Novel synthetic approaches to CHBrFI, CHClFI and CHBrClI

Article abstract of DOI:10.1016/S0040-4020(02)00532-X

Three new facile methods for the preparations of racemic mixtures of CHBrFI, CHClFI and CHBrClI are described. Mercuric fluoride was found to be an effective fluorinating agent in fluorinations of CHI2Br(6) and CHI2Cl(8) to yield CHBrFI, CHClFI, respectively. Chlorination of CHI2Br(6) by using antimony pentachloride as a chlorinating agent, afforded CHBrClI in convenient and mild condition.

Full text of DOI:10.1016/S0040-4020(02)00532-X

TETRAHEDRON
Pergamon
Tetrahedron 58 02002) 5923±5926
Novel synthetic approaches to CHBrFI, CHClFI and CHBrClI
Dong Bo Li, Siu-Choon Ngp and Igor Novak
Department of Chemistry, National University of Singapore, Singapore 117543, Singapore
Received 7 March 2002; revised 29 April 2002; accepted 23 May 2002
AbstractÐThree new facile methods for the preparations of racemic mixtures of CHBrFI, CHClFI and CHBrClI are described. Mercuric
¯uoride was found to be an effective ¯uorinating agent in ¯uorinations of CHI2Br 06) and CHI2Cl 08) to yield CHBrFI, CHClFI, respectively.
Chlorination of CHI2Br 06) by using antimony pentachloride as a chlorinating agent, afforded CHBrClI in convenient and mild condition.
q 2002 Published by Elsevier Science Ltd.
1. Introduction
¯uoroacetate and silver chloro¯uoroacetate, and required
harsh conditions, such as high temperature, high vacuum,
anhydrous environment etc. Also, the reported synthetic
approach to CHBrClI 03) involved tedious puri®cation
procedures. Consequently, our interest in the halomethanes
has encouraged us to search for more convenient synthetic
approaches for their preparation and the approaches are
reported in this paper.
Chiral halomethanes are the smallest chiral molecules1 and
have general formula 0CWXYZ) where W, X, Y, Z can be
H, F, Cl, Br, I. All such molecules lack any symmetry i.e.
belong to the C1 point group. There are ®ve molecules 1±5
0®ve enantiomeric pairs) belonging to the group 0Fig. 1).
Since the experimental determination of the maximum opti-
cal rotation and absolute con®guration of the halomethanes
are of great interest in the context of modern theories of
optical activity,2 numerous attempts to prepare and isolate
enantiomers of the halomethanes have been made to date.
One of them 0CHBrClF) 04) has been the subject of various
investigations pertaining to important chemical aspects of
chirality,3 halomethanes 1±3 have also been studied by UV
photoelectron spectroscopy as possible substrates for `chiral
photoionization'.4 Despite these explorations, little is
known about the other four halomethanes, arising mainly
from the lack of facile synthetic approaches. Although
Haszeldine5 reported the syntheses of CHBrFI 01) and
CHClFI 02) via classical Hunsdiecker reaction and Hine6
reported the preparation of CHBrClI 03) by the treatment
of CHBr2Cl with sodium iodide 0Scheme 1), limitations
associated with these syntheses and sample puri®cation
remained. As shown in Scheme 1, the reported methods
for the preparations of CHBrFI 01) and CHClFI 02) involved
inconvenient and expensive preparations of silver bromo-
2. Results and discussion
Various ¯uorinating agents have been developed for the
purpose of replacing halogens by ¯uorine in organic
halides.7 The direct replacement of a bromine or iodine
atom by reaction with mercury0II) or silver0I) ¯uoride
has frequently been the procedure of choice for such synth-
eses, since these reactions can proceed under mild condi-
tions. Furthermore, it has been found that mercuric ¯uoride
can be used instead of silver ¯uoride in most cases where
these silver salts could be used; the yields are considerably
higher, most reactions take place smoothly at room tempera-
ture and side reactions are minimized or absent.7c In parti-
cular, the ¯uorinating agent has been well developed for the
ef®cient method of preparation of CHBrClF 04).3d Very
stable bromodiiodomethane, CHI2Br 06),8 makes it possible
Figure 1. The formulae of halomethanes of type CWXYZ 0X, Y, W, ZˆH,
F, Cl, Br, I).
Keywords: halomethanes; ¯uorination; chlorination.
Corresponding author. Tel.: 165-6874-2675; fax: 165-779-1691; e-mail:
chmngsc@leonis.nus.edu.sg
p
Scheme 1. The reported methods for the preparation of halomethanes 1±3.
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020002)00532-X

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D. B. Li et al. / Tetrahedron 58 %2002) 5923±5926
Scheme 2.
Scheme 4.
to explore a new synthetic approach to CHBrFI 01) by using
mercuric ¯uoride as the ¯uorinating agent to replace one of
the iodine atoms in the molecule. Our initial study veri®ed
that 6 reacts smoothly with mercuric ¯uoride in dry
1,4-dichlorobenzene at room temperature and the 13C
NMR spectrum clearly showed the formation of crude 1.9
Since the melting point of 6 is 608C,8 it is possible to treat it
with mercuric ¯uoride directly without any extra solvent
when the reaction temperature is up to 608C. Hence, the
neat reaction of halomethane 6 with 0.5 equiv. of mercuric
¯uoride at 608C was examined and the expected CHBrFI 01)
was successfully prepared in 60% yield after convenient
puri®cation 0Scheme 2). In an effort to optimize the reaction
conditions, we have further discovered that the amount of
mercuric ¯uoride used is very critical to the reaction. When
a stoichiometric amount of mercuric ¯uoride was added,
almost no conversion of 6 to 1 was observed and only a
solid mixture was obtained. This may be due to further
conversion of 1 to a gaseous CHF2Br in the presence of
excess mercuric ¯uoride. In addition, when the reaction
time was extended upto 2 h or the reaction temperature
was over 708C, we observed that the yield fell drastically
and some liquids with higher boiling point were separated.
Presumably the thermal instability of 1 causes some of it to
decompose under more stringent conditions.5 Therefore,
both longer reaction time and higher reaction temperature
proved to be unfavorable.
because of its low boiling point 0ca. 768C) and high vola-
tility.5 Therefore, the neat reaction of diiodochloromethane,
CHI2Cl 08),11 with mercuric ¯uoride was attempted as an
alternative strategy for the preparation of 2. Although 8 is
unstable towards air and light, fresh halomethane 8 can still
be utilized as the starting material as indicated by 1H NMR
spectroscopy analysis. Furthermore, it makes it possible to
perform ¯uorination of 8 0by HgF2) at room temperature,
since 8 is a liquid. Therefore, halomethane 8 was treated
overnight with 0.5 equiv. of mercuric ¯uoride at room
temperature in a ¯ask with a Te¯on stopcock and the reac-
tion afforded the required 2 in 24% yield after distillation
0Scheme 4). Because of the instability of 8 and the physical
properties of 2, a higher reaction temperature is not suitable
for increasing the yield of 2. Furthermore, the increase of
the amount of mercuric ¯uoride from 0.5 to 0.7 equiv. only
caused a slight increase of the product yield. Although the
increase implied that the amount of mercuric ¯uoride used
was not very critical for the conversion, the minimum
amount used 00.5 equiv.) is still a good choice, considering
that HgF2 is highly toxic.
In view of the use of the same ¯uorinating agent and similar
substrate 0as for the preparation of 1), a similar mechanism
can be suggested for the ¯uorination of 8 0Scheme 3).
Furthermore, compared with Haszeldine's method,5 this
approach does not involve any harsh conditions, can be
performed even at room temperature, utilizes conveniently
available and inexpensive halomethane 8 as the starting
material, and affords halomethane 2 in comparable yield.
Therefore, our approach to the preparation of 2 appears
superior to the earlier method.
Scheme 3 illustrates a plausible mechanism for the reac-
tion.7c The initial stepis the formation of a halometallo-
ate complex, then the C±F bond-forming step in the reaction
can be achieved by the intermolecular transfer of ¯uoride
from the complex to the carbonium ion center to afford the
corresponding halomethane 1. Since only one iodine atom
in substrate 6 is involved in the reaction 0on the basis of the
proposed mechanism) and only halomethane 1 is the
expected product, the use of 0.5 equiv. of mercuric ¯uoride
was expected to be required, this was consistent with the
actual results observed.
Although chlorination of 7 has proved to be an unsuccessful
strategy for obtaining 2, our interest in chlorination reac-
tions of methyl halides prompted us to develop the synthetic
strategy for the other halomethanes. The high boiling point
of halomethane CHBrClI 03) makes it possible to utilize it to
replace Hine's method,6 since the properties of 3 are such
that the reaction solvent can be used. Antimony penta-
chloride is an ef®cient and inexpensive chlorinating agent,
used successfully in various chlorination reactions of
aliphatic halides under mild conditions.12 Hence, we tried
to utilize halomethane 6 and antimony pentachloride as
Our efforts to explore a more convenient and milder
synthetic approach to another halomethane 2 were initially
focused on chlorination of diiodo¯uoromethane, CHI2F
07),10 by using suitable chlorinating agents to replace the
iodine atom in 7. However, the efforts proved unsuccessful
due to several drawbacks related to the properties of 2. The
main problem was the choice of a suitable reaction solvent,
which is always needed for the chlorination reaction,
Scheme 3.
Scheme 5.

D. B. Li et al. / Tetrahedron 58 %2002) 5923±5926
5925
commercial suppliers and used without further puri®cation.
Mass spectra were recorded in electron ionization 0EI)
mode. FT-IR spectra were recorded as either neat ®lm or
KBr salt plate. 1H NMR spectra were recorded at 300 MHz
in CDCl3 and 13C NMR spectra were obtained at 75 MHz in
CDCl3, 19F NMR spectrum was obtained at 282 MHz in
CDCl3 and chemical shifts were referenced internally with
tri¯uoroacetic acid 0TFA) 0d 0.00 ppm) as the internal
standard. Dibromo¯uoromethane was prepared as reported
previously.13
Scheme 6.
potential reactants to explore the preparation of 3. The
reaction of 6 with 0.2 equiv. of 1.0 M solution of antimony
pentachloride in CH2Cl2 was performed in anhydrous CCl4
at room temperature, overnight under nitrogen and the
expected halomethane 3 was generated in 31% yield after
distillation under reduced pressure 0Scheme 5, Eq. 01)). We
further discovered that the amount of antimony penta-
chloride used is also critical in this reaction. When the
amount of antimony pentachloride was increased up to
1.0 equiv., no residues remained in the ¯ask after work-
up. This observation implies that a complete conversion of
6 to chloroform may occur under these conditions 0Scheme
5, Eq. 02)). A general chlorination mechanism by antimony
pentachloride as suggested by Kagan 0Scheme 6)12 may
rationalize the interpretation of both reactions. When
0.2 equiv. of antimony pentachloride was added, only one
iodine atom in 6 was subjected to chlorine±iodine exchange
with antimony pentachloride and the corresponding
halomethane 3 was produced. However, when 1.0 equiv.
of antimony pentachloride was loaded, all halogen atoms
in 6 were involved in chlorine±halogen exchange with
antimony pentachloride and the ®nal product, chloroform,
was formed and then easily removed during work-up.
4.1.1. Bromodiiodomethane *6).8 Iodoform 039.4 g,
100 mmol) and CCl4 070 mL) were charged into a 250 mL
round-bottom ¯ask at 08C. A solution of bromine 03.75 mL,
73.5 mmol) in CCl4 050 mL) was added dropwise at 08C
during a period of 1 h. After addition, the resulting mixture
was allowed to warm upto room temperature and stirred
overnight. Saturated Na2SO3 solution was added to remove
iodine formed and unreacted bromine. The CCl4 layer was
separated, washed with brine and dried over Na2SO4. After
removal of solvent, the light purple residue was recrystal-
lized from hexane to afford 6 as a yellow plate solid 018.2 g,
52%). Mp59 8C [Lit.8 608C], 1H NMR 0300 MHz, CDCl3) d
5.74 0s); 13C NMR 075 MHz, CDCl3) d 299.58; MS0EI):
m/z 0relative intensity) 348 0M112, 67), 346 0M1, 66), 219
0100), 140 059), 94 046); HRMS0EI): calcd for CHBrI2
345.7349, found 345.7351; IR 0KBr): 1114, 1064, 617,
591, 574 cm21
.
²
4.1.2. Diiodo¯uoromethane *7). Sodium iodide 075 g,
0.5 mol) and dibromo¯uoromethane13 019.2 g, 0.1 mol)
were charged into a 250 mL Te¯on stopcocked ¯ask
under nitrogen, anhydrous acetone 0100 mL) was added.
After closing the ¯ask tightly, the mixture was heated to
100±1108C for 8 days with stirring. After cooling down,
the resultants were distilled under high vacuum with dry-
ice condenser. The resulting liquid was concentrated under
water aspirator at room temperature to remove acetone and
the residue redistilled under reduced pressure to afford 7 as
Besides antimony pentachloride, other chlorinating agents,
such as mercuric chloride, zinc chloride and iron0III)
chloride were also tried, but proved unsuccessful in the
reaction. Although mercuric chloride reacted with halo-
methane 6 to afford halomethane 3, the poor yield and
low purity of 3 precluded its use as a suitable reagent.
Furthermore, zinc chloride and iron0III) chloride did not
show any reactivity even at longer reaction time and higher
reaction temperature. In comparison with Hine's method,6
the reaction is mild and affords good yield. Thus, we can
conclude that our novel approach to halomethane 3 using
antimony pentachloride is superior to the previously used
method.
1
an amber liquid 07.0 g, 25%). Bp62±64 8C/30 mmHg, H
NMR 0300 MHz, CDCl3) d 7.32 0d, JH±Fˆ48.1 Hz); 13C
NMR 075 MHz, CDCl3) d 25.33 0d, JC±Fˆ318.5 Hz); 19F
NMR 0282 MHz, CDCl3) 0TFA) d 226.38 0t, JF±C
ˆ
30.5 Hz, JF±Hˆ15.2 Hz); MS0EI): m/z 0relative intensity)
286 0M1, 79), 267 08), 159 0100), 140 048); HRMS0EI):
calcd for CHI2F 285.8149, found 285.8150; IR 0neat):
3. Conclusion
1682, 1615, 1090, 1054, 1017, 624 cm21
.
In conclusion, three new facile methods of ¯uorination and
chlorination for the interconversion of an iodine atom in
methyl halides into a ¯uorine or a chlorine atom to yield
the corresponding halomethanes 1±3 have shown synthetic
advantages due to their mild and convenient conditions.
This represents an important `supply route' for the study
of important physical and chemical aspects of chirality on
the example of halomethanes. Our effort to synthesize the
remaining halomethane, CBrClFI 05), is in progress.
4.1.3. Chlorodiiodomethane *8).11 Chloroform 040 mL,
0.5 mol), triethylbenzylammonium chloride 0TEBA)
02.0 g, 8.8 mmol), 50% of NaOH solution 040 mL) and the
solution of NaI 0200 g, 1.33 mol) in water 088 mL) were
charged into a 250 mL round-bottom ¯ask. The resulting
mixture was heated to 60±708C for 24 h. After cooling
down, the mixture was poured into water 0560 mL) and
extracted with CH2Cl2 0100 mL£4). The CH2Cl2 layer was
separated, washed with saturated Na2SO3 solution, dried
over Na2SO4, concentrated under reduced pressure to give
deepred liquid and redistilled under water aspirator to give
8 031.0 g, 21%) as a light sensitive liquid. Bp106±108 8C/
4. Experimental
4.1. General
²
The synthesis of diiodo¯uoromethane was previously reported,10 but we
prepared the compound by the modi®ed procedure as described herein.
Unless otherwise speci®ed, all materials were obtained from

5926
D. B. Li et al. / Tetrahedron 58 %2002) 5923±5926
1
30 mmHg [Lit.11 bp81 8C/13 mmHg], H NMR 0300 MHz,
CDCl3) d 6.19 0s); 13C NMR 075 MHz, CDCl3) d 267.78;
MS0EI): m/z 0relative intensity) 302 0M1, 63), 267 025), 175
0100), 140 025), 48 036); HRMS0EI): calcd for CHClI2
301.7854, found 301.7849; IR 0neat): 1163, 1105, 1069,
02.34 g, 31%). Bp88±90 8C/30 mmHg [Lit.6 bp68±69 8C/
1
30 mmHg], H NMR 0300 MHz, CDCl3) d 6.71 0s); 13C
NMR 075 MHz, CDCl3) d 215.43; MS0EI): m/z 0relative
intensity) 256 0M112, 20), 254 016), 175 017), 127 0100),
48 014); HRMS0EI): calcd for CHBrClI 253.7995, found
720 cm21
.
253.7999; IR 0neat): 1179, 1106, 785, 731, 629 cm21
.
4.1.4. Bromo¯uoroiodomethane *1). Dry bromodiiodo-
methane 06)8 08.7 g, 25 mmol) and mercuric ¯uoride
03.0 g, 12.5 mmol) were charged into a 50 mL Te¯on stop-
cock ¯ask under nitrogen. The mixture was continuously
mixed with stirring and slowly heated to 608C for 1 h.
After cooling down, the resultants were distilled under
high vacuum with dry-ice condenser to give a light sensitive
liquid, redistilled under water aspirator to give 1 as a light-
sensitive liquid 03.61 g, 60%). Bp36±38 8C/30 mmHg [Lit.5
Acknowledgements
We acknowledge the National University of Singapore for
generous ®nancial support.
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bp35 8C/70 mmHg], H NMR 0300 MHz, CDCl3) d 7.58
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250 mL Te¯on stopcocked ¯ask under nitrogen. With
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small portions at 08C under nitrogen. After addition, the
resulting mixture was allowed to warm upto the room
temperature and stirred for 36 h. The resultants were
distilled under high vacuum with dry-ice condenser to
give a light sensitive liquid, redistilled under nitrogen to
give 2 as a light sensitive liquid 03.85 g, 24%). Bp74±
768C [Lit.5 bp35 8C/150 mmHg], 1H NMR 0300 MHz,
CDCl3) d 7.64 0d, JH±Fˆ50.1 Hz); 13C NMR 075 MHz,
CDCl3) d 55.04 0d, JC±Fˆ306.2 Hz); 19F NMR 0282 MHz,
CDCl3) 0TFA) d 211.04 0d, JF±Hˆ53.3 Hz); MS0EI): m/z
0relative intensity) 194 0M1, 43), 159 018), 67 0100), 48 09);
HRMS0EI): calcd for CHClFI 193.8794, found 193.8798;
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