Published on Web 01/28/2005
Anhydrous Tetrabutylammonium Fluoride
Haoran Sun and Stephen G. DiMagno*
Department of Chemistry, UniVersity of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304
Received September 29, 2004; E-mail: sdimagno1@unl.edu
Table 1. 19F NMR Data of Anhydrous Fluoride Salts
Fluorine substitution is a powerful tool to improve the bioavail-
ability of pharmaceuticals and agrochemicals; thus, an expansive
set of nucleophilic and electrophilic reagents has been developed
to replace various C-X functional groups with C-F.1 Simplest
among the nucleophilic fluorinating reagents are “anhydrous” or
“naked” organic fluoride salts, represented by tetramethylammo-
nium fluoride (TMAF),2 1-methylhexamethylenetetramine fluoride
(MHAF),3 and tetramethylphosphonium fluoride (TMPF).4 These
compounds are commonly prepared in a hydrated state and are
subsequently dried by heating under dynamic vacuum or by
azeotropic distillation. However, the conditions used to dry these
salts are often incompatible with a variety of desirable cations. For
example, dried tetrabutylammonium fluoride (TBAF)5 is reported
to decompose by Hofmann elimination at room temperature; the
salt isolated after dehydration is contaminated with copious amounts
of bifluoride ion (HF2-) and tributylamine.6 These considerations
have led to the belief that “it is very unlikely that pure, anhydrous
tetraalkylammonium fluoride salts have ever, in fact, been produced
in the case of ammonium ions susceptible to E2 eliminations.”6
Here we show that low-temperature nucleophilic aromatic substitu-
tion (SNAr) can be used to generate anhydrous TBAF directly in
aprotic solvents, and we discuss the stability and reactivity of “truly”
anhydrous TBAF.
compd
solvent
chemical shift
ref.
TBAF
THF
CD3CN
(CD3)2SO
(CD3)2SO
CD3CN
-86 ppm
-72 ppm
-75 ppm
-75 ppma
-74 ppm
-70 ppm
this work
this work
this work
this work
2
TMAF
TMPF
CD3CN
4
a Generated in situ with TMACN.
impurities in 70% yield. Freshly isolated TBAF displayed one
singlet 19F NMR signal at -86 ppm in THF and four H NMR
signals for the TBA cation. The characteristic doublet of HF2 at
δ ) -147 ppm (JH-F ) 120 Hz) was observed in freshly prepared
solution samples and in samples precipitated from THF and
redissolved. The concentration of TBA HF2 was generally less
than 2% that of TBAF. Solid anhydrous TBAF is stable under
nitrogen at -35 °C for weeks. TBAF decomposes slowly in THF
or in the solid state by E2 elimination if warmed above 0 °C.
TBAF can be prepared conveniently in situ in polar aprotic
solvents at room temperature and used without isolation or
purification. Treatment of (CD3)2SO or CD3CN solutions of
TBACN with C6F6 (at 25 °C) gave highly colored, concentrated
(up to 2 M) solutions of TBAF exhibiting the characteristic 19F
NMR signals for ion-paired fluoride (Table 1). Small amounts
1
-
-
-
(generally <4%) of HF2 are also generated in these solvents.
TBAF is stable for hours in CD3CN and for more than 24 h in
DMSO at 25 °C. For sluggish reactions, DMSO is the solvent of
choice.
The origins of the unexpected stability of TBAF in THF, CH3-
CN, and DMSO lie in the relatively low temperatures used for
generation of the salt and in the dehydrating properties of the main
reaction byproduct, hexacyanobenzene.10 Hexacyanobenzene has
been shown to add water to form the strong acid pentacyanophenol
(pKa ) -2.9).11 Thus, adventitious water is removed from solution
during the course of the initial fluoride-generating SNAr reaction,
forming 2 equiv of bifluoride ion per 1 equiv of water and the
innocuous byproduct TBA pentacyanophenoxide. Added water
(0.08 equiv) is scavenged from TBAF solutions prepared in this
manner, as is evidenced by time-dependent changes in the line width
and chemical shift of the F- 19F NMR resonance and by the
The constraints on a fluoride-generating synthesis grounded in
SNAr reactions are quite severe and dictate a careful choice of the
nucleophile. Because the enthalpic driving force for fluoride-
liberating SNAr derives almost exclusively from ion-pairing and
∆BDE terms, and because the Csp2-F bond in aromatics is
exceptionally strong (126 kcal/mol),7 only diffusely charged anionic
nucleophiles capable of forming strong bonds to carbon should be
capable of acting in SNAr reactions at low temperature in polar
aprotic solvents. Cyanide ion, a potent, weakly basic nucleophile
that forms strong bonds to sp2-hybridized carbon (BDE ) 133 kcal/
mol),8 is an excellent candidate. Treatment of hexafluorobenzene
with tetrabutylammonium cyanide (TBACN) (in 1:1 to 1:6 molar
ratios) in the polar aprotic solvents THF, acetonitrile, or DMSO at
or below room temperature gave excellent yields of anhydrous
TBAF.9 19F NMR spectroscopy indicated that the overall yield of
TBAF in solution in all cases was >95%. Cyano substitution
dramatically increases the fluorinated benzene ring’s susceptibility
to further nucleophilic attack, as is evidenced by observation of
pentacyanofluorobenzene and hexafluorobenzene as the principal
fluorinated aromatic species in the reaction solution, even if 1:1
TBACN/C6F6 stoichiometry is employed.
-
generation of 0.16 equiv of HF2 (see Supporting Information.)
Friedrich has shown that the addition of alkoxide nucleophiles
to hexacyanobenzene is rapid under basic conditions and that the
resultant pentacyanophenyl alkyl ethers are subject to SN2 displace-
ment.12 This pathway is amply demonstrated by the direct fluorina-
tion of simple alcohols. For example, if excess TBAF (12 equiv)
is generated in situ in (CD3)2SO and used directly, benzyl alcohol
is converted quantitatively to benzyl fluoride, presumably via the
intermediacy of benzyl pentacyanophenyl ether. Thus, generation
of TBAF in the presence of hexacyanobenzene can provide DAST-
like deoxofluorination of alcohols.
The modest solubility of TBAF in THF at low temperature allows
the salt to be precipitated (at -65 °C) and isolated free of aromatic
9
2050
J. AM. CHEM. SOC. 2005, 127, 2050-2051
10.1021/ja0440497 CCC: $30.25 © 2005 American Chemical Society