Nucleophilic trifluoromethylation of carbonyl compounds: Trifluoroacetaldehyde hydrate as a trifluoromethyl source

Article abstract of DOI:10.1021/jo400202w

A feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atom-economical trifluoromethyl source. The reaction was found to be applicable to the nucleophilic trifluoromethylation of a broad spectrum of carbonyl compounds with satisfactory yields in general. DFT calculations have been performed to provide mechanistic insight into the present and related reactions employing 2,2,2-trifluoro-1- methoxyethanol and hexafluoroacetone hydrate.

Full text of DOI:10.1021/jo400202w

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Article
Nucleophilic Trifluoromethylation of Carbonyl Compounds:
Trifluoroacetaldehyde Hydrate as a Trifluoromethyl Source
G. K. Surya Prakash, Zhe Zhang, Fang Wang, Socrates Munoz, and George A Olah
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400202w • Publication Date (Web): 20 Feb 2013
Downloaded from http://pubs.acs.org on February 23, 2013
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Nucleophilic Trifluoromethylation of Carbonyl Compounds: Trifluoroacetaldehyde Hydrate
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as a Trifluoromethyl Source
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G. K. Surya Prakash,* Zhe Zhang, Fang Wang, Socrates Munoz, George A. Olah
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Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern
California, Los Angeles, CA 90089ꢀ1661
gprakash@usc.edu
TOC
Abstract
A
feasible nucleophilic trifluoromethylating protocol has been developed using
trifluoroacetaldehyde hydrate as an atom economical trifluoromethyl source. The reaction was
found to be applicable to the nucleophilic trifluoromethylation of a broad spectrum of carbonyl
compounds with satisfactory yields in general. DFT calculations have been performed to provide
mechanistic
insight
into
the
present
and
related
reactions
employing
2,2,2ꢀtrifluoroꢀ1ꢀmethoxyethanol and hexafluoroacetone hydrate.
Introduction
Among various synthetic pathways, the nucleophilic trifluoromethylation of carbonyl
compounds has provided a facile access to αꢀtrifluoromethyl alcohols.1ꢀ4 Although TMSCF3 (the
RuppertꢀPrakash reagent) is a versatile reagent capable of transferring the CF3 group (Scheme
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1ꢀa),5,6 chemists have also strived for alternative nucleophilic trifluoromethylating reagents
applicable to various synthetic purposes7ꢀ10 including direct deprotonation of trifluoromethane.4 In
recent years, a series of nucleophilic trifluoromethylation reactions has been established based on
the in situ formation of transient negatively charged species, which can release trifluoromethyl
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ꢀ
anion (CF3 ) along with a stable byꢀproduct (Scheme 1ꢀb).11 Langlois and others have
demonstrated the direct trifluoromethylation of various electrophiles using trifluoromethane
ꢀ
(CF3H) in DMF via
a
trifluoromethylated hemiaminal derivative (CF3 ꢀDMF adduct
analogue).12ꢀ19 Prakash et al. utilized phenyl trifluoromethyl sulfone (PhSO2CF3) and phenyl
trifluoromethyl sulfoxide (PhSOCF3) in nucleophilic trifluoromethylation reactions, which
allowed the generation of CF3 via pentavalent and tetravalent sulfur intermediates, respectively.20
ꢀ
In line with this work, an alkoxideꢀinduced trifluoromethylation was also reported by Beier and
coworkers using diethyl trifluoromethylphosphate [(EtO)2POCF3].21 Recently, Colby et al.
elegantly showed that hexafluoroacetone hydrate amidinate complex could also be exploited as a
novel nucleophilic trifluoromethylating reagent.22ꢀ24 By releasing thermodynamically stable
ꢀ
trifluoroacetate anion (CF3CO2 ), such a reagent was able to incorporate the CF3 moiety into
various electrophiles. On the basis of these reactions, we envisaged that ready available
trifluoroacetaldehyde hemiacetal derivatives (1) could enable nucleophilic trifluoromethylation by
expelling formates as leaving groups. Compared with other similar reagents, the advantages of 1
lie in not only its high atom economy but also its maximum utilization of the CF3 motif (Scheme
1ꢀc).
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Scheme 1. Generation of "CF3 " synthon through the release of neutral or stable species.
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Results and Discussion
Our initial effort was focused on the trifluoromethylation of benzaldehyde (PhCHO, 2a)
using 2,2,2ꢀtrifluoroꢀ1ꢀmethoxyethanol (1a) and 2,2,2ꢀtrifluoroꢀ1ꢀethoxyethanol (1b). By treating
1a and 1b with potassium tertꢀbutoxide (tꢀBuOK) in DMF, neither CF3H nor the desired
αꢀtrifluoromethyl alcohol (3a) was observed after numerous attempts (Scheme 2). This could be
ꢀ
ascribed to the plausible reverse addition of CF3 to alkyl formates, which could significantly
impede the trifluoromethylation of benzaldehyde (Scheme 2, Eq. 1).
-
Scheme 2. Generation of CF3 from different trifluoroacetaldehyde hemiacetal derivatives.
ꢀ
Considering the essential low electrophilicity of formate anion (HCO2 ),
trifluoroacetaldehyde hydrate (1c) was adopted in our further investigation to avoid the reverse
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CF3 ꢀbyꢀproduct addition (Scheme 2, Eq. 2). According to 19F NMR spectroscopy, 3a was
obtained in 64% yield by treating 1c (1.2 equiv.) with 6.0 equiv. of tꢀBuOK in DMF (Table 1,
Entries 1ꢀ4). Further reaction condition screening was focused on alternative bases, reaction
temperatures and the proportion of reagents; however, the yields did not improve (Table 1, Entry
5ꢀ11).
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Table 1. Reaction condition optimization using 1c [CF3CH(OH)2-2H2O] as a CF3 precursor.
Whereas the above mentioned results seemed to be satisfactory, its practicality was largely
limited by the requirement of large excess of base. This was presumably due to the fact that
commercial 1c was a dihydrate CF3CH(OH)2ꢁ2H2O.25 To remove the excess amount of H2O,
CF3CH(OH)2 was treated with various amines expecting the formation of the corresponding salts
similar to the hexafluoroacetone hydrate amidinate salts.24 However, no solid complexes could be
obtained by these means, probably due to the lower acidity of CF3CH(OH)2 compared with
(CF3)2C(OH)2. We further exploited 4 Å molecular sieves as a drying agent, which unfortunately
absorbed majority of CF3CH(OH)2 along with water. After a brief screening, calcium chloride
(CaCl2) was shown to be an efficient drying agent allowing recovery of 95% 1c with a
composition of CF3CH(OH)2ꢁ½H2O.26 With such processed 1c in hand, the required tꢀBuOK:1c
ratio was reduced from 5:1 to 4:1 (Table 1, Entry 4, Table 2, Entries 4 and 5). The optimal reaction
conditions were found by treating 1c (1.5 equiv.) with tꢀBuOK (6.0 equiv.) in DMF at ꢀ50 °C for
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30 min, followed by the addition of PhCHO (1.0 equiv.) (Table 2, Entries 5ꢀ7). Noticeably, despite
ꢀ
the fact that THF and DMSO allowed the release of CF3 from 1c, the nucleophilic
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trifluoromethylation of benzaldehyde did not take place (Table 2, Entries 8 and 9).
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Table 2. Reaction condition optimization using 1c [CF3CH(OH)2-½H2O] as a CF3 precursor.
With the optimal reaction conditions, the scope of substrates was investigated. As shown in
Table 3, various aldehydes and ketones readily reacted. Aryl aldehydes bearing electronꢀdonating
substituents and halides were shown to participate in the reaction to afford products in good to
excellent yields (Table 3, Entries 1ꢀ5, 8ꢀ11, and 13). However, other strong electronꢀwithdrawing
moieties, such as NO2 and CF3 groups, on the phenyl ring impeded the reaction (Table 3, Entries 6
and 7). In comparison with the significant electronic effects, the steric hindrance of substituents
did not play a major role in the reactivity of the substrates (Table 3, Entries 5 and 9ꢀ11). As
anticipated, the trifluoromethylation reaction with enolizable aldehydes was quite sluggish under
such strong basic conditions (Table 3, Entry 14). Similar to aryl aldehydes, various benzophenone
derivatives were also found to be reactive (Table 3, Entry 12, 14, 15). Bulky phenyl ketone (2s)
also reacted to yield the corresponding product in excellent yield (Table 3, Entry 19). Intriguingly,
although enolizable acetophenone was not a viable substrate in the present reaction,
adamantanꢀ2ꢀone (2t) was smoothly trifluoromethylated, due to its low enolizability (Table 3,
Entry 20).
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Table 3. Nucleophilic trifluoromethylation of carbonyl compounds
trifluoroacetaldehyde hydrate 1c [CF3CH(OH)2-½H2O].
2
with
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To elucidate mechanistic aspects of the reaction, theoretical calculations were performed at
the B3LYP/6ꢀ31+G(d,p) level in DMF27,28 using Gaussian 09 package.29,30 As shown in Scheme 3,
trifluoroacetaldehyde hydrate 1c preferentially underwent deprotonation in the presence of
tꢀBuOK. Although further deprotonated intermediate 1c-K2 was slightly higher in energy by +0.7
kcal/mol, ca. 60% of 1c-K could still be deprotonated with 4 eq. of tꢀBuOK under the reaction
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conditions (Scheme 3, Eq. 2). It has also been found that salts 1c-K and 1c-K2 were
ꢀ
thermodynamically unstable species tending to expel CF3 . Since these processes involve a Gibbs
ꢀ
free energy change of approximately ꢀ30 kcal/mol, the reversible addition of CF3 to HCO2K was
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rather unlikely to occur (Scheme 3, Eq. 4 and 5). In contrast, the products 3a-K and tꢀBuOH were
found to be more stable than the corresponding starting materials (2a, tꢀBuOK, and benzaldehyde)
by ꢀ1.7 kcal/mol (Scheme 3, Eq. 6). This has not only provided a theoretical support for the
success in isolating 3a, but also agreed with the observed essential stability of 3a in the presence
of tꢀBuOK in DMF. Overall, the Gibbs energy change was calculated to be downhill by ꢀ52.2
kcal/mol, which is mainly due to the highly exothermic deprotonation and degradation processes
(Scheme 3, Eq. 7). Noticeably, the analogous hydride transfer by releasing trifluoroacetate was
also found to be an exothermic reaction, which was however slightly less thermodynamically
favorable (Table 1, Entry 9 and Scheme 3, Eq. 8).
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Scheme 3. Calculated thermodynamics of the nucleophilic trifluoromethylation reaction
using 1c and the related reactions.
We further explored transition states to achieve a continuous reaction pathway from 1c to
3a-K (Figure 1). As mentioned above, both 1c-K and 1c-K2 could irreversibly degrade to release
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CF3H and HCO2K. However, such fragmentation was more likely to proceed via 1c-K2
intermediate due to the significantly lower barrier involving TS2 than TS1 (+6.5 kcal/mol v.s.
+21.0 kcal/mol). Whereas TS2’ was also located on the reaction pathway suggesting the possible
hydride transfer and trifluoroacetate formation, it was substantially unfavorable compared with
TS2. This is in good agreement with the fact that the trifluoromethyl transfer predominated in the
present reaction. The calculation of analogous transition states involving lithium countercations
also showed that the CꢀCF3 bond cleavage is kinetically preferred over hydride transfer by 9.1
kcal/mol (see SI), which rationalizes the observed trifluoroacetate formation (Table 1, Entry 9).
Presumably, the nucleophilic addition involved the deprotonation of CF3H by tꢀBuOK, which was
predicted to have a small barrier of +9.3 kcal/mol. In spite of the endothermic deprotonation by
+5.6 kcal/mol, the forward nucleophilic addition was both thermodynamically favored and
kinetically facile due to a rather small activation barrier of +19.4 kcal/mol (compared with CF3H).
Apparently, both of these two factors facilitated the nucleophilic trifluoromethylation under the
present reaction conditions.
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Figure 1. Calculated reaction coordinate from 1c to 3a-K.
Gibbs Free Energy
(kcal/mol)
O
H
O
K
O
K
OH
H
O
K
F3C
F3C
OH
F3C
H
1c
H
TS1
+0.7
O
0.0
K
TS2'
-5.0
H
F3C
O
K
TS2
-13.1
K
H
-19.6
OK
-20.3
OK
O
CF3
H
CF3
Ph
F3C
OK
TS4
F3C
OH
H
H
1c-K2
O
-31.1
K
t-Bu
1c-K
TS3
-41.2
CF3K
-44.9
-50.5
CF3H
-52.2
OK
Calculated at the B3LYP/6-31+G(d,p) level
of theory with implicit consideration of DMF
solvation. Only CF3-containing species are
shown.
Ph
CF3
H
3a-K
Reaction Coordinate
In addition to the above mentioned studies, we also performed theoretical calculations to
explore the mechanism of nucleophilic trifluoromethylations using trifluoroacetaldehyde
hemiacetal (1a) and hexafluoroacetone hydrate (5). As show in Figure 2ꢀA, although the
deprotonation of 1a was thermodynamically feasible, the exothermicity of the subsequent CF3
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release was rather insignificant (ꢀ2.9 kcal/mol), indicating a facile reverse addition of “CF3 ” to
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methyl formate. This is indeed consistent with the observed low ability of trifluoroacetaldehyde
ꢀ
hemiacetals to release the “CF3 ” anion. Moreover, the formations of trifluoroacetaldehyde (via
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methoxide release) and methyl trifluoromethylacetate (via hydride release) were found to be
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highly endothermic, suggesting that the low reactivity of 1a was mainly due to the reversibility of
ꢀ
the “CF3 ” release. Kinetically, the barrier to the nucleophilic trifluoromethylation of
benzaldehyde was found to be fairly similar to nucleophilic trifluoromethylation of methyl
formate (+21.5 kcal/mol versus +19.4 kcal/mol). Considering the overall Gibbs energy change
from 1a-K to 3a-K was ꢀ4.6 kcal/mol, the interconversion between these two species was
essentially reversible (Figure 2ꢀC).
Figure 2. Calculated reaction coordinate of nucleophilic trifluoromethylation of aldehyde
using trifluoroacetaldehyde hemiacetal (1a) and hexafluoroacetone hydrate (5).
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As shown in Figure 2ꢀB, both the first and the second deprotonations of hexafluoroacetone
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hydrate (5) were highly exothermic due to the presence of geminal CF3 groups. Although the
ꢀ
release of the “CF3 ” anion were thermodynamically downhill from both deprotonated products
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(5-K and 5-K2), a significantly higher kinetic barrier was found during the course of CF3 release
from 5-K (+24.6 kcal/mol versus +5.6 kcal/mol). This resembled the CF3 release coordinate of 1c,
therefore implying that the primary kinetic driving force for CF3 release was the formation of the
highly ionic dipotassium salts 1c-K2 and 5-K2. In contrast, 1a could only form a
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monopotassiumꢀcontaining species 1a-K, which thus retarded to expel CF3 . Noticeably, the
nucleophilic trifluoromethylation using 5 was calculated to be thermodynamically more favorable
than that using 1c by ca. 13 kcal/mol. This was presumably due to the generation of byꢀproduct
CF3CO2K, whose conjugate acid is more acidic than formic acid. Since both reactions involving
1c-K2 and 5-K2 were highly exothermic processes, the substantially irreversible nature of these
two reactions was not altered by such relatively small difference in Gibbs free energy release.
Conclusion
In conclusion, we have developed a novel nucleophilic trifluoromethylation of carbonyl
ꢀ
compounds using trifluoroacetaldehyde hydrate 1c as a CF3 precursor. The utilization of readily
available trifluoroacetaldehyde hydrate has not only provided a facile synthetic access towards
αꢀtrifluoromethyl alcohols, but also allowed maximum utilization of the CF3 moiety in the
precursor (compared with hexafluoroacetone hydrate). Theoretical calculations have suggested
that both trifluoroacetaldehyde hydrate deprotonation and subsequent CF3 release from potassium
salt 1c-K2 were highly exothermic processes. These two steps contributed ca. +50 kcal/mol Gibbs
free energy release as the actual driving force for the reaction. Further theoretical calculations of
nucleophilic trifluoromethylations using trifluoroacetaldehyde hemiacetal 1a and
hexafluoroacetone hydrate 5 provided mechanistic rationalizations of their different reactivity
from trifluoroacetaldehyde hydrate 1c.
Experimental Section
General Methods. Unless otherwise mentioned, all the chemicals were purchased from
commercial sources and used without further purification. Preparative thin layer chromatography
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or flash column chromatography were performed to isolate products with suitable eluent. 1H, 13C,
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and 19F spectra were recorded on 400 MHz or 500 MHz NMR spectrometers. H NMR chemical
shifts were determined relative to CDCl3 as the internal standard at δ 7.26 ppm. 13C NMR shifts
were determined relative to CDCl3 at δ 77.16 ppm. 19F NMR chemical shifts were determined
relative to CFCl3 at δ 0.00 ppm. Mass spectra were recorded on a high resolution mass
spectrometer, in the EI, FAB or ESI modes.
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Typical Procedure for Removal of Excess Water from Commercial
Trifluoroacetaldehyde Hydrate 1c. Commercial trifluoroacetaldehyde hydrate 1c (5.00 g, 32.9
mmol) in 100 mL anhydrous Et2O was added CaCl2 (1.21 g, 11.0 mmol) in small portions with
vigorous stirring. The mixture was stirred for 2 h and quickly subjected to suction filtration under
air. The solvent of the filtrate was removed under reduced pressure to give partially dried product
(4.11 g). The concentration of CF3CHO in this sample was determined by 19F NMR spectrum with
PhCF3 as an internal standard, which indicated a formula of CF3CH(OH)2ꢁ½H2O and > 95% yield.
The newly prepared trifluoroacetaldehyde hydrate was transferred into a tightly sealed vial and
stored in a glove box.
Typical Procedure for Nucleophilic Trifluoromethylation of Carbonyl Compounds. To a
stirred solution of trifluoroacetaldehyde hydrate (1c, 1.5 mmol) in DMF (1.0 mL) at ꢀ50 °C, a
solution of tꢀBuOK (673 mg, 6.0 mmol) in DMF (3.0 mL) was added dropwise over 5 min. The
reaction was stirred for 30 min while maintaining the temperature at ꢀ50 °C. A solution of
carbonyl compounds (2, 1.0 mmol) in DMF (1.0 mL) was then added into the reaction mixture at
ꢀ50 °C and stirred for 1 h. The reaction mixture was allowed to gradually warm up to room
temperature before quenching with water. The resulting mixture was extracted with diethyl ether
(3×10 mL). The combined organic phase was then washed with saturated NH4Cl aqueous solution,
water, and dried over Na2SO4. The solvent was removed under reduced pressure and the residue
was purified with silica gel flash chromatography using pentaneꢀdiethyl ether as eluent.
1
1ꢀPhenylꢀ2,2,2ꢀtrifluoroethanol (3a).20 Colorless oil (146 mg, 83%). H NMR (400 MHz,
CDCl3) δ. 7.55ꢀ7.37 (m, 5H), 5.00 (q, J = 6.7 Hz, 1H), 2.78 (br, 1H). 19F NMR (376 MHz, CDCl3)
δ ꢀ78.9 (d, J = 6.7 Hz, 3F).
1
1ꢀ(4ꢀFluorophenyl)ꢀ2,2,2ꢀtrifluoroethanol (3b).31 Colorless oil (99 mg, 51%). H NMR (400
MHz, CDCl3) δ 7.48ꢀ7.44 (m, 2H), 7.15ꢀ7.05 (m, 2H), 5.01 (q, J = 6.6 Hz, 1H), 2.74 (br, 1H). 19
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NMR (376 MHz, CDCl3) δ ꢀ79.2 (d, J = 6.6 Hz, 3F), ꢀ112.4 (m, 1F).
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1ꢀ(4ꢀChlorophenyl)ꢀ2,2,2ꢀtrifluoroethanol (3c).20,32 Colorless oil (122 mg, 58%). H NMR
(400 MHz, CDCl3) δ 7.48ꢀ7.33 (m, 4H), 5.01 (q, J = 6.5 Hz, 1H), 2.72 (br, 1H). 19F NMR (376
MHz, CDCl3) δ ꢀ79.0 (d, J = 6.5 Hz, 3F).
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1ꢀ(4ꢀBromophenyl)ꢀ2,2,2ꢀtrifluoroethanol (3d).33 Colorless oil (143 mg, 56%). 1H NMR (400
MHz, CDCl3) δ 7.57ꢀ7.53 (m, 2H), 7.36ꢀ7.33 (m, 2H), 4.98 (dq, J = 4.3, 6.6 Hz, 1H), 2.83 (d, J =
4.3 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ ꢀ79.0 (d, J = 6.6 Hz, 3F).
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1ꢀ(4ꢀMethylphenyl)ꢀ2,2,2ꢀtrifluoroethanol (3e).33 Colorless oil (86 mg, 45%). H NMR (400
MHz, CDCl3) δ 7.36 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.98 (q, J = 6.7 Hz, 1H), 2.56
(br, 1H), 2.38 (s, 3H). 19F NMR (376 MHz, CDCl3) δ ꢀ78.9 (d, J = 6.7 Hz, 3F).
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1ꢀ(4ꢀDimethylaminophenyl)ꢀ2,2,2ꢀtrifluoroethanol (3h).24 Reddish solid (206 mg, 94%). H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.88 (q, J = 6.8 Hz,
1H), 2.97 (s, 6H), 2.66 (br, 1H). 19F NMR (376 MHz, CDCl3) δ ꢀ78.9 (d, J = 6.8 Hz, 3F).
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1ꢀ(3ꢀMethylphenyl)ꢀ2,2,2ꢀtrifluoroethanol (3i).4 Colorless oil (137 mg, 72%). H NMR (400
MHz, CDCl3) δ 7.34ꢀ7.18 (m, 4H), 4.96 (q, J = 6.7 Hz, 1H), 2.68 (br, 1H), 2.39 (s, 3H). 19F NMR
(376 MHz, CDCl3) δ ꢀ78.8 (d, J = 6.7 Hz, 3F).
1ꢀ(2ꢀMethylphenyl)ꢀ2,2,2ꢀtrifluoroethanol (3j).34 Colorless oil (101 mg, 53%). 1H NMR (400
MHz, CDCl3) δ 7.66ꢀ7.56 (m, 1H), 7.34ꢀ7.19 (m, 3H), 5.31 (dq, J = 6.6, 4.3 Hz, 1H), 2.67 (d, J =
4.5 Hz, 1H), 2.39 (s, 3H). 19F NMR (376 MHz, CDCl3) δ ꢀ78.2 (d, J = 6.6 Hz, 3F).
1ꢀ(2,4,6ꢀTrimethoxyphenyl)ꢀ2,2,2ꢀtrifluoroethanol (3k). White solid (186 mg, 70%). 1H NMR
(400 MHz, CDCl3) δ 6.17 (d, J = 11.6 Hz, 2H), 5.44 (dq, J = 11.8, 7.8 Hz, 1H), 4.86 (d, J = 11.8
Hz, 1H), 3.83 (s, 6H), 3.80 (s, 3H). 19F NMR (376 MHz, CDCl3) δ ꢀ78.6 (d, J =7.8 Hz, 3F). 13C
NMR (125 MHz, CDCl3) δ 162.1, 159.8, 125.3 (q, J =284.4 Hz), 103.0, 91.4, 67.1 (q, J =33.4 Hz),
56.1, 55.5. HRMS (EIꢀTOF): exact mass calcd for C11H13O4F3 [M+]: 266.0760, Found : 266.0770.
2,2,2ꢀTrifluoroꢀ1ꢀ(naphthalenꢀ2ꢀyl)ethanol (3m).20 White solid (129 mg, 57%). 1H NMR (400
MHz, CDCl3) δ 7.84 (d, J = 0.5 Hz, 1H), 7.81ꢀ7.73(m, 3H), 7.49ꢀ7.40 (m, 3H), 5.06 (dq, J = 6.7,
4.2 Hz, 1H), 2.76 (d, J = 4.2 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ ꢀ78.6 (d, J =6.7 Hz, 3F).
2,2,2ꢀTrifluoroꢀ1,1ꢀdiphenylethanol (3p).20 Colorless oil (227 mg, 90%). 1H NMR (400 MHz,
CDCl3) δ. 7.58ꢀ7.53 (m, 4H), 7.43ꢀ7.37 (m, 6H), 3.06 (br, 1H). 19F NMR (376 MHz, CDCl3) δ
ꢀ74.3 (s, 3F).
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2,2,2ꢀTrifluoroꢀ1,1ꢀbis(4ꢀmethoxyphenyl)ethanol (3q).24 Colorless oil (250 mg, 80%). H
NMR (400 MHz, CDCl3) δ. 7.41 (d, J = 8.6 Hz, 4H), 6.89ꢀ6.85 (m, 4H), 3.80 (s, 6H), 3.03 (br,
1H). 19F NMR (376 MHz, CDCl3) δ ꢀ75.1 (s, 3F).
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2,2,2ꢀtrifluoroꢀ1ꢀ(4ꢀnitrophenyl)ꢀ1ꢀphenylethanol (3r).20 Colorless oil (134 mg, 45%). H
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NMR (400 MHz, CDCl3) δ. 8.17 (t, J = 11.5 Hz, 2H), 7.68 (dd, J = 17.5, 8.5 Hz, 2H), 7.54ꢀ7.51
(m, 2H), 7.4527.35 (m, 3H), 3.26 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ꢀ74.7 (s, 3F).
1ꢀAdamantanꢀ1ꢀylꢀ2,2,2ꢀtrifluoroꢀ1ꢀphenylethanol (3s). White solid (298 mg, 96%). 1H NMR
(400 MHz, CDCl3) δ. 7.74ꢀ7.30 (m, 5H), 2.52 (s, 1H), 2.02 (s, 3H), 1.76 (dd, J = 49.5, 12.2 Hz,
6H), 1.61 (dd, J = 38.1, 12.2 Hz, 6H). 19F NMR (376 MHz, CDCl3) δ ꢀ66.8 (s, 3F). 13C NMR (100
MHz, CDCl3) δ 136.2, 128.1, 127.1 (q, J = 290.1 Hz), 127.9 (br), 127.3 (br), 127.2 (br), 82.4 (q, J
= 25.4 Hz), 39.8, 36.71, 36.68, 28.5. HRMS (EIꢀTOF): exact mass calcd for C18H19F3 [MꢀH2O]+:
292.1433, Found : 292.1439.
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2ꢀ(Trifluoromethyl)adamantanꢀ2ꢀol (3t).20 White solid (209 mg, 95%). H NMR (400 MHz,
CDCl3) δ. 2.29ꢀ2.21 (m, 2H), 2.14ꢀ2.04 (m, 4H), 1.90 (s, 1H), 1.89ꢀ1.80 (m, 2H), 1.80ꢀ1.70 (m,
4H), 1.64ꢀ1.54 (m, 2H). 19F NMR (376 MHz, CDCl3) δ ꢀ75.7 (s, 3F).
Theoretical Calculations. Theoretical calculations were performed at the
B3LYP/6ꢀ31+G(d,p) level in DMF using Gaussian 09 package.29,30 Solvent effects were included
implicitly through the selfꢀconsistent reaction field approach, as implemented in the default
Polarizable Continuum Model (PCM) in Gaussian 09.27,28 Thermal and entropic corrections for
PCMꢀoptimized structures were obtained by frequency analysis at the B3LYP/6ꢀ31+G(d,p) level.
The frequency analyses confirmed that all considered ground state structures were true minima on
the PES. All transition states were also identified and validated using vibrational frequency
analysis.
Associated Content
Supporting Information
19F and 1H NMR spectra for all compounds. 13C NMR spectra and HRMS for new compounds: 3k
and 3s. Details of theoretical calculations are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Author Information
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Corresponding Author
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(G. K. Surya Prakash) Tel: +1ꢀ213ꢀ740ꢀ5984. Eꢀmail: gprakash@usc.edu.
The authors declare no competing financial interest.
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Acknowledgment
Support of our work by the Loker Hydrocarbon Research Institute is gratefully acknowledged.
We appreciate grants from the NSF (DBIꢀ0821671, CHEꢀ0840366) and NIH (S10 RR25432) to
support NMR spectrometers. The computational studies were supported by the University of
Southern California Center for HighꢀPerformance Computing and Communications. Mr. J.ꢀP.
Jones is gratefully acknowledged for providing additional computational resources.
References
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