Verification of stereospecific dyotropic racemisation of enantiopure d and l-1,2-dibromo-1,2-diphenylethane in non-polar media

Article abstract of DOI:10.1039/c2cc33676f

The first example of a dyotropic rearrangement of an enantiomerically pure, conformationally unconstrained, vicinal dibromide confirms theoretical predictions: d and l-1,2-dibromo-1,2-diphenylethane racemise stereospecifically in refluxing benzene without crossover to the meso-isomer. An orbital analysis of this six-electron pericyclic process is presented.

Full text of DOI:10.1039/c2cc33676f

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COMMUNICATION
Verification of stereospecific dyotropic racemisation of enantiopure D and
L-1,2-dibromo-1,2-diphenylethane in non-polar mediaw
D. Christopher Braddock,*a Debjani Roy,b Dieter Lenoir,c Edward Moore,a Henry S. Rzepa,a
b
b
´
Judy I-Chia Wu and Paul von Rague Schleyer*
Received 22nd May 2012, Accepted 5th July 2012
DOI: 10.1039/c2cc33676f
The first example of a dyotropic rearrangement of an enantio-
merically pure, conformationally unconstrained, vicinal dibromide
confirms theoretical predictions: D and L-1,2-dibromo-1,2-diphenyl-
ethane racemise stereospecifically in refluxing benzene without
crossover to the meso-isomer. An orbital analysis of this six-
electron pericyclic process is presented.
without any interconversion into the meso isomer.z Such a
stereochemical outcome would be a signature for a dyotropic
mechanism and amenable to experimental study. The only report of
a simple, optically active, 1,2-dibromide in which both stereogenic
centres bear bromine atoms indicated that chiral 2,3-dibromo-
butane had not racemised after nine years!y This corresponds to a
29 kcal molꢀ1 lower limit for the free energy of a dyotropic
rearrangement. The present study seeks to demonstrate such
rearrangements by employing computational searches to identify
promising candidates and conditions for experimental verification.
We show herein that computations predict that the dyotropic
rearrangement of D or L-1,2-dibromo-1,2-diphenylethane (stilbene
dibromide, 1) in solvents of low polarity is favoured over
alternative ionic interconversion mechanisms,11 and demonstrate
experimentally that enantiomerically enriched D and L-1 undergo
smooth interconversion (i.e. racemisation) via dyotropic rearran-
gement in benzene solution at reflux with no crossover to the
meso-diastereoisomer (2). We also present an orbital analysis for
this six-electron pericyclic process.
In 1952 Grob and Winstein1 elucidated the mechanism of
the long-known mutarotation of 5a,6b-dibromocholestane
(the bromination product of cholest-5-ene).2 Remarkably,
they concluded that the two bromines migrate simultaneously
and intramolecularly via an intermediate or TS3 (typically
represented by A) with essentially equivalent Br’s having very
little charge separation. Reetz4 named, classified, and defined
such ‘‘dyotropic’’ rearrangements5 as uncatalysed6 pericyclic
processes in which two sigma bonds interchange under orbital
symmetry control: dyotropic rearrangements involving the
stereospecific exchange of two migrating groups in 1,2-anti
conformations necessarily lead to inversion of configuration at
both positions.3–5 The observation of rearrangements of substituted
1,2-dibromocyclohexanes and other alkyl dibromides7 as well
as several computational studies8–10 support the generality of such
vicinal dihalide reactions. However, there has been no direct
experimental verification of a concerted dyotropic rearrangement
of an acyclic 1,2-dibromide. Such dyotropic rearrangements of
symmetrical dibromides having DL and meso isomers should result
in the smooth racemisation of the D- or L-dibromide enantiomers
by inversion of configuration at each of the stereocentres,
The first objective, to locate a simple dibromide more reactive
than 2,3-dibromobutane toward dyotropic rearrangement, was
met when our computations predicted that DL-1,2-dibromo-1,2-
diphenylethane (1) had a sufficiently low free energy barrier to
faciliate experimental study. The available theoretical data on
dyotropic barriers8–10 had not included this compound.z
Isomerisation of 1 and its meso isomer 2 via ion-pair or other
polar mechanisms may also be expected, at least in ionising
solvents where benzyl cation-type stabilisation favor ionic
processes.11 Indeed, the related bromination of trans- and
cis-stilbenes and the debromination and other reactions of
the corresponding meso- and DL-dibromides in such solvents
are reported to be complex and to depend on the conditions.11
Although the possibility has not been considered in the
literature, we wondered if our predicted exchange in low
dielectric media of two bromine atoms of the D- or L-1
enantiomer through non-polar dyotropic transition states
(A) would actually be favoured.
a Department of Chemistry, Imperial College London, London,
SW7 2AZ, UK. E-mail: c.braddock@imperial.ac.uk;
Fax: +44 (0)2075945805; Tel: +44 (0)2075945772
b Department of Chemistry, University of Georgia, Athens, GA 30602,
USA. E-mail: schleyer@uga.edu; Tel: +1 7065427510
c Institute of Ecological Chemistry, Helmholtz-Center Munich,
D-85758 Neuherg, Germany
w Electronic supplementary information (ESI) available: General experi-
mental, experimental details and characterising data for bromides 1 and 2,
1H and 13C NMR spectra for dibromides 1 and 2, separation of D- and
L-1,2-dibromo-1,2-diphenylethane by chiral HPLC methods, experimental
details for dyotropic rearrangement of D and L-1, HPLC analysis of
dyotropic rearrangement, 1H NMR spectra post-dyotropic rearrange-
ments, kinetic analysis of dyotropic rearrangements, data for dyotropic
rearrangement of D- and L-1 in benzene at 80 1C and graphical extraction
of rate constant for dyotropic rearrangement of D- and L-1 in benzene at
80 1C. See DOI: 10.1039/c2cc33676f
c
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Chem. Commun., 2012, 48, 8943–8945 8943

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Table 1 Substituent effects on dyotropic isomerization barriersa,b
were unsuccessful; good yields of E and Z stilbene mixtures
(typically 3 : 1) were obtained instead. However, chiral HPLC
methods** were able to separate DL-dibromide 1ww (obtained
by bromination of Z-stilbene with Br2 in dichloromethane
solution)16 into its enantiomers. Analogous bromination of
E-stilbene gave meso-1,2-dibromo-1,2-diphenylethane 2,ww
required as an authentic control sample.
Free energy barrier,
DGz
Entry Dibromide
353
1
2
3
4
5
1,2-Dibromoethane
DL-2,3-Dibromobutane
DL-1,2-Dibromocyclohexane
31.3
23.7
25.4
DL-1,2-Dibromo-1,2-diphenylethane (1) 21.7 (21.0)c
1, ion-pair mechanism
27.0 (27.8)c
Our aim was to test the theoretical predictions that racemisation
(by a dyotropic rearrangement) but not DL-meso interconversion
should occur under favorable (i.e., non-polar) conditions.zz We
first explored the thermal stability of dibromides 1 and 2 in various
solvents.17 Heating either DL-1 or meso-2 in polar aprotic (DMF at
120 1C, DMSO at 80 1C) or in polar protic solvents (1,1,1,3,3,3-
hexafluoroisopropanol at 60 1C) led to complex product mixtures.yy
On the basis of earlier observations,1,3,7,11 and our computations,
we expected non-ionizing solvents to be optimal for the detection of
dyotropic rearrangements and the suppression of side reactions.
Indeed, in direct contrast to our results in polar media, no
a
In kcal molꢀ1 computed for a benzene continuum solvent model at
b
c
the B3LYP/Def-2 QZVPP level.8 See interactivity box. At the
B3LYP/6-311G(d,p)-simulated benzene level.
The computed,12,138 transition structures for dyotropic
rearrangement lack ion-pair character, having modest dipole
moments (B4.6 D for 1) and are little affected (B1–2 kcal molꢀ1
)
by low polarity solvents such as benzene (Table 1). Methyl or
alkyl substituents lower the barriers modestly (entries 1–3); the
computed barrier for the dissymmetric system with two phenyl
groups (entry 4) is low enough for experimental verification. The
computed intrinsic reaction coordinate, as well as the transition
structure, reactant, and product geometries for the dyotropic
DL-1,2-dibromo-1,2-diphenylethane (1) rearrangement are depicted
in Fig. 1. Dyotropic shifts of the bromines result in direct
interconversion (i.e. racemisation) of the D- or L-enantiomer
without any intervention of the meso isomer.
1
appreciable changes in the H NMR spectra of either DL-1 or
meso-2 were observed after extended heating at reflux in either
benzene solution (5 days) or in dichloromethane (3 days), in
the absence of catalysts.zz
As this establishes that no DL-meso interconversion occurs in
benzene solution at 80 1C, single D and L-dibromide enantiomers
were heated separately in benzene solution at 80 1C to monitor any
dyotropic rearrangement. Much to our delight, slow conversions
of R,R-1 into S,S-1, and also S,S-1 into R,R-1 at identical rates,
were observed with typical first order kinetics (k = 0.0015 sꢀ1 at
80 1C, equivalent to DGz353 25.3 kcal molꢀ1),** and without any
formation of meso-dibromide diastereoisomer 2. Thus, this behavior
of individual stilbene dibromide enantiomers as stereochemical
probes demonstrates the first dyotropic rearrangement of
enantiomerically pure, conformationally unconstrained vicinal
dibromides. The absence of meso-isomer 2 under these conditions
rules out possible alternative dissociation–recombination pathways
involving an intermediate bromonium ion–bromide anion pair
(as seen in solvents of high polarity), or free stilbene and
molecular bromine.11 In line with the theoretical prediction
that the dyotropic transition state is stabilized by the two phenyl
groups (Table 1), our observed first order rate constants are up
to two orders of magnitude faster than the rate constants for the
mutarotation of dibromocholestane previously determined by
Grob and Winstein1 and by Barton and Head,3 as well as the
rate measurements of Barili et al.7 on sterically uncongested
trans-1,2-dibromocyclohexanes.
In contrast to the dyotropic mechanism (Table 1), our
computations8 find that the lowest energy alternative transition
state for 1 with ion-pair character (entry 5) has a much larger
dipole moment (B13 D). The highest computed free energy
barrier for this pathway (in simulated benzene) is B5.3 kcal molꢀ1
above that of the dyotropic mechanism; hence, the latter is clearly
favoured in such non-polar media.
Individual DL-1,2-dibromo-1,2-diphenylethane enantiomers
(1) were required for the experimental study. Attempts to
prepare the D or L-dibromide14 by double Appel bromination15
of the readily available enantiomerically pure hydrobenzoin
The computed C–C bond lengths (B1.44 A)8 of the dibromo
dyotropic transition states suggest partial double bond character
(Wiberg bond index B1.215)8 and require explanation. Previous
orbital analyses4,5,10 did not address this issue directly nor clearly
define the number of electrons participating in this pericyclic
process. Our orbital analysis of 1,2-dibromoethane shown in
Fig. 2 defines this as a six-electron pericyclic process; three
doubly occupied orbitals (4b1g, 9b3u and 11ag) comprising what
can be described as tangential, p, and radial MOs, respectively,
are involved. The previous analyses5,10 did not include the radial
MO. The combination of these three MOs, as well as lower MOs
(see interactivity box), result in the partial double bond character.
Thus, representation A showing partial double bond character,
first used by Winstein1 and by Barton,3 is clearly appropriate.
Fig. 1 Intrinsic reaction coordinate (IRC) for the dyotropic inter-
conversion of D/L-1,2-diphenyl-1,2-dibromoethane, computed at the
B3LYP/6-311g(d,p) level with a continuum solvent correction for
benzene. As C2-symmetry is maintained throughout, the asymmetry
of the IRC is due to the different phenyl conformations of reactant and
product. These conformations can interconvert by a second dynamic
process with only a small barrier. The C–C bond length is 1.437 A at
the transition state.8 See interactivity box for animations.
c
8944 Chem. Commun., 2012, 48, 8943–8945
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zz The DL-meso interconversion might occur by mechanisms involving
(a) elimination to free E or Z stilbene and Br2 followed by non-
stereospecific re-addition (ref. 16) or (b) free carbocations and/or
(partially) bridged bromonium ions, C–C bond rotation and/or non-
selective bromide return. See ref. 11 for excellent discussions.
yy E-stilbene and monobromostilbene were the major constituents of
the reaction mixtures using meso-2 and DL-1 respectively in DMSO at
80 1C. This implicates the loss of molecular bromine (cf. note above)
from meso-2 and non-selective bromination/oxidation of substrate
and/or solvent, and loss of HBr and subsequent acid mediated
processes for DL-1 (also see ref. 17).
zz A DL-1 to meso-2 isomerization in refluxing benzene with catalytic
molecular iodine has been reported (ref. 11d).
1 C. A. Grob and S. Winstein, Helv. Chim. Acta, 1952, 99, 782–802.
2 J. Mauthner, Monatsh. Chem., 1906, 27, 421–431. See ref. 10 for
relevant computations.
3 D. H. R. Barton and A. J. Head, J. Chem. Soc., 1956, 932–937.
4 (a) M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1972, 11, 129–130;
(b) M. T. Reetz, Tetrahedron, 1973, 29, 2189–2194; (c) M. T. Reetz,
Adv. Organomet. Chem., 1977, 16, 33–65.
5 For a recent review of the mechanisms and synthetic applications
of dyotropic rearrangements, see: I. Fernandez, F. P. Cossıo and
´ ´
M. A. Sierra, Chem. Rev., 2009, 109, 6687–6711.
6 General acid catalysis has been discussed: H. Kwart and
L. B. Weisfeld, J. Am. Chem. Soc., 1956, 78, 635–639.
7 (a) P. L. Barili, G. Bellucci, G. Berti, F. Marioni, A. Marsili and
I. Morelli, Chem. Commun., 1970, 1437–1438; (b) G. Bellucci,
A. Marsili, E. Mastrorilli, I. Morelli and V. Scartoni, J. Chem.
Soc., Perkin Trans. 2, 1974, 201–204.
Fig. 2 Orbital analysis for dyotopic rearrangement of 1,2-dibromo-
methane showing the three molecular orbitals involved in the transi-
tion state and a comparison with the corresponding B2H6 MO’s. The
NICS(0)MOzz values and their sums are the out-of-plane (zz) tensor
component of the isotropic NICS of each MO shown, computed at the
molecule centers at PW91/6-311+G(d,p).188 See the interactivity box
for further detail.
8 A. Frontera, G. A. Suner and P. M. Deya
6731–6735.
9 J.-W. Zou and C.-H. Yu, J. Phys. Chem. A, 2004, 108, 5649–5654.
10 I. Fernandez, M. A. Sierra and F. P. Cossıo, Chem.–Eur. J., 2006,
12, 6323–6330.
´
, J. Org. Chem., 1992, 57,
The strong diatropic ring current shown by the dissected
NICS(0)MOzz sum of the three orbitals in Fig. 2 (ꢀ27.0 ppm)
documents the strongly aromatic character of the six-electron,
dyotropic transition state. In contrast, NICS(0)MOzz = +3.5 ppm
of the bridging B2H68 system, involving only four electrons, is
clearly not aromatic.
´
´
11 For excellent discussions see: (a) R. Bianchini and C. Chiappe,
J. Org. Chem., 1992, 57, 6474–6478; (b) M.-F. Ruasse, G. Lo
Moro, B. Galland, R. Bianchini, C. Chiappe and G. Bellucci,
J. Am. Chem. Soc., 1997, 119, 12492–12502; (c) R. E. Buckles,
J. M. Bauer and R. J. Thurmaier, J. Org. Chem., 1962, 27,
4523–4527; (d) W. K. Kwok, I. M. Mathai and S. I. Miller,
J. Org. Chem., 1970, 35, 3420–3423.
We thank Thais Cailleau (Imperial College London) for
preliminary research on attempted Appel brominations of
hydrobenzoins, and Dr Andrew McKinley (Imperial College
London) for helpful discussions. The work in Georgia was
supported by NSF Grant CHE-105-7466. This paper is dedicated
to the memory of Saul Winstein and Cyril A. Grob on their
100th and 95th birthdays, respectively.
12 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A.
Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin,
V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.
Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
Notes and references
z Dyotropic rearrangement of such meso isomers cannot be detected
since it merely involves interconversion to its superimposable mirror
image (i.e., RS 2 SR).
y A neat sample of optically active 2,3-dibromobutane, [a]D ꢀ2.43,
gave a reading of [a]D ꢀ2.17 after standing for nine years in a sealed
ampoule (ref. 1).
z The dyotropic rearrangements of (1,2-dichloroethyl)benzene, and
9,10-dibromo-9,10-dihydrophenananthrene have been investigated
computationally (see ref. 10), but not the effect of simple phenyl
groups in the stilbene dibromides.
8 The computations used the Gaussian 09 program (ref. 12) at the
B3LYP/Def-2 QZVPP (ref. 13a) density functional level. All computed
harmonic frequencies of fully optimized minima were real, whereas
transition structures had a single imaginary frequency. Intrinsic reaction
coordinate (IRC) analyses of the minimum energy pathways (MEPs)
confirmed the connection of transition structures to the reactants and
products described in the text. The polarized continuum model (CPCM)
(ref. 13b and c) implemented in the Gaussian 09 program was used to
simulate the bulk solvation. See the interactivity box for full details.
** See ESIw for details.
¨
Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman,
J. V. Ortiz, J. Cioslowski and D. J. Fox, Gaussian 09, Revision C.1,
Gaussian, Inc., Wallingford CT, 2009.
13 (a) F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys., 2005, 7,
3297–3305; (b) G. Scalmani and M. J. J. Frisch, Chem. Phys., 2010,
132, 114110–114115; (c) D. M. York and M. Karplus, J. Phys.
Chem. A, 1999, 103, 11060–11079.
14 (-)-1,2-Dibromo-1,2-diphenylethane has been reported as being
prepared in low yield (4.5%) as a minor product along with
meso-2 (23%) from (RR)-trans-stilbene oxide in a two-step procedure.
It was assigned as the RR-dibromide: L. Stoev and Y. Stefanovsky,
Izv. Khim., 1977, 10, 587–592.
15 R. Appel, Angew. Chem., Int. Ed. Engl., 1975, 14, 801–811.
16 J. C. Amburgey-Peters and L. W. Haynes, J. Chem. Educ., 2005,
82, 1051–1052.
ww The DL- and meso-isomers can be distinguished readily by their
17 In an early study in pyridine, meso-2 eliminated Br2 giving back
stilbene, while DL-1 eliminated HBr yielding monobromostilbene.
P. Pfeiffer, Ber. Dtsch. Chem. Ges., 1912, 45, 1810–1819.
18 H. Fallah-Bagher-Shaidaei, C. S. Wannere, C. Corminboeuf,
R. Puchta and P. v. R. Schleyer, Org. Lett., 2006, 8, 863–866.
benzylic 13C NMR (CDCl3) resonances at 59.2 and 56.1 ppm, respectively,
by their H NMR (CDCl3) spectra in the aromatic region, and by their
1
100–102 and 240–242 1C melting points, respectively. The meso compound
is much less soluble than its DL-isomer.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8943–8945 8945