Influence of the structure of polyfluorinated alcohols on Bronsted acidity/hydrogen-bond donor ability and consequences on the promoter effect

Article abstract of DOI:10.1021/jo1023816

The influence of substituents on the properties of tri-and hexafluorinated alcohols derived from 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2- propanol (HFIP) was examined. Measurements of specific solvent-solute interactions revealed that H-

Full text of DOI:10.1021/jo1023816

pubs.acs.org/joc
Influence of the Structure of Polyfluorinated Alcohols on Brønsted
Acidity/Hydrogen-Bond Donor Ability and Consequences on the
Promoter Effect
Daniela Vuluga,† Julien Legros,*,† Benoit Crousse,† Alexandra M. Z. Slawin,‡
§
Christian Laurence, Pierre Nicolet, and Daniele Bonnet-Delpon
§
†
ꢀ
†
ꢁ
ꢁ
Laboratoire BioCIS-CNRS, Faculte de Pharmacie, Univ. Paris Sud, 5 rue Jean-Baptiste Clement,
‡
F-92296 Chatenay-Malabry, France, Molecular Structure Laboratory, School of Chemistry,
^
University of St. Andrews, St. Andrews, Fife KY16 9ST, United Kingdom, and CEISAM CNRS UMR
ꢁ ꢀ
6230, Faculte des Sciences et des Techniques, Univ. Nantes, 2 rue de la Houssiniere, F-44322 Nantes, France
§
julien.legros@u-psud.fr
Received December 2, 2010
The influence of substituents on the properties of tri- and hexafluorinated alcohols derived from
2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was examined. Mea-
surements of specific solvent-solute interactions revealed that H-bond donation (HBD) of fluori-
nated alcohols is sensitive to the steric hindrance of the OH group, whereas their Brønsted acidity is
dependent only on the number of fluorine atoms. For hexafluorinated alcohols (HFAs), their
association with amines characterized by X-ray diffraction showed that the balance between HBD
and acidity is influenced by their structure. Moreover, the ability of HFAs to donate H-bonds is
exerted in synclinal (sc), synperiplanar (sp), and also antiperiplanar (ap) conformations along the
C-O bond. Comparison of the effects of fluorinated alcohols as promoting solvents in three
reactions is reported. The positive correlation between rate constants and H-bonding donation
ability for sulfide oxidation and imino Diels-Alder reaction brings to light the role of this property,
while acidity might have a minor influence. In the third reaction, epoxide opening by piperidine, none
of these properties can clearly be put forward at this stage.
Introduction
far different from those of their hydrogenated counterparts
ethanol and isopropanol (Figure 1a). Indeed, the presence of
the strong electron-withdrawing trifluoromethyl group in-
fluences several key parameters: ionizing power, Brønsted
acidity, and hydrogen-bond donation HBD (or H-bond
acidity) are increased, whereas nucleophilicity and hydro-
gen-bond acceptance HBA (or H-bond basicity) are signifi-
cantly depleted.2,3 Because of such specificities, these
fluorinated alcohols have met noteworthy applications in
various domains. For example, in biochemistry TFE and
HFIP are used to modify the conformation of proteins,4 and
they are also widely accepted as exceptional promotion media
to perform organic reactions.5,6 To explain this “booster
The impact of fluorine atom on organic molecules is con-
siderable, with dramatic consequences at physical and chemical
levels.1 This effect is particularly striking for the fluorinated
alcohols trifluoroethanol (TFE) and hexafluoroisopropanol
(HFIP); these easily available chemicals exhibit unique features,
ꢁ
ꢁ
(1) (a) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chem-
istry of Fluorine; Wiley: Hoboken, 2008. (b) Uneyama, K. Organofluorine
Chemistry; Blackwell Publishing: Oxford, 2006. (c) Kirsch, P. Modern
Fluoroorganic Chemistry; Wiley: Weinheim, 2004. (d) Hiyama, T. Organo-
fluorine Compounds, Chemistry and Applications; Springer: Berlin, 2000. (e)
Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry,
Principles and Commercial Applications; Plenum: New York, 1994.
1126 J. Org. Chem. 2011, 76, 1126–1133
Published on Web 01/18/2011
DOI: 10.1021/jo1023816
r
2011 American Chemical Society

Vuluga et al.
JOCArticle
fluorinated alcohols for oxidation reactions,8-11 the role of
HBD seemed to be prominent as supported by theoretical and
experimental studies.7,12 In particular, Berkessel deduced
from crystal structures that the HBD was strongly connected
to the conformation along the C-O bond and that synclinal (sc)
and synperiplanar (sp) conformations were essential (Figure 1b).
Moreover, it was suggested that aggregation of HFIP as
dimers or trimers could also enhance this property.7
To a much lesser extent some tertiary hexafluorinated
alcohols (HFAs) have also been shown to have a remarkable
influence as additives on the course of reactions, even much
better than that of HFIP (Figure 1).13 Thus, Radinov
reported that the presence of 2-10 mol % of Ph(CF3)2COH
or 1,3-bis-HFAB controlled the selectivity of a Pd-catalyzed
isomerization of a diene mono-oxide.14 The authors con-
nected this effect to the relative Brønsted acidity of the HFA
additives. More recently, Hedrick showed that a 1,3-bis-
HFAB-type catalyst was able to catalytically assist the ring-
opening polymerization of lactides through hydrogen bond-
ing with the carbonyl group.15
In this context, we now report on the influence of the structure
of tri- and hexafluorinated alcohols on their hydrogen-bonding
properties through quantitative (spectroscopic measurements)
and qualitative experiments (formation of adducts with amines)
and the consequences on their behavior as reaction media.
FIGURE 1. (a) Some primary, secondary, and tertiary polyfluori-
nated alcohols. (b) Conformations of HFIP.
effect”,7 fluorinated alcohols are often compared to Lewis
acids, acting thus as electron acceptors, either through
proton release or through hydrogen-bond donation. So, it
is not unusual to see the terms Brønsted acidity and H-bond
donor ability being indifferently evoked in the literature,
inducing sometimes confusion between these two notions.
Nevertheless, in the activation of hydrogen peroxide by
Results and Discussion
It is already known from the literature that the introduc-
tion of aromatic or aliphatic substituents on fluorinated
alcohols has a weak influence on their acidity. For example,
(2) (a) Reichardt, C. Chem. Rev. 1994, 94, 2319–2358. (b) Eberson, L.;
Hartshorn, M. P.; Persson, O.; Radner, F. Chem. Commun. 1996, 2105–2112.
(c) Eberson, L.; Hartshorn, M. P.; Persson, O. J. Chem. Soc., Perkin Trans. 2
1995, 1735–1744. (d) Laurence, C.; Nicolet, P.; Reichardt, C. Bull. Soc. Chim.
Fr. 1987, 125–130.
€
€
(7) Berkessel, A.; Adrio, J. A.; Huttenhain, D.; Neudorfl, J. M. J. Am.
Chem. Soc. 2006, 128, 8421–8426.
(8) Sulfoxidation: (a) Ravikumar, K. S.; Kesavan, V.; Bonnet-Delpon,
(3) Laurence, C.; Gal, J. F. Lewis Basicity and Affinity Scales. Data and
Measurement; Wiley: Chichester, 2010.
(4) (a) Othon, C. M.; Kwon, O. H.; Lin, M. M.; Zewail, A. H. Proc. Natl.
Acad. Sci. U.S.A. 2009, 106, 12593–12598. (b) Chatterjee, C.; Hovagimyan,
G.; Gerig, J. T. In Current Fluoroorganic Chemistry; Soloshonok, V. A.,
Mikami, K., Yamazaki, T., Welch, J. T., Honek, J. F., Eds.; ACS Sympo-
sium Series; American Chemical Society: Washington, DC, 2007; p 379. (c)
Chatterjee, C.; Gerig, J. T. Biopolymers 2007, 87, 115–123. (d) Roccatano,
D.; Fioroni, M.; Zacharias, M.; Colombo, G. Protein Sci. 2005, 14, 2582–
2589. (e) Santiveri, C. M.; Pantoja-Uceda, D.; Rico, M.; Jimenez, M. A.
Biopolymers 2005, 79, 150–162. (f) Gerig, J. T. Biophys. J. 2004, 86, 3166–
3175. (g) Mulla, H. R.; Cammers-Goodwin, A. J. Am. Chem. Soc. 2000, 122,
738–739. (h) Andersen, N. H.; Dyer, R. B.; Fesinmeyer, R. M.; Gai, F.; Liu,
Z. H.; Neidigh, J. W.; Tong, H. J. Am. Chem. Soc. 1999, 121, 9879–9880. (i)
Hong, D.-P.; Hoshino, M.; Kuboi, R.; Goto, Y. J. Am. Chem. Soc. 1999, 121,
8427–8433. (j) Cammers-Goodwin, A.; Allen, T. J.; Oslick, S. L.; McClure,
K. F.; Lee, J. H.; Kemp, D. S. J. Am. Chem. Soc. 1996, 118, 3082–3090.
(5) For reviews on fluorinated alcohols, see: (a) Shuklov, I. A.; Dubro-
ꢁ
ꢁ
D.; Begue, J.-P. Org. Synth. 2003, vol. 80, 184–186. (b) Ravikumar, K. S.;
Begue, J.-P.; Bonnet-Delpon, D. Tetrahedron Lett. 1998, 39, 3141–3144. (c)
ꢁ
ꢁ
ꢁ
ꢁ
Ravikumar, K. S.; Zhang, Y. M.; Begue, J.-P.; Bonnet-Delpon, D. Eur. J.
Org. Chem. 1998, 2937–2940.
ꢁ
ꢁ
(9) Epoxidation: (a) Legros, J.; Crousse, B.; Bonnet-Delpon, D.; Begue,
J.-P. Eur. J. Org. Chem. 2002, 3290–3293. (b) van Vliet, M. C. A.; Arends, I.
W. C. E.; Sheldon, R. A. Synlett 2001, 248–250. (c) ten Brink, G. J.;
Fernandes, B. C. M.; van Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon,
R. A. J. Chem. Soc., Perkin Trans. 1 2001, 224–228. (d) Neimann, K.;
Neumann, R. Org. Lett. 2000, 2, 2861–2863. (e) van Vliet, M. C. A.; Arends,
I. W. C. E.; Sheldon, R. A. J. Chem. Soc., Perkin Trans. 1 2000, 377–380. (f)
van Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon, R. A. Tetrahedron Lett.
1999, 40, 5239–5242. (g) van Vliet, M. C. A.; Arends, I. W. C. E.; Sheldon,
R. A. Chem. Commun. 1999, 263–264.
(10) Transformation of ketones into tetraoxanes and/or lactones: (a)
Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Charneau, S.;
ꢂ
Grellier, P.; Iskra, J. Bioorg. Med. Chem. 2006, 14, 7790–7795. (b) Zmitek,
K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra, J. Tetrahedron 2006,
62, 1479–1484. (c) Berkessel, A.; Andreae, M. R. M.; Schmickler, H.; Lex, J.
Angew. Chem., Int. Ed. 2002, 41, 4481–4484. (d) Berkessel, A.; Andreae,
M. R. M. Tetrahedron Lett. 2001, 42, 2293–2295. (e) ten Brink, G.-J.; Vis, J.-
M.; Arends, I. W. C. E.; Sheldon, R. A. J. Org. Chem. 2001, 66, 2429–2433. (f)
Matsumoto, M.; Kobayashi, H. Heterocycles 1986, 24, 2443–2247. (g) see
also ref 9d.
ꢂ
€
ꢁ ꢁ
vina, N. V.; Borner, A. Synthesis 2007, 2925–2943. (b) Begue, J.-P.; Bonnet-
ꢁ
ꢁ
Delpon, D.; Crousse, B. Synlett 2004, 18–29. (c) Begue, J.-P.; Bonnet-
Delpon, D.; Crousse, B. In Handbook of Fluorous Chemistry; Gladysz,
J. A., Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004;
pp 341-350.
(6) For recent contributions on reactions in fluoroalcohol as solvents, see:
(a) Saito, A.; Kasai, J.; Konishi, T.; Hanzawa, Y. J. Org. Chem. 2010, 75,
6980–6982. (b) Li, G.-X.; Qu, J. Chem. Commun. 2010, 2653–2655. (c) Kirste,
A.; Nieger, M.; Malkowsky, I. M.; Stecker, F.; Fischer, A.; Waldvogel, S. R.
ꢁ
Chem.;Eur. J. 2009, 15, 2273–2277. (d) Guerard, K. C.; Chapelle, C.;
(11) Oxidative chlorination: Ben-Daniel, R.; de Visser, S. P.; Shaik, S.;
Neumann, R. J. Am. Chem. Soc. 2003, 125, 12116–12117.
(12) (a) Berkessel, A.; Adrio, J. A. J. Am. Chem. Soc. 2006, 128, 13412–
13420. (b) Berkessel, A.; Adrio, J. A. Adv. Synth. Catal. 2004, 346, 275–280.
(c) de Visser, S. P.; Kaneti, J.; Neumann, R.; Shaik, S. J. Org. Chem. 2003, 68,
2903–2912.
(13) For a convenient access to HFA patterns, see: Sridhar, M.; Nar-
saiah, C.; Ramanaiah, B. C.; Ankathi, V. M.; Pawar, R. B.; Asthana, S. N.
Tetrahedron Lett. 2009, 50, 1777–1779.
(14) Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.;
Liu, W.; Okabe, M.; Radinov, R.; Zhou, Y. J. Org. Chem. 2001, 66, 6141–
6150.
(15) Coulembier, O.; Sanders, D. P.; Nelson, A.; Hollenbeck, A. N.;
Horn, H. W.; Rice, J. E.; Fujiwara, M.; Dubois, P.; Hedrick, J. L. Angew.
Chem., Int. Ed. 2009, 48, 5170–5173.
Giroux, M.-A.; Sabot, C.; Beaulieu, M.-A.; Achache, N.; Canesi, S. Org.
Lett. 2009, 11, 4756–4759. (e) De, K.; Legros, J.; Crousse, B.; Bonnet-
Delpon, D. J. Org. Chem. 2009, 74, 6260–6265. (f) Willot, M.; Chen, J. C.;
Zhu, J. Synlett 2009, 577–580. (g) Philippe, C.; Milcent, T.; Crousse, B.;
Bonnet-Delpon, D. Org. Biomol. Chem. 2009, 7, 2026–2028. (h) Ratnikov,
M. O.; Tumanov, V. V.; Smit, W. A. Angew. Chem., Int. Ed. 2008, 47, 9739–
9742. (i) Ilardi, E. A.; Stivala, C. A.; Zakarian, A. Org. Lett. 2008, 10, 1727–
ꢁ
1730. (j) Fustero, S.; Roman, R.; Sanz-Cervera, J. F.; Simon-Fuentes, A.;
Cunat, A. C.; Villanova, S.; Murguıa, M. J. Org. Chem. 2008, 73, 3523–3529.
ꢁ
~
(k) De, K.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Tetrahedron 2008, 64,
10497–10500. (l) Westermaier, M.; Mayr, H. Chem.;Eur. J. 2008, 14, 1638–
1647. (m) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2008, 73, 2894–2897. (n) Heydari, A.; Khaksar, S.; Tajbakhsh, M. Synthesis
2008, 3126–3130.
J. Org. Chem. Vol. 76, No. 4, 2011 1127

Vuluga et al.
JOCArticle
TABLE 1. Empirical Solvent Parameters of Fluorinated Alcoholsa
compound
βb
ET(30) [ETN]
AN
EtOH
TFE
Ph(CF3)CHOH
HFIP
Ph(CF3)2COH
All(CF3)2COH
Pr(CF3)2COH
0.81
0.22
0.28
∼0 (-0.12)
∼0 (-0.08)
0.03
51.8 [0.65]
59.8 [0.90]
55.0 [0.75]
66.0 [1.07]
49.5 [0.58]
52.6 [0.68]
51.4 [0.64]
37.1
51.1
46.7
59.3
41.8
44.1
42.3
∼0 (-0.02)
aβ = Kamlet-Taft HBA scale; ET(30) = Reichardt HBD scale, [ETN
= normalized Reichardt scale with Me4Si = 0 and H2O = 1.0, see ref
2a]; AN = Gutmann’s acceptor number. bFor hexafluorinated alcohols
where β < 0, β values were assimilated to 0. Measured values are
indicated in parentheses.
FIGURE 2. Molecular probes 1-4 used for the determination of β
(1, 2), ET(30) (3), and AN (4) scales: (open arrow) H-bond acceptor
sites; (black arrow) H-bond donor site.
with a phenyl group the pKa slightly decreases, as exemplified
by pKa(TFE)H O = 12.4 versus pKa(Ph(CF3)CHOH)H O =
2 compared to 4-nitroanisole 1.3,20 For non-H-bond donor
solvents, this enhanced shift measures unambiguously the
H-bond acceptance ability of the solvent. However, for
strong H-bond donor solvents the solvatochromic compar-
ison fails, because the nitro group of 4-nitroanisole is a better
H-bond acceptor than the nitro group of 4-nitrophenol, and
negative values of β are obtained.24 Hence, the negative
values of most hexafluorinated alcohols are assimilated to
zero. The observed order EtOH . Ph(CF3)CHOH ≈ TFE .
HFAs illustrates the impact of the number of fluorine atoms
that lowers significantly the HBA of the oxygen lone pairs.
Hydrogen-Bond Donation (HBD): ET(30) and AN Para-
meters. ET(30) is defined from the solvatochromic shift of the
charge transfer transition of the 30th Reichardt’s betaine
2
2
11.9,16,17 and pKa(HFIP)H O = 9.3 versus pKa(Ph(CF3)2-
2
COH)H O = 8.8.16,18 In contrast the presence of an alkyl
chain renders the compound slightly less acidic: pKa(CH3-
2
(CF3)2COH)H O =9.6.16 Globally, the pKa of such substi-
2
tuted fluorinated alcohols differs from those of TFE and
HFIP by only (0.5 unit. Their Brønsted acidity thus mostly
depends on the number of CF3 groups rather than on the
degree of substitution. However, the structure could influence
some other features, and our investigations were oriented
toward various fluorinated alcohols for which pKa values
have been determined in a methanol/water mixture: TFE
(11.8), Ph(CF3)CHOH(11.7), HFIP (9.5), Ph(CF3)2COH (9.3),
All(CF3)2COH (9.6), and Pr(CF3)2COH (10.1), confirming
thus the influence of fluoroalkyl chains on acidity.19
Some specific solvent parameters have been measured for
these compounds and compared to ethanol: β parameter to
measure the hydrogen-bond acceptance of the oxygen lone
pairs, and ET(30)2a,21 and AN (acceptor number)22 para-
meters for which the H-bond donation of the OH group is the
main contributor.
Investigations on solute-solvent interactions have been
performed at the molecular level. In this approach the
solvent effect on the molecular property of a probe is
measured.23 In the following, three spectroscopic properties,
giving rise to three solvent parameters (β, ET(30), and AN),
have been evaluated (Table 1). The corresponding molecular
probes 1-4 are shown in Figure 2.
(3),2d,21 and AN from the NMR chemical shift δ of the 31
P
atom of triethylphosphine oxide 4 (Figure 2).22 To the first
approximation ET(30) measures the bulk polarity of the
solvent since polar solvents stabilize the zwitterionic ground
state of the dye. However, some additional solvent-probe
specific interactions can contaminate the overall polarity
measurement.25 For H-bond donor solvents such as alco-
hols, both parameters actually register their ability to donate
hydrogen bonds, since the oxygen atoms of 3 and of Et3PO
are strong H-bond acceptors (Figure 2). Fluorinated alco-
hols are rather strong H-bond donors, and it can be con-
sidered that their ET(30) and AN values vary mainly
according to the influence of their HBD. Indeed, there exists
a good correlation, ET(30) = 0.614 ꢀ AN þ 29.28 (R2 =
0.986), for 8 alcohols as H-bond donors (n-BuOH, i-PrOH,
n-PrOH, EtOH, MeOH, TFE, HFIP, and H2O) for which
both parameters have been measured (Figure 3). This corre-
lation shows that, for OH donors, a common single property
explains the variance of ET(30) and AN values. The presence
of a strongly basic oxygen atom in the structure of the probes
3 and 4 clearly indicates that this property is the HBD.
However, whereas HFIP obeys the above correlation, Ph-
(CF3)CHOH, Ph(CF3)2COH, All(CF3)2COH, and Pr(CF3)2-
COH deviate significantly below the correlation line, and
tertiary HFAs exhibit the greatest deviations (Figure 3).26
We attribute these deviations to a steric effect of the
phenyl, allyl, and propyl substituents on the hydrogen bonding
of these alcohols to the betaine 3, as confirmed by the
Hydrogen-Bond Acceptance (HBA): β Parameter. This
parameter is defined from the enhanced solvatochromic shift
of the longest wavelength π f π* transition of 4-nitrophenol
(16) Filler, R.; Schure, R. M. J. Org. Chem. 1967, 32, 1217–1219.
(17) Stewart, R.; Van der Linden, R. Can. J. Chem. 1960, 38, 399–406.
(18) Chang, I. S.; Price, J. T.; Tomlinson, A. J.; Willis, C. J. Can. J. Chem.
1972, 50, 512–520.
(19) Tertiary hexafluorinated alcohols are poorly soluble in water but
fully soluble in MeOH/water (6:4). The pKa’s have been determined poten-
tiometrically. See Supporting Information for details.
(20) Taft, R. W.; Kamlet, M. J. J. Am. Chem. Soc. 1976, 98, 2886–2894.
(21) (a) Reichardt, C. Angew. Chem, Int. Ed. Engl. 1965, 4, 29–40. (b)
Dimroth, K.; Reichardt, C. Justus Liebigs Ann. Chem. 1969, 727, 93–105. (c)
Dimroth, K.; Reichardt, C.; Siepmann, T.; Bohlmann, F. Liebigs Ann. Chem.
1963, 661, 1–37.
(22) (a) Mayer, U.; Gutmann, V.; Gerger, W. Monatsh. Chem. 1975, 106,
1235–1257. (b) Mayer, U.; Gerger, W.; Gutmann, V. Monatsh. Chem. 1977,
108, 489–498.
(23) (a) Buncel, E.; Stairs, R. A.; Wilson, H. The Role of Solvent in
Chemical Reaction; Oxford University Press: Oxford, 2003. (b) Reichardt, C.
Solvents and Solvent Effect in Organic Chemistry, 3rd ed.; Wiley: Weinheim,
2003. (c) Handbook of Solvents; Wypych, G., Ed.; ChemTec Publishing:
Toronto, 2001. (d) Marcus, Y. The Properties of Solvents; Wiley: Chichester,
1998.
(24) Sraidi, K. Ph.D. thesis, University of Nantes, 1991.
(25) (a) Catalan, J. J. Phys. Chem. B 2009, 113, 5951–5960. (b) Riddle,
F. L.; Fowkes, F. M. J. Am. Chem. Soc. 1990, 112, 3259–3264.
(26) It can also be noted that a very good correlation among fluorinated
alcohols is observed in Figure 3 (R2 = 0.989). However, no rationale could be
found to explain this observation.
1128 J. Org. Chem. Vol. 76, No. 4, 2011

Vuluga et al.
JOCArticle
favored only under sc or sp conformation, since “the donor
orbital energy (σ*OH) decreased and the dipole moment (μ)
increased drastically from ap to sp conformation”.7
This HFIP-piperidine structure is clearly contradictory to
H-bond measurements (AN and β), where HFIP appeared to
be an excellent H-bond donor with almost no inclination for
acceptance. However, it is important to distinguish proper-
ties that are determined in liquid or solid state. In the latter
case, crystal packing effect might play an important role, and
comparison of these two types of measurement must be
interpreted with caution.
The ability of tertiary HFAs to donate hydrogen bonds
has also been shown to be significant. Indeed, their associa-
tion with sp2 oxygens has been brought to light and exploited
in the design of chemical vapor sensors for the detection of
phosphonate nerve agents.29 Recently, we disclosed the
preparation of gold nanoparticles coated with a tertiary
HFA terminated by a thiol group (HFA-AuNPs), which
were able to make supramolecular associations with amines.30
In this context, we reasoned that associating various fluori-
nated alcohols with amines to obtain crystalline adducts,
characterizable by crystallography, would bring additional
structural elements to the H-bond scales described above.
Thus, tertiary hexafluorinated alcohols were first mixed
with piperidine, but no solid adducts were obtained with
this partner. However, with piperazine,31 crystalline struc-
tures were afforded from the hexafluorinated alcohols
HFIP, Ph(CF3)2COH, and All(CF3)2COH (Figure 4a-c and
Table 2).32 For all these HFA-amine adducts reported here,
the corresponding X-ray structures were obtained with a
residual factor R-factor < 0.08, allowing unambiguous
location of hydrogen atoms (i.e., to distinguish between a
H-bond adduct and a salt).
FIGURE 3. Plot of ET(30) versus AN, showing the deviations of
alcohols with hindered OH groups (2, fluorinated alcohols; b,
others ). The full line corresponds to the relation ET(30) = 0.614
ꢀ AN þ 29.28.
deviation also observed for t-BuOH. Indeed, the oxygen of
betaine 3 is flanked by two bulky phenyl groups in the ortho
positions (see Figure 2). In contrast, the phosphoryl oxygen
of Et3PO is unhindered and is consequently less sensitive to
steric effects in the fluorinated alcohols. Thus, from AN
measurements reported in Table 1, it emerged that HFIP acts
as the strongest H-bond donor (AN = 59.3), followed by
TFE (51.1). Whereas it is not surprising to see that HFIP is
the best hydrogen-bond donor, it appears that TFE is a better
donor than Ph(CF3)CHOH and even better than tertiary
hexafluorinated alcohols. These latter ones have a H-bond
donor ability standing between those of TFE and EtOH.
From these studies on ethanol and fluorinated alcohols, it
is clear that acidity and H-bond acceptance are connected to
the number of fluorine atoms, while the bulkiness of fluori-
nated alcohols seems to play a prominent role in their HBD.
Hydrogen-Bonding versus Acidity: Influence of the Struc-
ture and Conformation. In addition to spectroscopic analyses,
the H-bond donor ability can also be measured qualitatively
through the formation of complexes with Lewis bases. This has
been well exemplified between fluorinated alcohols and ethers:
for example, the THF-HFIP adduct has a bp =100 ꢀC, far
above the boiling point of each component.7,27 Recently, we
reported that amines could also be excellent partners since
piperidine afforded a solid adduct with HFIP through
H-bonding.28 X-ray diffraction showed that the structure
was composed of 2 molecules of piperidine for 4 molecules of
HFIP in a hexagonal arrangement. A surprising result thus
emerged: HFIP actually acted as a very poor H-bond donor
HFIP-Piperazine. (Figure 4a) An excess of HFIP was
added to piperazine, and after slow evaporation, white
crystals were afforded (mp = 79 ꢀC). The cohesion is due
to an H-bond network between 2 HFIP and 2 nonequivalent
piperazines, where the four of them behave as acceptor and
donor. However, conversely to the previously described adduct
with piperidine, HFIP acted here as a better H-bond donor
than acceptor as shown by H(11O) N(1) (d = 1.58 A and
3 3 3
—(OHN) = 173ꢀ) compared to N(1)-H(1A) O(11) (d =
3 3 3
2.21 A and —(OHN) = 157ꢀ). Moreover, it can be noted that
some non-negligible interactions occurred between F and
hydrogen from NH as for N(4)-H(4A) F(12) (d = 2.47 A
3 3 3
and —(FHN) = 140ꢀ). Moreover, in accordance with the
HBD/conformation relation assumed by Berkessel, HFIP
adopted in this structure a sp conformation (—H(11O)-
O(11)-C(11)-H(11A) = 8ꢀ). While there is no clear evi-
dence to explain this difference between HFIP-piperidine
and HFIP-piperazine, it can be assumed that it could result
from different crystal packing forces in these two cases.
(d(OH N) = 2.30 A and —(OHN) = 95ꢀ) but behaved as a
3 3 3
very good H-bond acceptor with N-H (d(NH O) = 1.71 A
3 3 3
and —(OHN) = 164ꢀ).28 It is also worth noting that, in this
structure, HFIP adopted an anticlinal conformation (ac; tor-
sion angle =104ꢀ). It thus confirms previous reports from
Berkessel in which it was assumed that H-bond donation was
(29) (a) Kong, L.; Wang, J.; Fu, X.; Zhon, Y.; Meng, F.; Luo, T.; Liu, J.
Carbon 2010, 48, 1262–1270. (b) Snow, E. S.; Perkins, F. K.; Houser, E. J.;
Badescu, S. C.; Reinecke, T. L. Science 2005, 307, 1942–1945. For a review,
see: (c) Grate, J. W. Chem. Rev. 2008, 108, 726–745.
(30) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Chem.
Commun. 2008, 4954–4955.
(31) Piperazine is a white solid with mp = 109-112 ꢀC, bp = 145-146
(27) Middleton, W. J.; Lindsey, R. V., Jr. J. Am. Chem. Soc. 1964, 86,
4948–4952.
ꢀC; pKa1(piperazine)H O = 9.73 and pKa2(piperazine)H O = 5.35: Khalili,
2
2
F.; Henni, A.; East, A. L. L. J. Chem. Eng. Data 2009, 54, 2914–2917.
(32) No solid adducts were obtained from TFE and Ph(CF3)CHOH with
piperazine or any other amine assessed.
ꢁ
(28) Berrien, J.-F.; Ourevitch, M.; Morgant, G.; Ghermani, N. E.;
Crousse, B.; Bonnet-Delpon, D. J. Fluorine Chem. 2007, 128, 839–843.
J. Org. Chem. Vol. 76, No. 4, 2011 1129

Vuluga et al.
JOCArticle
FIGURE 4. Single crystal X-ray structures of fluoroalcohol-amine adducts: (a) HFIP-piperazine, (b) All(CF3)2COH-piperazine, (c) Ph(CF3-
)2COH-piperazine, and (d) Pr(CF3)2COH-DABCO (DABCO = diazabicyclo[2.2.2]octane). Hydrogen atoms (C-H) in amines have been
omitted for clarity.
TABLE 2. Characteristics of Hexafluoroalcohol-Amine Adducts
OH
N
NH
O
3 3 3
3 3 3
torsion angle
[deg] /conformation
HFA-amine adduct
HFIP-piperidinea
HFIP-piperazine
All(CF3)2COH-piperazine
Ph(CF3)2COH-piperazine
Pr(CF3)2COH-DABCO
mp [ꢀC]
d [A]
— [deg]
d [A]
— [deg]
95
79
62
78
79
2.30
1.58
1.66
95
173
169
1.71
2.21
2.20
164
157
150
104/ac
8/sp
42/sc
1.74
165
173/ap
aTaken from ref 28.
All(CF3)2COH-Piperazine. (Figure 4b) In the same way,
mixing All(CF3)2COH and piperazine afforded a solid,
albeit with a melting point lower than the previous one
(mp=62ꢀC). In this case, the H-bond arrangement is tetragonal
with two All(CF3)2COH molecules for two piperazines
(equivalent), each one being H-bond acceptor and donor. As
for the HFIP-piperazine complex, the HBD is clearly
F
F
HN bonds can reasonably be considered since some
H distances of 2.36 A are observed (however, the
3 3 3
3 3 3
F-H-N angle varies from 116ꢀ to 162ꢀ). It can be noted
that in head-to-tail arrangement of Ph(CF3)2COH by pairs
aromatic rings appear to be parallel (albeit with a too long
distance to assume a π-stacking interaction), each pair being
orthogonal to the other.
dominating: O(11)-H(11O) N(1) (d = 1.66 A and
Compared to HFIP and All(CF3)2COH, this result is
surprising and could be a priori the consequence of the
slightly highest acidity of Ph(CF3)2COH (pKa H O = 8.8
for Ph(CF3)2COH versus 9.3 for HFIP), but this does not
appear to be completely satisfactory. Actually, this phenom-
enon could be related to a competition between acidity and
HBD ability where steric factors would play an important
3 3 3
—(OHN)=169ꢀ) versus N(1)-H(1N) O(11) (d=2.20 A
3 3 3
and —(NHO)=157ꢀ). It is observed that these distance and
angle values are close to those measured for HFIP with the
same amine and that the torsion angle was also low
(—H(11O)-O(11)-C(11)-C(14)=42ꢀ; sc conformation).
Ph(CF3)2COH-Piperazine. (Figure 4c) A solid was also
obtained, with mp = 78 ꢀC. Crystal structure revealed that
the ratio Ph(CF3)2COH/piperazine was 4:2. Actually, this
solid was not formed of hydrogen bonds but was an alcoholate/
ammonium salt, where each nitrogen atom of piperazine was
protonated. Concerning other interactions, the possibility of
2
€
role: in the presence of a molecule being both a Bronsted and
a Lewis base, a polyfluorinated alcohol can behave either as a
proton or as an H-bond donor. As noticed from Figure 3,
Ph(CF3)2COH exhibits the greatest deviation to the linear
relation between ET(30)/AN, showing thus that its tendency
1130 J. Org. Chem. Vol. 76, No. 4, 2011

Vuluga et al.
JOCArticle
to donate H-bond is strongly connected to the size and nature
of the acceptor partner. Therefore, it is likely that the competi-
tion between proton and H-bond donation is driven by steric
factors, and in the case of Ph(CF3)2COH its association with
piperazine is “easier” through the formation of an alcoho-
late/ammonium salt than through H-bond association.33
Pr(CF3)2COH-DABCO. (Figure 4d) We finally assessed
tertiary alcohols with a tertiary amine to know whether the
HBD from amines plays a significant role in the global
cohesion structure. For this purpose, DABCO (diazabicyclo
[2.2.2]octane) was used as H-bond acceptor partner: unfor-
tunately no crystal structures could be obtained with any of
the three HFAs assessed above. However, from Pr(CF3)2-
COH as fluoroalcohol, ordered crystals were isolated and
characterized (mp = 79 ꢀC). In this case, each nitrogen atom
of the diamine formed a hydrogen bond with a fluoroalcohol
reactions. Since H-bond donation decreases when tempera-
ture rises, its influence can be properly evaluated only in
reactions performed at moderate temperatures.6a Secondary
and tertiary fluorinated alcohols were thus assessed in three
typical test reactions in which HFIP and/or TFE have been
previously shown to have a remarkable effect at room
temperature, without any supplementary additive: (1) the
oxidation of thioanisole into methyl phenyl sulfoxide,8a,b (2)
the opening of 1,2-epoxy-3-phenoxypropane with piperidine,34
and (3) the imino Diels-Alder reaction (or Povarov reaction)
between benzalaniline and butyl vinyl ether.35,36 To measure
kinetics and to obtain rate constants, these reactions usually
performed at room temperature have been performed at
0 ꢀC. Results are reported in Table 3.
As already reported, ethanol was ineffective as solvent for
sulfide oxidation and imino Diels-Alder reaction. Concern-
ing fluorinated alcohols, their behavior was extremely dif-
ferent according to the reaction studied. In the sulfide
oxidation, all of the fluorinated solvents were able to pro-
mote the selective oxidation of sulfide into sulfoxide, albeit
with a huge difference in the rate of conversion between
HFIP and the others. While trifluorinated and tertiary
hexafluorinated alcohols fell into the same range (1.7 < k
molecule (d N(1) H(11O) = 1.74 A, —(OHN) = 165ꢀ,
3 3 3
and d N(4) H(21O) = 1.73 A, —(OHN) = 166ꢀ). Surpris-
3 3 3
ingly, in this structure, the fluoroalcohol adopted an anti-
periplanar (ap) conformation (— H(21O)-O(21)-C(21)-
C(24)=173ꢀ). It is worth noting that in HFIP- and All(CF3)2-
COH-piperazine adducts (sp and sc conformations, respec-
tively) the OH groups behave as strong H-bond donor along
with a weaker H-bond acceptance. These two contributions
might be cooperative and responsible for the low angle value
conformation of the fluorinated alcohols. Conversely, for
Pr(CF3)2COH-DABCO only the HBD of the hydroxyl is
involved, resulting in an “increase of its size” and forcing
thus the fluorinated alcohol to adopt a conformation with a
minimal steric hindrance between the substituents.
< 2.3 L mol-1
h
-1), the reaction was extremely fast in
3
3
HFIP (k=676 L mol-1 h-1). For the opening of the epoxide
with piperidine, tertiary HFAs hardly behave better than
3
3
ethanol (7.5 ꢀ 10-2 and 8.7 ꢀ 10-2 L mol-1
h
-1 for All(CF3)2-
3
3
COH and Ph(CF3)2COH versus 5.9ꢀ10-2 L mol-1 h-1 for
3
3
EtOH), and trifluorinated alcohols were the best promoters,
the reaction being two times faster in Ph(CF3)CHOH than in
These crystal structure studies show that the tertiarization
of HFAs does not prevent them from acting as H-bond
donors, as exemplified by the formation of adducts between
All(CF3)2COH and Pr(CF3)2COH with secondary and ter-
tiary amines. However, for all HFAs there is a competition
between proton and H-bond donation where HBD appears
to be prominent for less sterically hindered alcohols (HFIP,
All(CF3)2COH, and Pr(CF3)2COH); conversely, Brønsted
acidity seems to override H-bond donation for the bulky
Ph(CF3)2COH. In the case of association through hydrogen
bonding, despite the very weak HBA of hexafluorinated
alcohols measured in solution, HFAs can act as H-bond
acceptors in the solid state. Torsion angle comparisons
confirm that HFAs exhibit a stronger HBD under sp and
sc conformation than under ac conformation. However,
these two first conformations appear to be favored when
the hydroxyl group combines strong HBD to a weaker HBA.
When the OH is the only H-bond donor (Pr(CF3)2COH-
DABCO adduct), the alcohols adopt the less sterically
demanding ap conformation.
TFE (56.7 ꢀ 10-2 versus 27.6 ꢀ 10-2 L mol-1
h
-1, respec-
3
3
tively). The most striking result was the total absence of any
conversion in HFIP as solvent. As a matter of fact, as soon as
piperidine was dissolved in HFIP, a white precipitate was
irreversibly formed for which analyses (1H NMR, mp)
matched those of the HFIP-piperidine adduct.28 Concerning
the imino Diels-Alder reaction, only TFE and HFIP pro-
moted the reaction to yield the tetrahydroquinoline, and the
reaction was incredibly faster in the hexafluorinated alcohol
(>31 ꢀ 103 times). In all other media, the substrate remained
unchanged.
To estimate the role that H-bond donation and acidity of
the solvents could play in the promotion of these three reactions,
their rate constants k have been plotted according to the AN
and pKa values of the alcohols, and the corresponding
correlation coefficients R2 were measured (Table 4).
On a mechanistic standpoint, sulfoxidation is an electro-
philic process where free protons as well H-bond donation
could activate H2O2. In the first case, if there is a negative
correlation between k and pKa, the low value of R2 = 0.217
rules out the possibility of a major role of acidity in the
promotion of this transformation. In contrast, the positive
correlation and the significant value of R2 (0.637) for k/AN
are more satisfactory and are in favor of an action of the
H-bond donation, as already assumed in previous investigations
Assessment of Fluorinated Alcohols As Promoting Solvents.
When fluorinated alcohols are used as reaction media,
acidity and H-bond donation are often claimed to be major
factors responsible for the promotion of the transformation.
By exploiting the scales of HBD and Brønsted acidities
obtained from the various fluorinated alcohols studied
above, we reasoned that we could assign the respective role
of these two parameters in the “booster effect” for some
(34) Khaksar, S.; Heydari, A.; Tajbakhsh, M.; Bijanzadeh, H. R. J.
Fluorine Chem. 2010, 131, 106–110.
ꢁ
(35) Reviews on the Povarov reaction: (a) Bello, D.; Ramon, R.; Lavilla,
R. Curr. Org. Chem. 2010, 14, 332–356. (b) Kouznetsov, V. V. Tetrahedron
2009, 65, 2721–2750.
ꢁ
(36) (a) Legros, J.; Crousse, B.; Ourevitch, M.; Bonnet-Delpon, D.
Synlett 2006, 1899–1902. (b) Spanedda, M. V.; Hoang, V. D.; Crousse, B.;
(33) For a discussion on hydrogen-bonding/zwitterionic forms of R-
trifluoromethyl-R0-aminoalcohols, see: Katagiri, T.; Fujiwara, Y.; Takaha-
shi, S.; Uneyama, K. J. Fluorine Chem. 2005, 126, 1134–1139.
ꢁ
Bonnet-Delpon, D.; Begue, J.-P. Tetrahedron Lett. 2003, 44, 217–219.
ꢁ
J. Org. Chem. Vol. 76, No. 4, 2011 1131

Vuluga et al.
JOCArticle
TABLE 3. Fluorinated Alcohols As Reaction Media in Sulfoxidation, Epoxide Opening, and Imino Diels-Alder Reactionsa
rate constant k (L mol-1 h-1
)
3
3
solvent
EtOH
TFE
Ph(CF3)CHOH
HFIP
sulfide oxidationb
epoxide openingc
imino Diels-Alder reactiond
0
2.1
2.3
676
1.9
1.7
5.9 ꢀ 10-2
27.6 ꢀ 10-2
56.7 ꢀ 10-2
0
0
0.05
0
1574
0
Ph(CF3)2COH
All(CF3)2COH
8.7 ꢀ 10-2
7.5 ꢀ 10-2
0
aBased on refs 8, 34, and 36. In all cases, no side product was detected. bReaction monitored by GC with 4-nitrotoluene as internal standard.
cReactions monitored by 1H NMR with tert-butylbenzene as internal standard. dReactions monitored by 1H NMR with dichloromethane as internal
standard.
TABLE 4. Relation between Rate Constants k of Various Reactions and
AN and pKa of Alcoholsa
of an implication of the role of H-bond in the promotion of
the reaction, it is insufficient to understand why the reaction
takes place only in these two solvents, and we cannot provide
any rationale for that at this stage.
correlation coefficient R2
reaction
AN
pKa
From the evaluation of three reactions in polyfluorinated
solvents, the following conclusions can be drawn: the pro-
moter effect of fluorinated alcohols does not stem from
Brønsted acidity, since for k/pKa the correlation coefficients
R2 were all below 0.217. In contrast, the H-bond donation
ability of fluorinated alcohol seems to play a role in the
oxidation of thioanisole into methyl phenyl sulfoxide and in
the imino Diels-Alder between benzalaniline and butyl vinyl
ether (R2 > 0.635). It can be suggested that fluorinated
alcohols form a complex in the transition state that is
prevented by steric effect of tertiary HFAs. However, in
both these reactions HFIP exhibited an outstanding effect,
being far more potent than any other fluorinated alcohol;
this effect cannot be imputed to the sole HBD ability, and
some other factors are certainly involved. Finally, in the
opening of epoxide by piperidine, Ph(CF3)CHOH and TFE
were the most effective media, whereas HFIP completely
inhibited the reaction by forming an H-bond adduct with
piperidine in an irreversible fashion. No correlation could be
found with the acceptor number, and the solvent parameters
promoting this transformation remain unclear at this stage.
sulfide oxidation
epoxide opening
imino Diels-Alder reaction
aSee Supporting Information for details.
0.637
3 ꢀ 10-5
0.635
0.217
0.017
0.215
for the oxidation of olefins with the same oxidant.12 How-
ever, the solvent effect cannot be attributed to the sole HBD
ability, since the difference between AN values cannot explain
the close k values for trifluorinated alcohols and tertiary
HFAs and even less the incredible effect of HFIP with regard
to the other alcohols (the rate constant of HFIP is more than
300 times higher than for any other fluorinated alcohol,
whereas the AN value is only 0.4 times superior compared
with that of the weakest). The absence of reaction in ethanol
is also surprising since its AN value is only 11% below that of
Ph(CF3)2COH (37.1 versus 41.8). However, in this case the
strong H-bond acceptance of EtOH could have a negative
influence by counterbalancing the HBD for H2O2 activation.
In the opening of epoxide with piperidine, absolutely no
correlation was found. For AN, the slope was close to 0
(R2=3 ꢀ 10-5), and when considering pKa, the correlation
was even positive (R2 = 0.017). Thus for this reaction, it is
clear that neither the acidity nor the H-bond donation can be
evoked to justify the booster effect occurring in TFE and
Ph(CF3)CHOH (respectively, 4.6 and 9.6 times faster than in
ethanol). This surprising absence of correlation is in opposition
to the common claim: for these reactants where a too strong
HBD deactivates the nucleophile, the effect of trifluorinated
alcohols certainly also stems from other properties.
Conclusion
The results obtained in this study can be summarized as
follows:
(i) Measurement in the liquid state revealed that
Brønsted acidity of polyfluorinated alcohols is only
connected to the number of CF3 groups and is not
affected by the structure and topology. Conversely,
H-bond donor ability is very sensitive to steric hin-
drance, and this property decreases for tertiary fluori-
nated alcohols (HFAs).
In the case of the imino Diels-Alder reaction, the difference
of reactivity is striking since it occurs only in HFIP and TFE
with an outstanding rate in the hexafluorinated solvent. However,
if the positive correlation for k/AN with R2=0.635 is in favor
1132 J. Org. Chem. Vol. 76, No. 4, 2011

Vuluga et al.
JOCArticle
(ii) However, tertiary HFAs are able to form adducts
with secondary and tertiary amines, and crystal struc-
tures have been examined. The competition between
acidity and HBD appeared to be driven by steric
factors, where the bulky Ph(CF3)2COH seemed to
exhibit acid properties, while other HFAs behave as
H-bond donors.
(iii) In the H-bond adducts with secondary amines,
crystal structures showed that, in the solid state,
HFAs behave both as H-bond donors and acceptors
with different conformations according to the
strength of the H-bonds.
(iv) For three typical test reactions in which fluorinated
alcohols exerted a booster effect (sulfide oxidation
with hydrogen peroxide, oxirane opening with piper-
idine, and imino Diels-Alder), correlation between
rate constants and HBD or pKa showed that acidity
cannot be reasonably involved. For sulfoxidation
and imino Diels-Alder, HFIP was by far the best
solvent. Although H-bond donation ability seems to
have a beneficial effect, the reaction promotion
cannot be imputed to this parameter only. Conver-
sely, in the opening of epoxide with piperidine,
trifluorinated alcohols gave the best results, and
further studies with other nucleophiles will be per-
formed to unveil the factors involved.
δ 2.85 (s, 8H), 4.95 (s, 4H), 7.45 (m, 6H), 7.75 (m, 4H). 13C NMR
(CDCl3, 75 MHz): δ 45.5, 77.2 (sept, J=28.5), 123.2 (q, J=
287.6), 126.8, 128.3, 129.8, 131.3. 19F NMR (CDCl3, 188 MHz):
δ -75.4 (s). Anal. Calcd for C22H22F12N2O2: C, 46.00; H, 3.86;
N, 4.88. Found: C, 45.96; H, 3.72; N, 4.87.
Pr(CF3)2COH-DABCO Adduct. White crystals; crystallized
from light petroleum ether; mp=79 ꢀC. 1H NMR (CDCl3, 200
MHz): δ 0.95 (t, J=7.5, 3H), 1.55 (m, 2H), 1.80 (m, 2H), 2.75 (s,
6H). 13C NMR (CDCl3, 75 MHz): δ 14.5, 15.5, 46.0, 77.0 (sept,
J=28.5), 123.7 (q, J=287.9). 19F NMR (CDCl3, 188 MHz):
δ -76.8 (s). Anal. Calcd for C18H28F12N2O2: C, 40.61; H, 5.30;
N, 5.26. Found: C, 40.71; H, 5.49; N, 5.26.
Methyl Phenyl Sulfoxide38. A 5 mL round-bottom flask was
charged with thioanisole (124 mg, 1 mmol), 4-nitrotoluene
(internal standard, 0.1 mmol, 14 mg), and the solvent (2 mL)
and then cooled to 0 ꢀC. Hydrogen peroxide (15% aq soln; 226 mg,
1 mmol), previously cooled at 0 ꢀC, was then added. The reaction
mixture was left under stirring at 0 ꢀC. Aliquots (1 μL) were takenz
at regular intervals and immediately analyzed by GC. 1H NMR
(CDCl3, 200 MHz): δ 2.72 (s, 3H), 7.52 (m, 3H), 7.65 (m, 2H).
1-Phenoxy-3-(piperidin-1-yl)propan-2-ol39. A solution of 1,
2-epoxy-3-phenoxypropane (150 mg, 1 mmol) and tert-butyl-
benzene (internal standard, 0.1 mmol, 13 mg) in the solvent (0.5 mL)
was cooled at 0 ꢀC and then added to the amine (1 mmol)
charged in a 5 mL round-bottom flask. The reaction mixture
was left under stirring at 0 ꢀC. Aliquots (10 μL) were taken at
regular intervals, dissolved in CDCl3 (0.6 mL), and analyzed by
1H NMR. 1H NMR (CDCl3, 200 MHz): δ 1.45-1.75 (m, 6H),
2.35-2.70 (m, 6H), 3.2 (br s, 1H), 3.9-4.2 (m, 3H), 6.9 (m, 3H),
7.3 (m, 2H).
cis-4-Butoxy-1,2,3,4-tetrahydro-2-phenylquinoline40. A 5 mL
round-bottom flask was charged with benzalaniline (118 mg, 1
mmol) and dichloromethane (internal standard, 0.15 mmol, 13 mg)
in the solvent (1 mL) and cooled to 0 ꢀC. A solution of butyl
vinyl ether (400 mg, 4 mmol) in the same solvent (1 mL) was then
added. The reaction mixture was left under stirring at 0 ꢀC.
Aliquots (10 μL) were taken at regular intervals, dissolved in
CDCl3 (0.6 mL), and analyzed by 1H NMR. 1H NMR (CDCl3,
200 MHz): δ 1.00 (t, J=7.2, 3H), 1.45-1.57 (m, 2H), 1.62-1.72
(m, 2H), 2.04-2.13 (m, 1H), 2.44-2.51 (m, 1H), 3.52-3.75 (m,
2H), 3.98 (br s, 1H), 4.58 (dd, J=11.7, J=2.5, 1H), 4.86 (dd, J=
10.6, J=5.7, 1H), 6.57 (dd, J=8.1, J=1.0, 1H), 6.80 (td, J=7.5,
J=1.0, 1H), 7.11 (td, J=7.5, J = 1.0, 1H), 7.34-7.53 (m, 6H).
Experimental Section
1,1,1-Trifluoro-2-(trifluoromethyl)pent-4-en-2-ol (Pr(CF3)2C-
OH)37. A round-bottom flask was charged with All(CF3)2COH
(10 g, 48 mmol) and Pd/C (1 g). A hydrogen balloon (1 atm) was
added, and the reaction mixture was left under stirring at room
temperature. After 18 h, the mixture was filtered and the product
was distilled (bp = 97 ꢀC, lit. bp = 98 ꢀC37) to afford Pr(CF3)2-
COH as a colorless liquid (9.1 g, 90% yield). 1H NMR (CDCl3,
200 MHz): δ 1.02 (t, J=7.1, 3H), 1.60 (sext, J=7.1, 2H), 1.95 (t,
J=7.1, 2H), 3.09 (br s, 1H). 13C NMR (CDCl3, 75 MHz): δ 14.1,
15.4, 32.6, 76.5 (hept, J=28.5), 123.3 (q, J=287.6). 19F NMR
(CDCl3, 188 MHz), δ: -77.6. APCI m/z (relative intensity): 209
[M - H]- (100%), 419 [2M - H]- (60%).
General Procedure for the Preparation of the Fluorinated
Alcohol-Amine Adducts. A round-bottom flask was charged
with the amine (5 mmol) and the fluorinated alcohol (25 mmol)
was added. The mixture was left at room temperature for 2 days,
and the crystals formed were filtered and crystallized.
Acknowledgment. The European Union within the EST
network BIOMEDCHEM (MEST-CT-2005-020580) is
gratefully acknowledged for the Ph.D. grant of D.V. and
financial support. The Region Ile-de-France and the GIS-
Fluor are also thanked for support. Central Glass is ac-
knowledged for the kind gift of HFIP, All(CF3)2COH. and
Ph(CF3)2COH. M. Luc-on (Univ. Nantes), Drs. C. Gueutin
and J. Rodrigo de Losada (Univ. Paris Sud) are thanked for
their kind help.
HFIP-Piperazine Adduct. White crystals; crystallized from
1
toluene; mp=79 ꢀC. H NMR (CDCl3, 200 MHz): δ 2.87 (s,
8H), 4.27 (s, 3H), 4.32 sept, J=6.3, 2H). 13C NMR (CDCl3, 75
MHz): δ 45.5, 69.3 (sept, J=32.9), 122.0 (q, J=281.0). 19F NMR
(CDCl3, 188MHz):δ-76.1 (d, J=6.3). Anal. Calcd for C10H14F12-
N2O2: C, 28.45; H, 3.34; N, 6.63. Found: C, 28.34; H, 2.98; N, 6.74.
All(CF3)2COH-Piperazine Adduct. White crystals; crystal-
lized from light petroleum ether; mp = 62 ꢀC. 1H NMR
(CDCl3, 200 MHz): δ 2.66 (d, J=7.7, 4H), 2.82 (s, 8H), 4.3 (s,
4H), 5.21 (m, 2H), 5.28 (m, 2H), 5.86 (m, 2H). 13C NMR (CD-
Cl3, 75 MHz): δ 35.4, 45.9, 75.6 (sept, J=28.5), 120.8, 123.4 (q,
J=287.6), 129.1. 19F NMR (CDCl3, 188 MHz): δ -76.6 (s).
Anal. Calcd for C16H22F12N2O2: C, 38.26; H, 4.41; N, 5.58.
Found: C, 38.11; H, 4.19; N, 5.63.
Supporting Information Available: Full experimental details
for the measurements of pKa, β, ET(30), AN parameters of
alcohols, rate constants, correlations, 1H and 13C NMR spectra
and crystallographic information files for the fluorinated alco-
hols-amine adducts (CIF files and crystal structure data). This
material is available free of charge via the Internet at http://
pubs.acs.org.
Ph(CF3)2COH-Piperazine Adduct. White crystals; crystal-
(38) Legros, J.; Bolm, C. Chem.;Eur. J. 2005, 11, 1086–1092.
(39) Mesropyan, E. G.; Ambartsumyan, G. B.; Avetisyan, A. A.; Galst-
yan, A. S.; Arutyunova, I. R. Russ. J. Org. Chem. 2005, 41, 67–69.
lized from toluene; mp=78 ꢀC. 1H NMR (CDCl3, 200 MHz):
ꢁ
(40) Sridharan, V.; Avendano, C.; Menendez, J. C. Synthesis 2008, 1039–
(37) Urry, W. H.; Nishihara, A; Niu, J. H. Y. J. Org. Chem. 1967, 32, 347–
352.
1044.
J. Org. Chem. Vol. 76, No. 4, 2011 1133