have been used either as a stereocontrol element or to
facilitate the departure of the fluoride.6 One controversial
interaction of CꢀF bonds is the H-bond7 where the
fluorine atom acts as a H-bond acceptor.6,8 While explo-
rations of crystal structure databases have yielded only
rare examples of short contacts which are consistent
than EtOH (R = 0.83) or i-PrOH (R = 0.76), the reaction
was heterogeneous due to poor solubility of the substrate
in water, which may explain the low conversion observed.
Using N,N-dimethylformamide (DMF), dimethylsulfox-
ide (DMSO), and acetonitrile (CH3CN), three commonly
used aprotic polar solvents for SN2 reactions, no conver-
sion wasobserved. Notably, in pure DMF, no reaction was
noticeable even after 7 days at 70 °C. However, since DMF
and DMSO are not HBDs (R = 0) and CH3CN is a very
poor HBD (R = 0.19), these results were anticipated. As a
point of comparison, both the corresponding benzyl chlo-
ride and bromide reacted completely under the same reac-
tion conditions in DMF.16
with CꢀF H bond,9 recent spectroscopic10 and compu-
3 3 3
tational11 evidence suggest that H-bonds with organic fluorine
are possible in solution. In any case, CꢀF H bonds would
3 3 3
be considered weak interactions,8,12 as a C(sp3)ꢀF HꢀO
3 3 3
H-bond has been calculated to be ca. 2.4 kcal/mol (compared
to ca. 4.8 kcal/mol for a CꢀO HꢀO interaction).9a
3 3 3
In light of these studies, we wondered if H-bond donor
(HBD) solvents suchas water could beusedtofacilitatethe
departure of the fluoride in substitution reactions. In
addition, it is well-known that fluoride forms a strong
H-bond with water (ca. 24 kcal/mol), which would assist
in increasing the stability of the fluoride ion.13 Overall,
this could enable the nucleophilic substitution reaction of
alkyl fluorides using H-bonding as a distinct activation
strategy.14 Herein, we report our initial findings that the
use of water, as a cosolvent, can be used to activate CꢀF
bonds and, thus, allow activated alkyl fluorides to partici-
pate in substitution reactions.
Investigations on the effect of the solvent were per-
formed using 4-phenylbenzyl fluoride (1a) as the substrate
and morpholine as the nucleophile, at 70 °C with a fixed
reaction time of 4 h (Figure 1). Using pure water, a low but
gratifying conversion of 7% was obtained. Performing the
reaction in anhydrous ethanol or i-PrOH also gave low but
quantifiable conversions of 7% and 5% respectively. Our
results can be rationalized using the R scale of solvent
H-bond donor acidities which describes the ability of the
solvent to donate a proton in a solvent-to-solute H-bond.15
In this case, even though water is a better HBD (R = 1.17)
Figure 1. Evaluation of the effect of the solvent on the SN2
reaction of benzyl fluoride 1a with morpholine. Conversions of
1a to 2 were estimated by 1H NMR of the crude mixture.16
(7) For a recent definition of the H-bond, see: Arunan, E.; Desiraju,
G. R.; Klein, R. A.; Sadlej, J.; Schneiner, S.; Alkorta, I.; Clary, D. C.;
Crabtree, R. H.; Dannenberg, J. J.; Hobza, P.; Kjaergaard, H. G.; Legon,
A. C.; Mennucci, B.; Nesbitt, D. J. Pure Appl. Chem. 2011, 83, 1637.
(8) Schneider, H.-J. Chem. Sci. 2012, 3, 1381.
To circumvent the solubility issue encountered with
water, mixtures of organic solvent/water were next ex-
plored. Interestingly, aprotic polar solvents, when mixed
with equal amounts of water, provided significant conver-
sions (16ꢀ33%). Unexpectedly, as protic solvents are
usually regarded as inferior solvents for SN2 transforma-
tions, alcohol/H2O (1:1) mixtures gave the best conver-
sions over 4 h with 46% and 51% for EtOH and i-PrOH,
respectively. Exploration of other ratios of alcohol/H2O
did not provide any improvement. Finally, increasing the
reaction time to 18 h resulted in a complete conversion and
an excellent isolated yield of 96%.16
After observing this superb enhancement of the fluoride
leaving group ability, we wondered if the effect was appli-
cable to all halogens (i.e., no specific CꢀF activation). We
therefore conducted a competition experiment (eq 1) be-
tween chloride and fluoride. Typically, fluoride is consid-
ered unreactive under SN2 conditions; we thus expected to
be able to compare the approximate reactivities of those
(9) (a) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T.
Tetrahedron 1996, 52, 12613. (b) Dunitz, J. D.; Taylor, R. Chem.;Eur.
€
J. 1997, 3, 89. (c) Dunitz, J. D. ChemBioChem 2004, 5, 614. (d) Frohlich,
R.; Rosen, T. C.; Meyer, O. G. J.; Rissanen, K.; Haufe, G. J. Mol. Struct.
2006, 787, 50.
(10) For selected recent examples, see: (a) Takemura, H.; Kaneko, M.;
Sako, K.; Iwanaga, T. New J. Chem. 2009, 33, 2004. (b) Scerba, M. T.;
Leavitt, C. M.; Diener, M. E.; DeBlase, A. F.; Guasco, T. L.; Siegler, M. A.;
Bair, N.; Johnson, M. A.; Lectka, T. J. Org. Chem. 2011, 76, 7975. (c)
Graton, J.; Wang, Z.; Brossard, A.-M.; Gonc-alves Monteiro, D.; Le
Questel, J.-Y.; Linclau, B. Angew. Chem., Int. Ed. 2012, 51, 6176.
(11) For selected recent examples, see: (a) Fonseca, T. A. O.; Freitas,
M. P.; Cormanich, R. A.; Ramalho, T. C.; Tormena, C. F.; Rittner, R.
Beilstein J. Org. Chem. 2012, 8, 112. (b) de Rezende, F. M. P.; Moreira,
M. A.; Cormanich, R. A.; Freitas, M. P. Beilstein J. Org. Chem. 2012, 8,
1227. (c) Silla, J. M.; Cormanich, R. A.; Rittner, R.; Freitas, M. P.
J. Phys. Chem. A 2013, 117, 1659.
(12) Desiraju, G.; Steiner, T. The Weak Hydrogen Bond: In Structural
Chemistry and Biology; Oxford University Press: Oxford, 2001.
(13) Tuck, D. G. Prog. Inorg. Chem. 1968, 9, 161.
(14) For the activation of a C(sp3)ꢀF bond resulting from an
intramolecular SN2 process assisted by noncovalent interactions, see:
Gonzalez-Duarte, P.; Nova, A.; Mas-Balleste, R.; Ujaque, G.; Lledos,
A. Chem. Commun. 2008, 3130.
(15) Kamlet, M. J.; Abboud, J. L. M.; Abraham, M. H.; Taft, R. W.
J. Org. Chem. 1983, 48, 2877.
(16) See the Supporting Information for details.
B
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