The highly stereoselective decarboxylation of (+)-1-bromo-1-chloro-2,2,2- trifluoropropanoic acid to give (+)-1-bromo-1-chloro-2,2,2-trifluoroethane [(+)-halothane] with retention of configuration

Article abstract of DOI:10.1016/j.tetasy.2012.01.023

The absolute configuration of the title acid 2 has been determined to be S by X-ray crystallography. Thus, decarboxylation of 2 produces (S)-(+)-halothane with 99% retention of configuration. This behavior is compared to other stereoselective decarboxylation reactions of α-haloacids from the literature that also gave high degrees of retention of configuration when in the form of their quaternary ammonium salts, which contain one proton. The proton of the ammonium salt is necessary in order to protonate the anionic intermediate formed from decarboxylation. In the absence of this relatively acidic proton, we had previously found that using triethylene glycol (TEG) as both the solvent and proton source for the decarboxylation reaction of acid 2 caused poor stereoselectivity. This was in contrast to 1,2,2,2-tetrafluoro-1- methoxypropionic acid 6, which showed a high degree of retention of configuration in TEG. In order to rationalize this differing behavior, we report DFT studies at PCM-B3LYP/6-31++G level of theory (the results were additionally confirmed with 6-311++G and aug-cc-pVDZ basis sets). The energy barrier to inversion of configuration of the anionic reaction intermediate 11 of acid 2 is 10.23 kcal/mol. However, we find that the anionic intermediate 10 from acid 6 would rather undergo β-elimination instead of inversion of configuration. Thus the planar transition state required for inversion of configuration is never reached, regardless of the rate of proton transfer to the anion.

Full text of DOI:10.1016/j.tetasy.2012.01.023

Tetrahedron: Asymmetry 23 (2012) 201–204
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The highly stereoselective decarboxylation of (+)-1-bromo-1-chloro-2,2,
2-trifluoropropanoic acid to give (+)-1-bromo-1-chloro-2,2,2-trifluoroethane
[(+)-halothane] with retention of configuration
⇑
Keith Ramig , Olga Lavinda, David J. Szalda
Baruch College of The City University of New York, Department of Natural Sciences, 17 Lexington Ave., New York, NY 10010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The absolute configuration of the title acid 2 has been determined to be S by X-ray crystallography. Thus,
decarboxylation of 2 produces (S)-(+)-halothane with 99% retention of configuration. This behavior is
compared to other stereoselective decarboxylation reactions of a-haloacids from the literature that also
Received 15 November 2011
Accepted 31 January 2012
Available online 28 February 2012
gave high degrees of retention of configuration when in the form of their quaternary ammonium salts,
which contain one proton. The proton of the ammonium salt is necessary in order to protonate the anio-
nic intermediate formed from decarboxylation. In the absence of this relatively acidic proton, we had pre-
viously found that using triethylene glycol (TEG) as both the solvent and proton source for the
decarboxylation reaction of acid 2 caused poor stereoselectivity. This was in contrast to 1,2,2,2-tetra-
fluoro-1-methoxypropionic acid 6, which showed a high degree of retention of configuration in TEG. In
order to rationalize this differing behavior, we report DFT studies at PCM-B3LYP/6-31++G⁄⁄ level of the-
ory (the results were additionally confirmed with 6-311++G⁄⁄ and aug-cc-pVDZ basis sets). The energy
barrier to inversion of configuration of the anionic reaction intermediate 11 of acid 2 is 10.23 kcal/mol.
However, we find that the anionic intermediate 10 from acid 6 would rather undergo b-elimination
instead of inversion of configuration. Thus the planar transition state required for inversion of configura-
tion is never reached, regardless of the rate of proton transfer to the anion.
This article is dedicated to Dr. Leonid Rozov
on the occasion of his 65th birthday and
retirement
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
approach is a part of our program to synthesize chiral non-racemic
halogenated inhaled anesthetics.6 The stereoselective decarboxyl-
Halothane 3 (1-bromo-1-chloro-2,2,2-trifluoroethane) was one
of the first halogenated non-flammable inhaled anesthetics to re-
place diethyl ether.1 Efforts have been made to synthesize halo-
thane and other chiral fluorinated anesthetics in enantiomerically
enriched form, with the anticipation that one enantiomer may
have improved pharmacological properties over the other or over
the racemate.2a Thus far, only three studies of the pharmacology
ation of halogenated carboxylic acids has been highly successful
in the synthesis of enantiomers of theoretically interesting haloge-
nated molecules7,8 and an intermediate in the synthesis of fluoroe-
ther anesthetics.9 The resolution of the enantiomers of halothane
and other highly halogenated molecules by enantioselective gas
chromatography (GC) has become a commonplace10 since the first
report by Meinwald et al.11 It is unlikely that preparative GC will be
able to supply the amounts needed for testing of anesthetic enan-
tiomers in humans, so efforts at their preparation by synthesis
should continue.
of halothane enantiomers have appeared, which contradict each
2b–d
other.
It is possible that this lack of studies is due to the lack
of availability of large amounts of the enantiomers.
Edamura and Larsen3 described the first synthesis of halothane
in enantiomerically enriched form, although the ee was not high.
Pearson4 improved upon this procedure, isolating halothane with
a high ee and also determining its absolute configuration. Our ap-
proach to an enantiomer of halothane relied on the stereoselective
decarboxylation of the title carboxylic acid 2 (Scheme 1).5 This
F3C
Br
F3C
Br
F3C
Br
(-)-strychnine
O
O
H
ethylene glycol,
heat
NH2
OH
Cl
Cl
Cl
(+)-1, 98% e.e.
(abs. config.
previously
(+)-2, 98% e.e.
(abs. config.
previously
(S)-(+)-3,
96% e.e.
unknown)
unknown)
⇑
Corresponding author. Tel.: +1 646 660 6243; fax: +1 646 660 6201.
E-mail address: keith.ramig@baruch.cuny.edu (K. Ramig).
Scheme 1. Stereoselective decarboxylation of (+)-2 giving (S)-(+)-halothane.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.023

202
K. Ramig et al. / Tetrahedron: Asymmetry 23 (2012) 201–204
2. Results and discussion
Herein we report that we have determined the absolute config-
uration of acid 2, and that the decarboxylation proceeds with the
retention of configuration. Suitable crystals of acid 2 could not be
grown, so amide 1, the immediate precursor of acid 2 in the syn-
thetic sequence5 giving (S)-(+)-3, was used. Slow crystallization
of (+)-amide 1 from its solution in hexane/dichloromethane gave
crystals suitable for X-ray analysis. The structure of 1 was solved
by direct methods in the space group P21. There are two molecules
in the asymmetric unit (Fig. 1). The two independent molecules in
the asymmetric unit are connected in an infinite chain of hydrogen
bonds involving one amine hydrogen atom and the carbonyl oxy-
gen atom (see Table 1). Both molecules in the asymmetric unit
are disordered (Fig. 2). One is only slightly disordered (labeled
without primes) while the other (labeled using primes and double
primes) is disordered by a rotation around C(20) so that all three
groups attached to it occupy two positions. As can be seen in Fig-
ure 2, the disordering does not significantly change the size, shape,
or volume occupied by the groups attached to C(2) or C(20). A sep-
arate occupancy factor was refined for each of the independent
molecules in the asymmetric unit. In the molecule which is only
slightly disordered, two positions for the chlorine and bromine
atoms are displaced by about half an Angstrom [0.71(3) and
0.29(3) occupancy factors]. However, while the disorder in this tri-
fluoromethyl group could not be resolved, it could be observed in
the large thermal ellipsoids for the atoms in this group. The trifluo-
romethyl group is held in position by hydrogen bonding between
the amine hydrogen atom and one of the fluorine atoms. In the
other molecule, the greater rotation about C(20) results in the chlo-
rine and bromine atoms occupying the same site as well as the
chlorine atom and trifluoromethyl group and the bromine atom
and trifluoromethyl group sharing a site [0.683(10) and 0.317(10)
Figure 2. The two disordered molecules in the asymmetric unit of 1.
Table 2
Selected bond lengths [Å] for the two independent molecules (atoms without primes
and the atoms labeled with primes) and for the disordered part of each independent
molecule (labeled with a star and a double prime)
Starred (⁄)
Prime (0)
Double prime (00)
N–C(1)
O–C(1)
C(1)–C(2)
C(2)–C(3)
C(2)–Cl
1.351(17)
1.197(13)
1.530(18)
1.50(2)
1.772(15)
1.960(14)
1.268(16)
1.301(16)
1.335(14)
1.308(15)
1.249(14)
1.552(19)
1.39(3)
1.835(11)
1.988(15)
1.29(2)
1.44(5)
1.80(3)
1.90(2)
1.982(18)
1.835(11)
1.34(2)
1.34(2)
1.33(2)
C(2)–Br
C(3)–F(3)
C(3)–F(1)
C(3)–F(2)
1.330(19)
1.286(18)
occupancy factors]. Disordering in molecules which contain both
chlorine and bromine atoms in which both atoms partially occupy
the same position is common.12 During the refinement, the C–F
distances were constrained to be 1.34(2) Å. The bond distances
are presented in Table 2. As can be observed, the distances in the
two molecules are very similar. The largest deviations are found
in the C(20)–C(30), C(20)–C(300), C(20)–Cl00 and the C(20)–Br00 bond
lengths. These differences are all due to the disordering. C(30) is
0.722 Å from Cl00 while C300 is 0.780 Å from Br0. In order to achieve
this separation, the two atoms move away from each other in the
refinement resulting in C(20)–C(30) becoming too short while the
C(20)–Cl00 bond becomes too long. The same is true for C(20)–C(300)
and C(20)–Br0, only in this case the effect is less because of the smal-
ler difference between the length of a C–C and a C–Cl versus a C–C
and a C–Br bond. The C(20)–Br00 bond appears to be too short
because Cl0 and Br00 share a common site due to the disorder and
refined as a Cl and a Br with occupancy factors of 0.683(10) and
0.317(10), respectively. As a result, the bond distance is a weighted
average of that of a carbon–chlorine and a carbon–bromine bond.
Close intramolecular contacts due to this disordering also result
in distorted thermal ellipsoids for some of the atoms such as
F(300), C(300), and Br⁄.
Figure 1. ORTEP (50% thermal ellipsoids) plot of the molecules in the asymmetric
unit of 1.
Table 1
Hydrogen bonds for 1 [Å and deg.]
The Friedel parameter is 0.01(9), however, in the collection of
the data Friedel pairs were not collected meaning that the correct
configuration of the molecule was also determined using the Ham-
ilton R value test.13 At the end of the refinement the (R)-configured
amide was refined to an R value of 0.0715. The ratio of the R value
for the (R)-configured amide (0.0715) to the (S)-configured amide
D–H. . .A
d(D–H)
d(H. . .A)
d(D. . .A)
<(DHA)
N–H(11). . .O(10)a
N–H(12). . .O(10)
N–H(12). . .F(100)
N–H(12). . .Cl⁄
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
2.15
2.46
2.53
2.56
2.12
2.55
2.58
2.64
3.011(16)
3.253(13)
3.22(2)
166.6
150.1
135.5
112.3
169.9
111.9
135.5
155.3
3.01(3)
N(10)–H(110). . .Ob
N(10)–H(120). . .Br00
N(10)–H(120). . .F(1)c
N(10)–H(120). . .Oc
2.987(17)
2.995(13)
3.264(14)
3.457(14)
(0.0711) was 1.006, which is greater than the R1,1024,
of
0.005
1.003. This result indicates that we can reject the hypothesis that
at the 0.005 level, amide 1 has the (R)-configuration. Therefore,
the dextrorotatory isomer of amide 1, and by correlation, acid
(+)-2, have the (S)-absolute configuration.
Since both acid 2 and its product halothane are of the same con-
figuration, the stereochemistry is retained to a very high degree.
Symmetry transformations used to generate equivalent atoms:
a
ꢀx+1, y+1/2, ꢀz+2.
b
ꢀx+1, yꢀ1/2, ꢀz+2.
c
x, y, z+1.

K. Ramig et al. / Tetrahedron: Asymmetry 23 (2012) 201–204
203
R1
F
R1
F
of configuration. The case of the conversion of acid 6 to ether 7 is
unusual, in that using a less acidic alcoholic solvent still gives a
high level of stereoselectivity. It was unclear to us why anion 10
should be so much more stable toward inversion of configuration
than anion 11.
O
base
R2
R2
H
alcohol,
heat
OH
4, R1=Cl, R2=Br (50% e.e.)
5, R1=Cl, R2=Br (36% e.e.)
In order to investigate the reasons for the unusual stability,
experimental conditions for anions 10 and 11 were modeled with
Gaussian0922 using PCM-B3LYP/6-31++G⁄⁄ level of theory which
included a temperature parameter. The results were confirmed
by two additional basis sets, 6-311++G⁄⁄ and aug-cc-pVDZ which
were in good agreement. In order to determine the energy barrier
to inversion of configuration, anions 10 and 11 were modeled in a
DMPU/TEG solvent mixture with TEG as the proton source. The
barrier to enantiomerization for anion 11 is 10.23 kcal/mol. Before
inversion of the anionic carbon atom in 11 can occur, the CF3 group
has to rotate by 30 degrees. This process is endothermic by
5.43 kcal/mol. For anion 10 however, our DFT studies showed that
it undergoes b-elimination rather than enantiomerization, with a
barrier of 6.34 kcal/mol. This explains the higher degree of reten-
tion of configuration in this species.
1
2
1
2
6
7
, R =CF3, R =OMe (99% e.e.)
, R =CF3, R =OMe (>99% e.e.)
8, R1=Cl, R2=I (67% e.e.)
9, R1=Cl, R2=I (63% e.e.)
(R)
(S)
(R)
(S)
or
Scheme 2. Decarboxylation of halogenated carboxylic acids from the literature.
This result is in line with the three previous stereoselective decarb-
oxylations of
a-halocarboxylic acids in the literature: Doyle and
Vogl7 obtained (+)-bromochlorofluoromethane 5 from (+)-bromo-
chlorofluoroacetic acid 4 (Scheme 2); the ee of product 5 was esti-
mated from the specific rotation. Koenig14 was the first to separate
the enantiomers of 5 by enantioselective GC, allowing the precise
determination of the ee. The stereochemical outcome of the reac-
tion was not known until it was shown that both the starting mate-
rial and product had the same absolute configuration.15 A second
example was given by Ramig et al.9 who decarboxylated acid (R)-
(+)-6 to obtain fluoroether (R)-(ꢀ)-7. The stereochemical course
of this reaction was first reported to be inversion of configura-
tion,9b,c but was subsequently amended to retention16 after some
reservations had been noted.17 This came about because the abso-
lute configuration of fluoroether 7 rested on conversion of it into
fluoroether anesthetic desflurane, which had originally been as-
signed by Polavarapu et al.18 as (R)-(+)/(S)-(ꢀ). The determination
was found to be incorrect,19 and had to be reversed.20 Confirmation
of this reversal came with the direct determination of the absolute
configuration of fluoroether 7.21 The third example of stereoselec-
tive decarboxylation was shown by Crassous et al.8 who converted
chlorofluoroiodoacetic acid 8 into chlorofluoroiodomethane 9 with
a high degree of stereoselectivity. Thus, the stereochemical inver-
sion of the presumed anionic intermediates in all of these cases ap-
pears to be much slower than their capture by a proton.
3. Conclusion
We have shown that the inhaled anesthetic halothane is pro-
duced from the decarboxylation of acid 2 with retention of config-
uration. It appears that halogenated carboxylic acid salts will
generally decarboxylate to give halohydrocarbons with retention
of configuration, when a relatively acidic proton source is available.
A computational study indicated that intermediate anion 11 has a
barrier to enantiomerization of 10.23 kcal/mol. When the proton
source is sufficiently acidic, proton transfer to anion 11 yielding
halothane results in a high level of retention of configuration.
The anionic intermediate 10 from acid 6 does not undergo inver-
sion of configuration even in the presence of a less acidic proton
source. Intermediate 10 is predicted to undergo b-elimination in-
stead. This is a relatively minor process however, as the yield of
the product formed from proton transfer to anion 10, namely ether
7, is reasonably high.
The putative intermediate anion 10 formed from the decarbox-
ylation of acid 6 appears to be more stable toward inversion of
configuration than the anion 11 formed from acid 2 (Scheme 3).
This assertion is based on the comparison of the decarboxylation
behavior of the two acids under identical conditions. When acid
6 is treated with KOH in a solvent system of triethylene glycol
(TEG)/DMPU, followed by heating to 200 °C, ether 7 is isolated in
a 75% yield and is nearly enantiomerically pure.9 However, when
acid 2 is subjected to the same conditions, albeit at a lower temper-
ature, the halothane 3 obtained in a 55% yield has an ee of only
20%, favoring retention of configuration.5 The production of halo-
thane and halocarbons 5 and 9 from Scheme 2 proceeds with good
stereoselectivity when the base is a tertiary amine (either strych-
nine or triethylamine) and when the solvent is ethylene glycol. In
these cases, the proton source for the protonation of the anionic
intermediates would be the quaternary ammonium ion, which is
much more acidic than the alcoholic solvent; therefore the anion
is presumably more likely to be protonated than undergo inversion
4. Experimental
4.1. General
1H, 13C, and 19F NMR spectra were recorded on a Bruker Biospin-
Avance 1 instrument, at 400.1, 100.6, and 199.7 MHz, respectively.
4.2. (S)-(+)-1-Bromo-1-chloro-2,2,2,-trifluoropropanamide 1
(S)-(+)-1-Bromo-1-chloro-2,2,2,-trifluoropropanamide
1
was
obtained as described previously,5 mp = 81–82 °C, ½a D25
ꢁ
¼ þ20 (c
1, CHCl3). 1H NMR (CDCl3) d 6.62 (br s, 1H, NH), 6.38 (br s, 1H,
HN). 13C NMR (CDCl3) d 162.4 (s, C@O), 121.1 (q, JCF = 283 Hz,
CF3), 65.61 (q, JCF = 34.4 Hz, CBrCl). 19F (CDCl3) d ꢀ73.62 (s). HRMS:
[MꢀH]ꢀ 237.8887 (calcd for C3HBrClF3NO 237.8888). X-ray crystal
structure, C3H2BrClF3NO: To a crystal (0.07 ꢂ 0.13 ꢂ 0.50 mm) of
(S)-(+)-1, a very thin coating of Vaseline was applied, and the crys-
tal was mounted inside a glass capillary and then transferred to an
Enraf Nonius CAD4 diffractometer using Cu radiation for the collec-
tion of diffraction data at a temperature of 200 K; M = 240.42,
monoclinic, space group P21, a = 10.8410(10), b = 6.1514(7), c =
F3C
R1
R2
O
-H+
F3C
R1
CF3
R1
OH
R2
R2
-CO2
10.9177(6) Å, b = 102.986(7)°, V = 709.45(11) Å3, Z = 4,
l = 11.435
mmꢀ1, Dcalcd = 2.251 g cmꢀ3; the structure was solved by direct
methods. A face indexing absorption correction was used. In the
least-squares refinement, anisotropic temperature parameters
were used for all the non-hydrogen atoms resulting in a model
6, R1=F, R2=OCH3
10, R1=F, R2=OCH3
1
2
1
2
11
, R =Br, R =Cl
, R =Br, R2=Cl
Scheme 3. Stereochemical inversion of anions derived from acids 2 and 6.

204
K. Ramig et al. / Tetrahedron: Asymmetry 23 (2012) 201–204
6. Ramig, K. Synthesis 2002, 2627–2631.
with R1 = 0.0711, wR2 = 0.2305 for all data (1479 independent
reflections) and 247 parameters; Flack parameter x = 0.01(9).
CCDC 852346 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
7. Doyle, T. R.; Vogl, O. J. Am. Chem. Soc. 1989, 111, 8510–8511.
8. Crassous, J.; Jiang, Z.; Schurig, V.; Polavarapu, P. Tetrahedron: Asymmetry 2004,
15, 1995–2001.
9. (a) Rozov, L. A.; Ramig, K. Tetrahedron Lett. 1994, 35, 4501–4504; (b) Ramig, K.;
Brockunier, L.; Rafalko, P. W.; Rozov, L. A. Angew. Chem., Int. Ed. Engl. 1995, 34,
222–223; (c) Rozov, L. A.; Rafalko, P. W.; Evans, S. M.; Brockunier, L.; Ramig, K. J.
Org. Chem. 1995, 60, 1319–1325.
10. Aboul-Enein, H. Y.; Bojarski, J.; Szymura-Oleksiak, J. Biomed. Chromatogra.
2000, 14, 213–218.
11. Meinwald, J.; Thompson, W. R.; Pearson, D. L.; Koenig, W. A.; Runge, T.;
Francke, W. Science 1991, 251, 560–561.
Role of the funding source
12. Olejniczak, A.; Katrusiak, A.; Metrangola, P.; Resnati, G. J. Fluorine Chem. 2009,
130, 248–253; Podsiadlo, M.; Katrusiak, A. Acta Cryst. 2007, B63, 903–911.
13. Hamilton, W. Acta Cryst. 1965, 18, 502–510.
The Professional Staff Congress of the City University of New
York, which funded this work, had no role in study design; in the
collection, analysis, and interpretation of data; in the writing of
the report; or in the decision to submit the manuscript for
publication.
14. Koenig, W. A. Gas Chromatographic Enantiomer Separation with Modified
Cyclodextrins; Huethig: Heidelberg, 1992. p. 126; Another report has
appeared describing the analytical separation of the enantiomers of 5,
without reference to Koenig’s earlier work: Grosenick, H.; Schurig, V.;
Costante, J.; Collet, A. Tetrahedron: Asymmetry 1995, 6, 87–88.
15. Costante, J.; Ehlinger, N.; Perrin, M.; Collet, A. Enantiomer 1996, 1, 377–386;
Costante-Crassous, J.; Marrone, T. J.; Briggs, J. M.; McCammon, J. A.; Collet, A. J.
Am. Chem. Soc. 1997, 119, 3818–3823; Costante, J.; Hecht, L.; Polavarapu, P. L.;
Collet, A.; Barron, L. D. Angew. Chem., Int. Ed. Engl. 1997, 36, 885–887.
16. Rozov, L. A.; Rafalko, P. W.; Evans, S. M.; Brockunier, L.; Ramig, K. J. Org. Chem.
1995, 62, 6094.
17. See footnote 28 in Ref. 9c, and Schurig, V.; Grosenick, H.; Juza, M. Rec. Trav.
Chim. Pays-Bas 1995, 114, 211–219.
18. Polavarapu, P. L.; Cholli, A. L.; Vernice, G. J. Pharm. Sci. 1993, 82, 791–793.
19. Schurig, V.; Juza, M.; Green, B. S.; Horakh, J.; Simon, A. Angew. Chem., Int. Ed.
1996, 35, 1680–1682.
Acknowledgments
We thank Dr. Gopal Subramaniam of Queens College of CUNY
for recording the NMR spectra and Dr. Cliff Soll of the CUNY Mass
Spectrometry Facility at Hunter College for recording the high-res-
olution mass spectra. We thank Dr. E. Fujita of Brookhaven Na-
tional Laboratory for the use of the Enraf Nonius CAD4
diffractometer for X-ray data collection. The Professional Staff Con-
gress of the City University of New York is acknowledged for finan-
cial support.
20. Polavarapu, P. L.; Cholli, A. L.; Vernice, G. J. Pharm. Sci. 1997, 86, 267. It
appears that the spectroscopic method used was not at fault; rather, the
vials containing the two enantiomers of desflurane had been mistakenly
switched before analysis, and the mistake was not discovered until after
publication.
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