as a donor–acceptor
interaction of a lone pair with an antibonding orbital.36(b),(c) The
assumption of such a character for the I(1)···Cl(3) interaction
will imply the elongation of the corresponding C–Cl bond,
while the observed C(13)–Cl(3) bond length is practically the
same [1.761(3) Å] as the remaining [1.768(3) and 1.766(3) Å].
In order to investigate the character of short I···Cl contacts,
we performed the QTAM analysis in the HCl2C–Cla···I– frag-
ment on the basis of calculations at the MP2 level of theory
(Gaussian 94) using the 6-31G* basis for Cl, C and H atoms
(a)
Cl(1)
C(4)
C(3)
C(2)
Cl(2)
C(5)
C(13)
C(6)
Cl(3)
C(1)
N(1)
Salt 1 was studied by X-ray diffraction analysis,¶ initially,
with the use of a random crystal and, subsequently, with a crys-
tal known to be optically active in order to determine the abso-
lute configuration. The crystal structure of 1 contains the (S)-(+)
quaternary ammonium cation, the iodide anion and the solvate
chloroform molecule [Figure 3(a)].
C(11)
C(8)
C(7)
C(10)
C(12)
C(9)
I(1)
The most striking features of 1 were found within the crystal
packing analysis. In addition to the weak Cl···H contacts [Cl···H
2.83 Å, Cl···H–C 172 and 137°, for Cl(2) and Cl(3), respecti-
vely] between the CHCl3 molecule and the allyl hydrogens of
the cation [even shorter intramolecular constants Cl···H (2.59 Å)
were observed for the Ti complexes],34 the former also takes
part in the formation of shortened contacts with the I– anion.
The CHCl3 molecule is assembled with the I– not only by
the short H(13)···I contact [H(13)···I(1') (–1 – x, /2 + y, /2 – z)
2.81 Å, C(13)–H(13)···I(1') 148°] but also by ‘long’ and ‘short’
I···Cl contacts [C(13)–Cl(3)···I(1) 3.599(2) Å, C(13)–Cl(3)–I(1)
168.6(1)°; Cl(1)···I(1'') (–1/2 – x, 1 – y, 1/2 + z) 3.889(2) Å, C(13)–
Cl(1)···I(1'') 155.1(1)°] [Figure 3(b)]. Thus, the crystal packing
in 1 can be described as a 3D framework formed by the CHCl3
molecule and the I– anion assembled by short I···H and I···Cl
contacts, with quaternary ammonium cations located in the
framework cavities [Figure 3(c)].
(b)
a
Cl(2)
C(13)
Cl(3)
Cl(1)
H(13)
1
1
I(1)
H(13'')
c
0b
It is noteworthy that according to CCDB (release 2000) the
Cl(3)···I(1) contact in 1 is one of the shortest for the Cl···I– type.
Taking into consideration the difference in the van der Waals
radii of I and Cl atoms (0.26 Å),35(a) this contact is comparable
with the Cl···Cl one in the crystal of chlorine (3.294 Å).35(b)
The recent topological analysis of the electron density func-
tion [r(r)] within the quantum theory of ‘Atoms in molecules’
(c)
c
0a
¶
Crystallographic data for 1: crystals of (C12H18N)(I)(CHCl3) are ortho-
rhombic at 100 K, space group P212121, a = 9.8591(6) Å, c = 13.7637(9) Å,
V = 1710.5(2) Å3, Z = 4, M = 422.54, dcalc = 1.641 g cm–3, m(MoKα) =
= 23.26 cm–1, F(000) = 832. The intensities of 17743 reflections were
measured with a Smart 1000 CCD diffractometer at 100 K [l(MoKa) =
= 0.71072 Å, w-scans with a 0.3° step in w and 10 s per frame exposure,
2q < 60°], and 4878 independent reflections (Rint = 0.0296) were used in
the further refinement. The absorption correction was carried out semi-
empirically from equivalents using the Sadabs program. The structure
was solved by a direct method and refined by the full-matrix least-
squares technique against F2 in the anisotropic–isotropic approximation.
Hydrogen atoms were located from the Fourier synthesis and refined in
the isotropic approximation. The absolute (+)-configuration of the N(1)
atom in 1 was confirmed by estimating the Flack absolute parameter
which, in case of (S) configuration of N(1), has a value close to zero with
a rather small e.s.d., 0.00(2). The refinement converged to wR2 = 0.0611
and GOF = 1.062 for all independent reflections [R1 = 0.0234 was calcu-
lated against F for 4623 observed reflections with I > 2s(I)]. The number
of the refined parameters was 218 (the ratio of the refined parameters for
observed reflections was more than 20). All calculations were performed
using SHELXTL PLUS 5.0 on IBM PC AT. Atomic coordinates, bond
lengths, bond angles and thermal parameters have been deposited at
the Cambridge Crystallographic Data Centre (CCDC). For details, see
‘Notice to Authors’, Mendeleev Commun., Issue 1, 2001. Any request to
the CCDC for data should quote the full literature citation and the
reference number 1135/78.
b
Figure 3 (a) The view of 1 [ellipsoids plot (50%)] illustrating the contents
of the unit cell. The main bond lengths (Å): N(1)–C(1) 1.490(3), N(1)–C(7)
1.546(3), N(1)–C(10) 1.541(3), N(1)–C(12) 1.490(3), C(13)–Cl(1) 1.768(3),
C(13)–Cl(2) 1.766(3), C(13)–Cl(3) 1.761(3); bond angles (°) C(1)–N(1)–
C(12) 113.6(2), C(12)–N(1)–C(10) 109.3(2), C(1)–N(1)–C(10) 109.3(2),
C(12)–N(1)–C(7) 107.3(2), C(1)–N(1)–C(7) 111.0(2), C(10)–N(1)–C(7)
105.9(2), Cl(1)–C1(3)–Cl(2) 110.2(1), Cl(1)–C(13)–Cl(3) 110.6(2), Cl(2)–
C(13)–Cl(3) 111.1(2). (b) H···I– and I–···Cl contacts. (c) The crystal
structure of 1.
– 4 –

, 2001, 11(1), 1–6
7
(a) J. A. Le Bel, Compt. Rend., 1891, 112, 724; (b) W. Marckwald and
A. F. Droste-Hülshoff, Ber. Dtsch. Chem. Ges., 1899, 32, 560; (c)
J. A. Le Bel, Compt. Rend., 1899, 129, 548.
N. Menschutkin, Ber. Dtsch. Chem. Ges., 1895, 28, 1398.
M. Scholtz, Ber. Dtsch. Chem. Ges., 1905, 38, 595.
and 3-21G* for I atoms. This calculation leads to the geometry
of the I···Cl contact (Cla···I, C–Cla···I equal to 3.476 Å and
177.87°, respectively) similar to that found for I(1)···Cl(3) in 1.
In spite of the shorter I···Cl contact observed in the ab initio
calculation of HCl2C–Cla···I– the C–Cla bond, instead of the
expected elongation, is significantly shortened (1.752 Å) in
comparison with remaining (1.784 Å).
8
9
10 (a) W. J. Pope and S. J. Peachey, J. Chem. Soc., 1899, 75, 1127; (b)
W. J. Pope and A. W. Harvey, J. Chem. Soc., 1901, 79, 828; (c)
M. B. Thomas and H. O. Jones, J. Chem. Soc., 1906, 89, 280; (d)
R. W. Everatt, J. Chem. Soc., 1908, 93, 1225; (e) F. S. Kipping and
The QTAM analysis of the HCl2C–Cl···I– revealed that critical
points (CP) (3,–1) (the necessary and sufficient condition of the
chemical bond36(a)) are observed on C–Cl and C–H bonds as
well as on the I···Cl contact. All bonds in the HCCl3 molecule
are characterised by negative values of the laplacian of r(r)
[Ñ2r(r)] and local energy density E(r) in CP (3,–1); that is, the
characteristic of the shared type of interaction. On the contrary,
the I···Cl contact is characterised by positive values of both
Ñ2r(r) and E(r) in CP (3,–1) thus indicating the closed-shell
type of this interaction. It is noteworthy that the values of r(r)
(0.085 eÅ–3) and Ñ2r(r) (0.839 eÅ–5) for CP (3,–1) of the I···Cl
contact are close to those obtained earlier for the Cl···Cl contact
in chlorine (0.062 eÅ–3, 0.805 eÅ–5)36(b) and ClF (0.135 eÅ–3,
1.06 eÅ–5)36(c) crystals. Taking into account that the value of
r(r) correlates with the bond order,36(a) this observation means
that the I···Cl interaction is characterised by the comparable
strengths with the Cl···Cl (3.294 Å)35(b) one in the chlorine
crystal. The same conclusion can also be made on the basis of
the Cl···Cl and I···Cl contacts.
W. J. Pope, J. Chem. Soc., 1898, 73, 606.
11 (a) J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates,
and Resolutions, Krieger Publ. Comp., Malabar, Florida, 1994; (b)
A. Collet, Enantiomer, 1999, 4, 157.
12 (a) A. L. Fock, Einleitung in die chemische Krystallographie, Engelmann,
Leipzig, 1888; (b) A. Fock, An Introduction in Chemical Crystallo-
graphy, ed. W. J. Pope, Clarendon Press, Oxford, 1895.
13 A. Fock, Z. Krystallogr. Mineralog., 1902, 35, 394.
14 G. B. Kauffman and I. Bernal, J. Chem. Educ., 1989, 66, 293.
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88
4693; (c) J. H. Brewster and R. S. Jones, J. Org. Chem., 1969, 34, 354.
16 (a) L. Horner, H. Winkler and E. Meyer, Tetrahedron Lett., 1965, 789;
(b) A. F. Peerdeman and J. P. C. Holst, Tetrahedron Lett., 1965, 811.
17 (a) V. F. Rudchenko and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR,
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A. C. Cope, W. R. Funke and F. N. Jones, J. Am. Chem. Soc., 1966,
,
An analysis of the C–Cl bond polarity by means of the
difference of bonded radii [the distance from the nucleus to CP
(3,–1)] have revealed that the C–Cla bond is characterised by
the lowest one (0.14 Å) in comparison with remaining C–Cl
bonds (0.22 Å). Thus, the observed shortening, instead of the
expected elongation, of the C–Cla bond is the result of the
reverse polarity, which is induced by the iodine negative charge.
38, 949; (e) G. V. Shustov, A. B. Zolotoi, N. L.
Zaichenko, O. A. Dyachenko, L. O. Atovmyan and R. G. Kostyanovsky,
Tetrahedron, 1984, 40, 2151.
Tetrahedron, 1982,
18 D. A. Lenev, K. A. Lyssenko and R. G. Kostyanovsky, Izv. Akad. Nauk,
Ser. Khim., 2000, 1244 (Russ. Chem. Bull., 2000, 49, 1241) .
19 E. Havinga, Enjoying Organic Chemistry, 1927–1987, in Profiles,
Pathways and Dreams. Autobiographies of Eminent Chemists, ed.
J. I. Seeman, ACS, Washington, DC, 1991.
20 B. S. Green, M. Lahav and D. Rabinovich, Acc. Chem. Res., 1979, 12,
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21 (a) E. Havinga, Chem. Weekblad, 1941, 38, 642 (Chem. Abstr., 1942,
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22 M. Calvin, Chemical Evolution, Oxford University Press, London,
1969, p. 150.
23 V. Avetisov and V. Goldanskii, Proc. Nat. Acad. Sci., 1996, 93, 11435.
24 Y. Okada, T. Takebayashi, M. Hashimoto, S. Kasuga, S. Sato and
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This work was supported by the Russian Foundation for Basic
Research (grant no. 00-03-32738), INTAS (grant no. 99-0157),
and DFG-RFBR (grants nos. 436 RUS 113/494/0 and 98-03-
04119, respectively).
We are grateful to Professor V. Schurig for the photo and
biography data of E. Wedekind, to Professors G. B. Kauffman,
H.-G. Schütte, and W. Thiemann for the information about
A. L. Fock, to Professor J. Cornelisse for the photo and bio-
graphy data of E. Havinga. Unfortunately, we failed to find a
portrait of Fock.
26 B. L. Feringa and R. A. van Deldon, Angew. Chem., Int. Ed. Engl.,
1999, 38, 3419.
27 H. Buschmann, R. Thede and D. Heller, Angew. Chem., Int. Ed. Engl.,
2000, 39, 4033.
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29 P. Chinna Chenhalah, H. L. Holland and M. F. Richardson, J. Chem.
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30 (a) I. Kuzmenko, I. Weissbuch, E. Gurovich, L. Leiserowitz and M. Lahav,
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33 E. Fröhlich, Ber. Dtsch. Chem. Ges., 1909, 42, 1561.
34 T. Spaniel, H. Gorls and J. Scholz, Angew. Chem., Int. Ed. Engl., 1998,
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Received: 15th January 2001; Com. 01/1746
– 5 –