Table 4 Deaminative fluorination of anilines
Entry
Substrate
Product (% yield)a
Entry
Substrate
Product (% yield)a
1
2
3
4
1a
2a (45),b 3a (10), 4a (5)
2a (40), 3a (10), 4a (5)
2a (15), 3a (0), 4a (0)
2a (45), 3a (10), 4a (5)
5
6
7
8
1b
1c
1d
1e
2b (43),b 3b (4)
2c (46),b 3c (8)
2d (41), 3d (6)
2e (45), 3e (5)
1ac
1ad
1ae
Conditions: 100 mmol CaF2, 100 mmol H2SO4, 25 mmol substrate, 25 mmol NaNO2, 50 ml CH2Cl2 (except where noted), 15 min at 0 ЊC followed by
2 h heating at 55 ЊC (except where noted). a Yield based on GC area, corrected by the presence of an internal standard. b Isolated yield. c 20 min
sonication at 15 ЊC instead of heating. d 15 min sonication at 15 ЊC instead of heating, n-hexane used as solvent. e 20 min sonication at 15 ЊC instead
of heating; additional 100 mmol of CaF2 added before sonication.
electrode, with SCE as the reference electrode.†,9 CaF2 residues
were determined by published methods.10 Reactions were per-
formed in capped PTFE/PE flasks sealed with PTFE tape.
Keeping acetone in such vessels at 30 ЊC for 3 days resulted
in <3% weight loss. Unless stated otherwise, chemicals were
purchased from commercial firms (>98% pure) and used with-
out further purification. Salts were vacuum dried. A standard
sample of 2-fluorooctane was prepared by halogen exchange of
2-chlorooctane.11 Products were either isolated and identified
Deaminative fluorination of anilines
Example: fluorobenzene. 50 mmol of CaF2 and 50 mmol of
H2SO4 were mixed in 50 ml CH2Cl2 as above for 3 h, after which
the mixture was cooled to 0 ЊC. 25 mmol of aniline and 25
mmol of NaNO2 were then added (both additions caused an
exothermic reaction and the color of the mixture changed to
red–brown). Formation of the diazonium salt was monitored
by UV-vis spectroscopy (aqueous solution; λmax = 360–380 nm;
ε = 6400 MϪ1 cmϪ1). After stirring for 15 min, the mixture was
heated to 55 ЊC and stirred for 2 h (alternatively sonicated for
20 min at 15 ЊC). Fluorobenzene formation was monitored by
GC. After 2 h the reaction was quenched with ice and fluoro-
benzene (1.08 g, 45 mol% based on starting material) was dis-
tilled over a short Vigreux column at 1 atm (84–85 ЊC). m/z: 96.
GCMS conditions: 4 min isotherm at 40 ЊC, heating at 15 ЊC/
minϪ1 to 250 ЊC, 2 min isotherm at 250 ЊC. Retention times
(min): benzene (1.6); fluorobenzene (1.8); aniline (7.5); phenol
(7.6); tetradecane (internal standard, 9.3).
CAUTION! Hydrogen fluoride is extremely corrosive to
human tissue. Any contact may result in painful and slow-
healing burns.12 All labwork should be conducted in an efficient
fume hood, with suitable facial and body protection. Glassware
should not be used with HF solutions. It is important to neu-
tralize all solutions prior to disposal. Any accident caused by
HF, even if it appears minor, must always be treated as a serious
accident requiring medical attention.
1
by comparison of their H and 19F NMR spectra to standard
samples, or identified by MS data and comparison of their GC
retention times with standard samples.
Typical procedure for HF generation
100 mmol (7.80 g) of dried CaF2 was added to 50 ml of CH2Cl2
in a sealed 100 ml PTFE flask equipped with two PE addition/
sampling tubes and a mechanical stirrer. After stirring for
1 min, 100 mmol of 98% H2SO4 was added dropwise over a
period of 5 min (to avoid aggregation). Stainless steel balls (2
mm diameter) can be used for better crushing of the solid and
obtaining a larger surface area. After stirring for 3–4 h at 25 ЊC,
the inorganic solid phase was filtered (PTFE funnel), washed
with a 1:1 solution of H2O–EtOH, and neutralized with a 0.1
M solution of NaOH. The solid residue was filtered and dried
under vacuum at 200 ЊC, weighed and analyzed for CaF2 and
CaSO4. The filtrates were analyzed separately for Hϩ, FϪ, and
sulfate ions. CaF2 conversion and HF yield (typically 37–42
mol% based on CaF2) were determined from the overall
FϪ mass-balance.
References
1 R. A. Smith, in Kirk-Othmer Encyclopedia of Chem. Technol.,
eds. J. I. Kroschwitz and M. Howe-Grant, Wiley-Interscience,
New York, 4th edn., 1994, vol. 1, pp. 355–376 and refs. cited therein.
2 E. A. Watson, Chem. Eng. News, 1997, 75, 6.
Hydrofluorination of olefins/substitution of alcohols with in situ
HF generation
3 (a) J. F. Roth, Chemtech, 1991, 21, 357; see also (b) Chem. Mark.
Rep., 1998, 254, 20; (c) Chem. Mark. Rep., 1990, 238, 11; (d) Eur.
Chem. News, 1989, 52, 14.
4 (a) D. J. Adams, J. H. Clark and H. McFarland, J. Fluorine Chem.,
1998, 92, 127; (b) S. Mabic and J.-P. Lepoittevin, Synlett, 1994, 851;
(c) R. Mietchen and G. Kolp, J. Fluorine Chem., 1993, 60, 49.
5 G. A. Olah, J. T. Welch, Y. D. Vankar, M. Nojima, I. Kerekes and
J. D. Olah, J. Org. Chem., 1979, 44, 3872.
6 For a discussion of the extractive properties of different ammonium
salts, see C. M. Starks, C. L. Liotta and M. Halpern, Phase Transfer
Catalysis, Chapman and Hall, New York, 1994.
7 G. Balz and G. Schiemann, Chem. Ber., 1927, 60, 1186.
8 P. Osswald and O. Scherer, GP 600,706/1934; to I. G. Farbenind
A.-G.; Chem. Abstr., 1934, 28, P7260-6.
Example: 2-fluorooctane. CaF2 and H2SO4 were mixed in
CH2Cl2 for 5 min as above, after which 30 mmol of oct-1-ene
and 0.7 mmol of TOAB were added. The mixture was stirred
for 30 h. Reaction progress was monitored by GC. At the end of
the reaction, 2-fluorooctane (2.2 g, 66 mol% based on starting
material) was distilled at 200 mmHg (92–94 ЊC). δH (CDCl3;
Me4Si) 1.26 (3H, dd, J 23 and 6, CH3CHF), 4.5 (1H, dm, J 48,
CHF), 1.9 (2H, m, CH2), 1.4 (10H, br m, 5 × CH2), 0.96 (3H, t).
δF (CDCl3; CFCl3) Ϫ165.0 (m). Unreacted substrate and
olefinic isomerization products were brominated (Br2) prior to
separation. GC conditions: 2 min isotherm at 60 ЊC, heating at
15 ЊC minϪ1 to 250 ЊC, 4 min isotherm at 250 ЊC. Retention
times (min): oct-1-ene (2.4); 2-fluorooctane (3.8); 1,2-dibromo-
octane (9.1); tetradecane (internal standard, 9.3).
9 (a) J. E. Harwood, Water Res., 1969, 3, 273; (b) M. S. Frant and
J. W. Ross, Jr., Anal. Chem., 1968, 40, 1169.
10 (a) R. T. Oliver and A. G. Clayton, Anal. Chim. Acta, 1970, 51, 409;
(b) R. B. Fisher, J. Chem. Educ., 1974, 51, 387.
11 A. I. Vogel, Textbook of Practical Organic Chemistry, Longman,
Essex, 5th edn., 1989, pp. 570–572.
12 M. A. Trevino, G. H. Hermann and W. L. Sprout, J. Occup. Med.,
1983, 25, 861.
† As this method of measurement is accurate only in aqueous solutions,
the fluoride content of organic phases was determined by extracting the
fluoride ions thrice with 0.2 M solutions of KNO3 prior to measure-
ment. Control samples containing similar strength solutions of
(n-Bu)4ϩFϪ in CH2Cl2 showed >99% extraction of fluoride ions into
the aqueous phase.
Paper 9/01187K
1494
J. Chem. Soc., Perkin Trans. 1, 1999, 1491–1494