Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR

Article abstract of DOI:10.1021/jacs.8b06777

The mechanism of CF₃ transfer from R₃SiCF₃ (R = Me, Et, iPr) to ketones and aldehydes, initiated by M⁺X^- (<0.004 to 10 mol %), has been investigated by analysis of kinetics (variable-ratio stopped-flo

Full text of DOI:10.1021/jacs.8b06777

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Article
Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution
of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR
Craig Johnston, Thomas West, Ruth Dooley, Marc Reid, Ariana B.
Jones, Edward King, Andrew G. Leach, and Guy C. Lloyd-Jones
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 Aug 2018
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Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of
the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR
†
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ò
ò
Craig P. Johnston, Thomas H. West, Ruth E. Dooley, Marc Reid, Ariana B. Jones, Edward
J. King,¥ Andrew G. Leach,‡ and Guy C. Lloyd-Jones*,
†
† EaStChem, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK
‡
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK
¥ TgK Scientific Limited, 7 Long’s Yard, St Margaret’s Street, Bradford-on-Avon, BA15 1DH, UK
+
–
ABSTRACT: The mechanism of CF
3
transfer from R
3
SiCF
3
(R = Me, Et, iPr) to ketones and aldehydes, initiated by M X
13
2
(<0.004 to 10 mol%) has been investigated by analysis of kinetics (variable-ratio stopped-flow NMR and IR), C/ H KIEs,
LFER, addition of ligands (18-c-6, crypt-222), and density functional theory (DFT) calculations. The kinetics, reaction
+
–
orders, and selectivity vary substantially with reagent (R
3
SiCF
3
) and initiator (M X ). Traces of exogenous inhibitors pre-
sent in the R SiCF reagents, which vary substantially in proportion and identity between batches and suppliers, also
3
3
affect the kinetics. Some reactions are complete in milliseconds, others take hours, others stall before completion. Despite
–
these differences, a general mechanism has been elucidated in which the product alkoxide and CF
3
anion act as chain
carriers in an anionic chain reaction. Silyl enol ether generation competes with 1,2-addition and involves protonation of
–
CF
3
by the a-C–H of the ketone, and the OH of the enol. The overarching mechanism for trifluoromethylation by 1, in
–
which pentacoordinate siliconate intermediates are unable to directly transfer CF
why the turnover rate (per M X initiator) depends on the initial concentration (but not identity) of X , the identity (but
not concentration) of M , the identity of the R
SiCF reagent effects the most rapid trifluoromethylation, for a specific M X initiator.
3
as a nucleophile or base, rationalizes
+
–
–
+
3
SiCF
3
reagent, and the carbonyl / R
3
SiCF ratio. It also rationalizes which
3
+
–
R
3
3
16
INTRODUCTION
salts as initiators. Indeed, over the last decade there has
17
been an explosion of interest in CF3 transfer from TMSCF3
(1a) to carbon (e.g. carbonyls,
aromatics ) and to heteroatoms such as sulfur-, selenium-
The inclusion of fluorine-substituents in organic molecules is
of pivotal importance to developments in, inter alia, pharma-
14-17
18
19
imines, vinylhalides and
20
21
1
2
3
4
ceuticals, agrochemicals, electronics, materials chemistry,
22
23
24
25
26
,
phosphorus-, boron-, iodine-, and bismuth. The for-
5
6
7
polymers, synthesis, and catalysis. The transfer of a for-
mally-nucleophilic CF3-moiety to an electrophile is a preemi-
nent method for the synthesis of trifluoromethylated com-
mal loss of fluoride from CF3 to facilitate electrophilic
27
28
TMSCF2-transfer, or carbenoid CF2-transfer, has also been
developed, as have numerous metal-mediated and catalyzed
8
pounds. Conditions range from base-mediated reactions
29
processes involving CF3 derived from TMSCF3 (1a).
9
with fluoroform (CF3H), through to finely-tuned borazine-
based CF3-carriers recently reported by Szymczak. In 1989,
Ruppert reported that TMSCF3 (1a) undergoes addition to
aldehydes and ketones in the presence of 10 mol% KF.
10
Despite anion-initiated trifluoromethylation by 1a having
become a mainstream synthetic method,
tle detail has emerged on the mechanism of CF3 transfer, un-
der the conditions of application, Scheme 1. Various mech-
anistic dichotomies, including, inter alia, fluoride-initiation
versus fluoride catalysis, and siliconate versus carbanion
pathways, have been noted by Denmark, and by Reich;
11
17-26
surprisingly lit-
12
A
30
faster process, using a soluble initiator (Bu4NF.xH2O; 0.6
mol%, 'TBAF') was reported soon after, by Prakash and
13
23a
Olah. Acidic work-up affords the corresponding trifluoro-
30a
30b
methylated alcohols in good yield, Scheme 1.
12,13a
both of whom emphasize the lack of salient kinetic data.
Scheme 1. Trifluoromethylation of ketones / aldehydes.
O
TMSCF3 (1a)
OTMS
Herein we report the first detailed study of the mechanism
OH
HCl, MeOH
R
CF3
R
CF3
of anion-initiated CF3 transfer from TMSCF3 (1a) to ketone
R
R
R
R
THF, 0 ºC to RT
0.6 mol% TBAF
THF, RT
12,17
and aldehyde electrophiles.
The in situ NMR/IR investiga-
R = Ar, alkyl, vinyl, alkynyl, H
tions include analysis of reaction kinetics, selectivity, and
side reactions, and the contrasting behaviour of homologues
TES- (1b) and TIPS- (1c). Throughout the investigation, the
kinetic studies have both informed, and been directed by,
14
This mild and selective process swiftly became adopted for
the preparation of trifluoromethyl-carbinols, including en-
15
antioselective additions involving enantiopure ammonium
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density functional theory (DFT) analysis of proposed inter-
mediates. What emerges is a nuanced kinetic landscape in
which trifluoromethyl transfer proceeds via a carbanion
dependent on the stoichiometry (M F / 1a), and the structure
of D was confirmed by single crystal X-ray diffraction. Addi-
tion of cyclohexanone at –60 °C, followed by hydrolysis, af-
forded the corresponding trifluoromethylated alcohol,
1
2
3
4
5
6
7
8
–
pathway (CF3 ), with the rate dictated by the identity of the
32,35
electrophile, the concentration of the initiating anion, the
identity of the initiator counter-cation, the electrophile /
R3SiCF3 (1) concentration ratio, and the identity of the rea-
gent (1a-c).
mechanism III.
36
37
In 2014, Prakash showed that the elusive trifluoromethyl
38
13
19
anion(oid) can be detected in situ ( C, F NMR) at low tem-
peratures after addition of KOtBu / 18-crown-6 to 1a. With
the much bulkier reagent TIPSCF3 (1c), the generation of ion-
Scheme 2. Mechanisms (I–IV) for anion-induced trifluoro-
9
11
+
–
methylation of ketones using Ruppert's reagent (1a) and
paired [K(18-c-6)] [CF3] (E) proceeds quantitatively at −78 °C
over a period of 30 mins. Subsequent addition of PhCOMe
(11 equiv.) or PhCHO (4 equiv.) afforded CF3-addition prod-
ucts (22-68%) after quenching with H2O, mechanism IV. In
2015, Grushin demonstrated that use of crypt-222 (L,
Scheme 2) facilitates generation of the free CF3 carbanion; a
THF solution-phase "noncovalently-bound ionic species".
The structure of the highly air- and temperature-sensitive
salt, [K(crypt-222)] [CF3] (E), was confirmed by single crys-
10
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homologues. L = 18-c-6, crypt-222. See text for full discussion.
Mechanism I
O
36
R
R
38
CF3
Si
(1a)
Me
–
Me
Me
38
O– +NBu4
R
+
–
R
CF3
(A)
38,39
tal X-ray diffraction.
O– +NBu4
OTMS
Mechanism II
(A)
The pioneering studies summarized above have been highly
enlightening regarding the structure and stability of penta-
coordinate (trifluoromethyl)siliconates (C, D),
ability to release the trifluoromethane anion(oid) (E) under
However, they do not yield direct de-
tail on the kinetics and mode of transfer of CF3 from TMSCF3
(1a) to a carbonyl electrophile, using a catalytic fluoride-
based initiator (M X ), at ambient temperature.
R
CF3
R
CF3
R
R
TMSCF3
32,33
(1a)
and their
O
R
+NBu4
CF3
36,38
Me
specific conditions.
Me Si–
R
Me
R
(B)
O
R
CF3
+
–
12,13
M+
Me
Mechanism III
CF3
Me Si–
(C)
2. Preliminary Investigations. We began by study of the
reaction of TMSCF3 (1a) with aldehydes and ketones in THF,
chlorobenzene, and DMF. After addition of catalytic quanti-
O
Me
CF3
Si
M+F–
OH
R
F
R
M+
Me
Me
Me
Me
Me
R
CF3
CF3
Me Si–
19
R
ties (0.1 to 1 mol%) of TBAF, F NMR readily facilitated anal-
then H2O
n (1a)
ysis of the proportions of residual reagent (1a) and the [1,2]-
addition products. The reaction of 4-fluoroacetophenone (2)
in THF at ambient temperatures proved ideal, the additional
F nucleus allowing simultaneous analysis of reagent (1a;
0.48 M), substrate (2; 0.40 M), and product (3OTMS), Scheme 3.
CF3
(D)
O– +K(L)
Mechanism IV
O
19
Me
Me
Me
CF3
Si
OH
R
R
–CF3 +K(L)
iPr
iPr
R
R
iPr
Scheme 3. Trifluoromethylation of ketone 2 (Ar = 4-F-C6H4).
then H2O
CF3
(E)
(1c)
OTIPS
TMSCF3
O
TMSO CF3
+ Ar
OTMS
OTMS
(1a)
Me
Me
F
+
Ar
Ar
Me
CF3H
Me
CF3
+
Me
Ar
Ar
4OTMS
cat. TBAF
THF
3OTMS
(∼92%)
2
5OTMS
(∼1%)
RESULTS AND DISCUSSION
(∼8-20%)
(∼ 7%)
1. Prior Studies. In early studies, a termolecular anionic
O
OTMS
chain-reaction (mechanism I, Scheme 2), was suggested for
OTMS
TMSO CF3
Ar
“CF2”
Ar
X–
1a, MX
F
F
13a
trifluoromethylation by 1a. This was later expanded to a
Ar
THF
F
F
two-step process (mechanism II), where a pentacoordinate
5OTMS
11
4OTMS
10
alkoxy-siliconate (B) delivers CF3 to the ketone, and in doing
14
so liberates the O-silylated product. Mechanism II has been
Reactions were assembled manually in 5 mm NMR tubes in
the glove box prior to analysis in situ by F NMR. Three side-
products were identified: fluoroform (CF3H), the silylenol
ether (4OTMS) and a homologated addition product 5OTMS. Re-
actions conducted in d8-THF proceeded analogously, and
generated CF3H, not CF3D. The identity of 5OTMS, which was
confirmed by independent synthesis, is consistent with
difluorocyclopropanation of silylenol ether 4OTMS to generate
10, followed by a known anion-induced ring-opening elim-
extensively adopted in the design and interpretation of
19
16,29,31
asymmetric trifluoromethylation.
32
33
In 1999, Naumann, and Kolomeitsev and Röschenthaler
independently reported on the reaction of a range of soluble
+
–
40
fluoride sources (e.g. [Me4N] F ) with TMSCF3 (1a) at low
temperature. Detailed H, C, F and Si NMR analysis
identified the products as pentacoordinate complexes
[Me3Si(F)(CF3)] M (C) and [Me3Si(CF3)2] M (D). Both com-
plexes decompose above –20 °C.
1
13
19
29
–
+
–
+
41
32,34
12
The speciation (C / D) is
ination to give fluoroenone 11, and subsequent 1,2-selective
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However, the reactions were inhibited by addition of the per-
trifluoromethylation. Addition of independently synthe-
sized 10 to the reaction (Scheme 3) generated 5OTMS.
1
2
3
4
5
6
7
8
42
sistent radical, TEMPO. Indeed, just 0.45 mM TEMPO in-
duced complete inhibition of the reaction of 1a with 2, initi-
ated by 0.15 mM TBAT (Scheme 4, A). In contrast, TEMPO
had negligible impact on reactions employing TES (1b) and
TIPS (1c), even when present at much higher concentrations
(80 mM TEMPO); the origins of this profound difference in
Reaction rates, and extent of fluoroform generation (Scheme
3), were found to vary significantly between batches of TBAF
(1 M, THF, ~5 wt% H2O). Replacing TBAF with anhydrous
[Bu4N][Ph3SiF2] ('TBAT') gave more reproducible data.
However, the fast turnover precluded detailed kinetic analy-
sis; this aspect was addressed using stopped-flow methods,
vide infra. Nonetheless, F NMR analysis revealed that CF3H
is liberated in two distinct phases. The first is an initial burst
of extremely rapid CF3H generation, and arises from TBAT-
catalyzed reaction of TMSCF3 (1a) with traces of adventitious
43
behavior is discussed later. Nonetheless, further tests for dis-
46,47
crete radical intermediates
were conclusively negative: 4-
19
9
F-benzophenone (12) exclusively underwent 1,2-addition
10
11
12
13
14
15
16
17
18
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48,49
(Scheme 4, B),
cyclopropyl ketones (6/7) reacted without
50
any trace of competing ring-opening (Scheme 4, C), and
competition between ketone 2 and 4-biphenyl methylketone
44
water. The second phase of CF3H generation proceeds in
concert with reaction of the ketone (2) and directly correlates
51
for limiting TMSCF3 (1a) favored 2 (krel = 1.93).
with the rate of generation of silylenol ether (4OTMS), as con-
firmed by H-labelling (d3-2 ® CF3D + d2-4OTMS). The selectiv-
ity (3OTMS versus 4OTMS) is discussed later.
4. General Effects of Initiator on Rate and Selectivity. A
2
+
–
range of initiators (M X ) were tested and found to strongly
impact the reaction outcome. In the majority of cases, the re-
–
actions initiated 'instantly' and the identity of X had no in-
3. Stability, Inhibition, and Tests for Radicals. The sta-
bility of the reaction system after complete consumption of
the limiting reagent (ketone 2 or TMSCF3 1a) was found to
depend on which one was in excess. Reactions in which 2
was in excess, underwent turn-over on addition of further
TMSCF3 1a, even after a period of many hours. In contrast,
for reactions where 1a was in excess, additional 2 had to be
added within a few minutes to fully reinstate turnover (see
SI); consistent with the known instability of pentacoordinate
52
fluence on the rate or selectivity (3OTMS / 4OTMS). Specific ef-
fects were found to be dictated by the identity of the counter-
+
cation (M ), Table 1.
+
Table 1. Examples of effect of initiator M and reagent (1a-c)
on selectivity (3OSi /4OSi) and rate of trifluoromethylation of 2.
OSi
O
OSi
R3SiCF3
(1a-c)
Me
CF3
Me
+
F
cat. MX
F
F
THF, 300 K
(trifluoromethyl)siliconates, e.g C and D, at ambient temper-
[3OSi
]
[4OSi]
+ CF3H
2
32-34
atures.
Further tests established that the reactions were
+
+
–
M
[M X ]
0
TMS 1a
TES 1b
TIPS 1c
not sensitive to exogenous water per se, as they rapidly self-
a
a
a
m
M
3
/
4
3
/
4
3/4
dehydrated via generation of CF3H + hexamethyldisiloxane,
b
b
b
45
(time)
12 / 1
(time)
(time)
1 / 1
prior to reaction of the ketone (2). The rates were unaffected
by visible light, by exogenous product (3OTMS), and by CF3H.
Deliberate sparging of the normal reaction mixture (1a / 2 /
TBAT 0.15 mM, 0.038 mol%, THF, Scheme 3) with air caused
complete inhibition of turnover, but only when a sufficient
volume of CO2 (~400 ppm) had been added to convert the
active anion(s) into trifluoroacetate (i.e. [Bu4N][CF3CO2], de-
1.5 / 1
(<90 s)
+
[Bu
4
N]
1.5
0.15
1.5
(<90 s)
(30 min.)
c
36 / 1
3.0 / 1
NR
+
[K]
(<90 s) (30 min.)
19
tected by F NMR). Separate controls confirmed that the rate
6.6 / 1
2.4 / 1
(<90 s)
1 / 1
+ d
[K(L)]
of trifluoromethylation is unaffected by CO2-scrubbed air,
and that [Bu4N][CF3CO2] is not effective as an initiator.
(6 min.)
(3.6 min.)
a
19
Selectivity
3
OSi/(
4
OSi+CF
3
H) measured in situ by F NMR
Scheme 4. Tests for radical intermediates.
after manual assembly in an NMR tube; selectivity is in-
A)a,b,c
R3SiCF3
(1a-1c)
–
b
dependent of X . times indicated are for >97% conver-
O
OSiR3
c
d
+
• R = Me (1a): 0%
sion of
2
, at 300 K. 85% conversion. [K(L)] = K(crypt-
cat. Bu4N+X–
TEMPO
(3 x cat.)
Ar
Me
Ph
Me
CF3
Ar
+,
• R = Et, iPr (1b,c): 100%
222)] generated in situ from KOPh + crypt-222.
2
3OSi
(+ 4OSi
)
B)a,b
Ar
+
+
+
O
Reactions where M = K , Cs proceeded rapidly to comple-
OTMS
• Exclusive product:
No 1,4- or 1,6-addition
1a
tion, with higher selectivity for 3OTMS / 4OTMS compared to
Ph
CF3
Ar
+
+
+ 53
Bu4N . Reactions stalled when the cation was Li or Na . For
12
+
the K -mediated system, the rate was strongly attenuated by
C)a,d
Ar
O
OTMS
CF3
R
R
1a
addition of 18-crown-6, or crypt-222, with the latter causing
• No cyclopropyl
ring opening
R
Ar
R
cat. Bu4N+X–
turnover to become slower and less selective (3OTMS / 4OTMS)
6, R = H
7, R = Ph
+
than reactions initiated by TBAT (counter-cation Bu4N ). The
+
identity of M was also found to affect the degree of charge-
a
(Ar = 4-F-C6H4); ketone (2, 6, 7, 12, 0.40 M), 1a-c (0.48 M), THF,
development (r ranging from 1.8 to 3.0) in the ketone (R =
Me, Scheme 5) at the product-determining transition state for
CF3 transfer. Benzaldehydes (R = H) behaved analogously.
b
c
21 °C. TBAT (0.04 mol%, 0.15 mM), TEMPO (0.12 mol%, 0.45
mM; up to 80 mM with 1b,c). TBAF (4 mM, 1 mol%).
d
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Scheme 5. Effect of initiator M on reaction constant (r).
enough to be accurately monitored in situ by F NMR, the
ratios of enol / addition product (4OSi / 3OSi) were all constant
throughout the reaction evolution, Figure 2. A further dis-
tinction originated from the impact of the addition of crypt-
222 to KOPh-initiated reactions. As noted above, for TMSCF3
1
2
3
4
5
6
7
8
O
OSiMe3
M+
ρ(Me)
ρ(H)
R
CF3
R
Na
K
Cs
K(18-c-6)
NBu4
1.76
1.79
2.00
2.00
2.62
--
1.27
--
2.01
2.35
2.55
1a
cat. MX
Z
F
Z
F
+
+
O
OSiMe3
THF, RT
+
(1a) the incarceration of the K in the crypt-222 ligand sub-
stantially attenuates the rate and selectivity. In stark contrast,
for TIPSCF3 (1c), turnover is substantially accelerated by addi-
R
CF3
R
K(crypt-222) 2.98
ρ = σlog10(kZ/kF) [19F NMR]
2 (R = Me)
13 (R = H)
+
tion of crypt-222 to inhibit K / anion pairing.
9
a
OSi
OSi
i) 4-Z-C6H4COR (0.2 M), 2/13 (0.2 M), 1a (0.04 M), PhF (0.4 M), MX
(0.00015 M; 0.038 mol%). Z = Ph, OMe, CF3, Me, Br. Hammett rho
values calculated from product ratios, see SI.
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
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44
45
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48
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50
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56
57
58
59
60
Me
CF3
R3SiCF3 (1a-c)
+
F
Me
F
cat. MX
F
2
[3OSi
]
[4OSi
]
5. Effect of Silyl Reagent on Rate and Selectivity. To fur-
ther probe the CF3 transfer process, we compared TMSCF3
(1a) with TESCF3 (1b) and TIPSCF3 (1c), Table 1. The effects
of changing the reagent were counter-intuitive and initially
misleading regarding the mechanism of CF3 transfer, vide in-
fra. Reactions employing TESCF3 (1b) gave lower selectivity
(3OTES / 4OTES » 1.5 / 1) and proceeded very rapidly, even at
low TBAT concentrations (150 µM, 0.0375 mol%; below this,
reactions failed to initiate). In contrast, reactions employing
TIPSCF3 (1c) proceeded very slowly, requiring high initiator
concentrations to proceed efficiently (> 1.5 mM, 0.375 mol%)
and gave even lower selectivity (3OTIPS / 4OTIPS » 1 / 1).
THF, 300 K
0.25
0.20
0.15
0.10
0.05
0.00
d[4OTIPS t
]
(1c)
= 1.04
d[3OTIPS t
]
d[4OTES t
]
= 0.33
d[3OTES t
]
(1b)
d[4OTMS t
]
= 0.09
(1a)
d[3OTMS t
]
0.00
0.10
0.20
[3OSi] (
0.30
0.40
M
)
Figure 2. Constant-ratio of [4OSi]t / [3OSi]t. Conditions: 2 (0.4
M), 1a-c (0.48 M), PhF (internal standard, 0.4 M), MX (TBAT
150 µM for 1a; KOPh 0.15 mM for 1b, TBAT 1.5 mM for 1c).
TMSCF3 (1a)
TESCF3 (1b)
O
OTMS
OTES
(1:1)
Me
CF3
Me
CF3
Me
+
TBAT
0.02 mol%
THF, 300 K
F
2
F
F
13
Reactions with labelled ketone (aryl-d4-2; CD3-2; CO-2)
3OTES (+ 4OTES
)
3
OTMS (+ 4OTMS)
0.45
were also instructive, Table 2. Reaction of TMSCF3 (1a) with
13
2 initiated by TBAT (0.15 mM) proceeds with a very low
C
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
2
kinetic isotope effect (KIE), determined by competition with
aryl-d4-2, after normalizing for the effect of aryl deuteration.
2
a,b
Table 2. KIEs and H-exchange in the reaction of ketone 2
1b
1a
OSi
OSi
O
3OTMS
1a-c
CL3
CL2
CL3
CF3
Dn-3OSi
cat. TBAT
F
F
+ CF3H
CF3D
F
3OTES
THF, 300 K
Dn-4OSi
L3-2
CL3 (reagent)
CH3
13C=O)
1a-c
kH / kD
2, 3OSi
(k12C/k13C = 1.008)c
400
0
100
200
300
TMSCF3 (1a)
TMSCF3 (1a)
TMSCF3 (1a)
CH3
CH3
CD3
–
(
time (s)
1.038d
CH3 (C6D4)
CD3
Figure 1. Competition between TMSCF3 (1a) / TESCF3 (1b);
see text for full discussion. Reaction conditions: 2 (0.4 M), 1a
(0.24 M), 1b (0.24 M), PhF (internal standard, 0.4 M), TBAT (75
(3/4OTMS = 72 / 1)
6.4
CD3 + CH3
TMSCF3 (1a) CD3 / CH3 only
6.1
(rate: CF3H/CF3D)
TESCF3 (1b)
CD3
(3/4OTES = 4.3 / 1)
(3/4OTES = 2.3 / 1)
(3/4OTIPS: 1.1 / 1)
(rate: CF3H/CF3D)
3.1
–
CD3
19
µM, 0.019 mol%); F NMR analysis, manual assembly.
CD3 + CH3
TESCF3 (1b) partial CD3-n/Hn
Further insight was afforded by reaction of a 50/50 mixture
of TMSCF3 (1a) and TESCF3 (1b), initiated by TBAT (75 µM,
0.019 mol%), Figure 1. The first 4 minutes of reaction is dom-
inated by turnover of TMSCF3 (1a) to generate 3OTMS/4OTMS
and upon near-complete consumption of 1a, turnover accel-
erates substantially as the TESCF3 (1b) is engaged to generate
3OTES/4OTES.The data indicate that the less-hindered reagent
(1a) monopolizes the anion, but undergoes slower turnover.
TIPSCF3 (1c)
TIPSCF3 (1c)
CD3
1.1
1.0
CD3
CD3 + CH3
full CD3-n/Hn
a
2
Ketone (2 / H3-2; 0.40 M), 1a-c (0.48 M), THF, 300 K. TBAT
b
(0.04 mol%, 0.15 mM), Selectivity 3OSi/(4OSi + CF3H/D) and ex-
change measured in situ by F NMR analysis. KIE deter-
mined by competition with aryl-d4-2. HKIE induced by
aryl-deuteration, determined by competition with unla-
belled 2.
19
c
d
2
Under conditions where anion-induced reactions of TMS
(1a), TES (1b) and TIPS (1c) with 2 could be conducted slowly
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Journal of the American Chemical Society
2
In contrast, a substantial primary H KIE, determined from
[CF3D] versus [d3-3OSi], as in Figure 2, increases the addition
/ enol selectivity (kH/kD = 6.4). Reactions of mixtures of 2 and
d3-2 proceeded with no detectable scrambling of D/H be-
tween 2 / D3-2 during turnover, provided that [1a]0 > [2]0, and
again proceeded with a high KIE (kH/kD = 6.1). With TESCF3
(1b) a moderate KIE (kH/kD = 3.1) was observed, with a trace
of D/H exchange between 2 and D3-2 on co-reaction, and thus
into products dn-3/dn-4. With TIPSCF3 (1a) there was no sig-
nificant KIE and a statistical mixture of isotopologues of dn-
2/3 (n = 0–3) was evident immediately after initiation of the
conditions, using just four stock solutions: mixing {i + iii + iv}
varies [2]0; mixing {ii + iii + iv} varies [1]0; and mixing {iii + iv
+ THF} varies [M X ]0, whilst keeping the other species con-
1
2
3
4
5
6
7
8
+
–
stant; see SI for full details. The new system was imple-
56
mented in two modes: IR and NMR. The former simply re-
quired adaptation of our recently developed thermostatted
57
ATR-FTIR stopped-flow cell, replacing the dual mixing
stage with a triple mixer and a gated reaction volume. The
56a
analogous set-up for variable ratio stopped-flow NMR re-
9
quired bespoke construction. The principles for continuous-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
58
flow NMR recently reported by Foley et al. were employed
54
for the basic design, such that the reaction vessel and associ-
ated components can be installed simply by insertion of the
device into the sample transit of a standard unmodified
NMR spectrometer. Nuclei pre-magnetization is facilitated
in three independent reservoirs (A, B, C) located as close as
possible to the magnetic field center, Figure 3c. The reser-
voirs connect at a tripodal-geometry mixer that discharges
via a 0.5 mm i.d. glass capillary into a 3 mm external diame-
ter 300 µL glass NMR flow-cell. The tube terminates at the
base of the cell, with the waste outlet at the top. A fourth in-
put to the mixer allows the system to be flushed with solvent
between runs. Thermostatting is achieved by passage of a
heat-transfer medium (aq. ethylene glycol), using an exter-
nally controlled recirculator, through an umbilical contain-
ing all stages of the stopped-flow circuit, except for the glass
flow-cell which is located within the spectrometer-thermo-
statted probe head; precalibration ensures temp1 = temp2.
During a typical stopped-flow 'shot', a total of 600 µL is de-
reaction.
6. Variable-Ratio Stopped-Flow NMR and IR. Detailed
exploration of the kinetics of the trifluoromethylation by 1a
required techniques for rapid acquisition of kinetic data
(some systems had formal turnover frequencies well in ex-
-1
cess of 5,000 s , vide infra) in a time- and material-efficient
manner. Stopped-flow techniques are ideal for rapid and re-
producible initiation and analysis of these reactions. How-
ever, the classic fixed-ratio dual input mode of operation (A
+ B; Figure 3a) requires separate solutions to be prepared for
every variation in conditions. For a three-component process
such as R3SiCF3 (1) + ketone 2 + initiator (M X ), a very large
number of stock solutions are required to study reactions
with different concentrations of reactants and initiator.
a)
+
–
drive (× 1)
mixing
A
stop +
trigger
B
VA
-1
livered through the flow-cell at a rate of 1–2 mL s , fully dis-
analysis
∝
VB
control unit
placing the previous contents and replacing it with 300 µL of
freshly-assembled reaction mixture; charging requires 70-
130 msec (measured independently by UV-Vis), with high
quality NMR spectra (N2-cryoprobe) achievable immediately
thereafter. Control of the timing of the NMR pulse sequence
is achieved by a trigger-signal, sent to the spectrometer con-
sole from the computer-controlled triple stepper-motor sys-
tem, immediately after the 300 µL flow-cell has been freshly
charged.
stock
solutions:
i) 1 + 2
ii) M+X–
(× n)
(× n)
trigger
waste
temp1
T/°C
(3n –2) stock solutions:
n independent variations
of [1]0, [2]0, [M+X–]0
solvent
drives
(× 3)
c)
b)
drives (× 3)
A B
5 ×T1
C
mixing
A
B
C
>90% B0
100% B0
7. Kinetics of Trifluoromethylation by TMSCF
3
(1a) and
NMR, IR
+
–
TIPSCF
3
(1c) The kinetics of reactions initiated by M X ,
stock
solutions:
i) 1
ii) 2
iii) 1 + 2
iv) M+X–
(× 1)
(× 1)
+
+
+
+
where M = Bu4N , K , and Cs , were studied in detail by SF-
(× 1)
(× 1)
IR and SF-NMR across a wide range of concentrations of 1a,
temp2
300 µL
3 mm o.d.
+
–
2 and [M X ]0. For FTIR, the decay in the IR C-F stretching
4 stock solutions:
-1
mode (1056 cm ) of the TMSCF3 (1a) and the growth in C–F
n independent variations
of [1]0, [2]0, [M+X–]0
spectrometer
console
-1
stretching mode (1165 cm ) of 3OTMS were collected at scan-
-1
-1
rates of 14 or 28 s with a resolution of 2 or 8 cm , respec-
Figure 3. Schematic representations of: (a) classic fixed-ratio
dual input stopped-flow; (b) a variable-ratio triple-input de-
sign; (c) variable-ratio stopped-flow NMR with thermostatic
pre-magnetization of reactants (A,B,C), for >5 ´ T1 at >90%
(B0).
19
tively. F NMR analysis allowed detailed analysis of the re-
action components, but was naturally more-limited in terms
of temporal resolution. For faster reactions, a technique in-
volving the interleaving of a series of spectra from a sequence
of stopped-flow NMR 'shots' was employed, affording a
higher virtual temporal resolution.
To address this issue, we constructed a stopped-flow system,
in which the delivered volumes of three solutions (A, B, C) are
independently variable, using a computer-controlled triple
stepper-motor system, Figure 3b. This set-up allowed sys-
tematic analysis of the kinetics across a wide range of initial
A key component in analysis of the kinetics was the depend-
ence of the temporal-concentration evolution of the product
(3OTMS) on the concentration ratio of ketone 2 and TMSCF3
(1a). Systematic studies of initial rates using TBAT led to an
55
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Journal of the American Chemical Society
Page 6 of 16
empirical rate equation for turnover frequency (TOF) in rate of trifluoromethylation is independent of [TBAT]0 (96–
1
2
3
4
5
6
7
8
+
–
which the initiator (Bu4N X ) and ketone 2 are first order, and
the TMSCF3 (1a) reagent approximately inverse first order
(equation 1). Control experiments in which the reactions
384 µM) and 1a (0.08 to 0.48 M). Overall, the data is indicative
that aldehyde 13 follows the same general kinetics as ketone
59
59,60
2, i.e. equation 1.
The rate of trifluoromethylation of ke-
were run in the presence of exogenous product (3OTMS) con-
firmed that it does not act as an inhibitor.
tone 2 using TIPSCF3 (1c) was much slower than with 1a.
Again, the kinetics were impacted by exogenous inhibitor(s)
in the reagent ([1c]0), the effect of which (xEI) varied from
batch to batch of 1c, see SI. Using TBAT as initiator, the reac-
tions evolve with a first order dependency on the initiator,
and on the reagent ([1c]t), with inhibition by the ketone (Ki2;
equation 2). In other words, the kinetic dependencies are the
opposite to that found for 1a (compare equations 1 and 2)
with reactions accelerating when there is an excess of 1c over
2. Reactions of 2 with 1c initiated by KOPh were slower than
those initiated by TBAT, and were accelerated on addition of
crypt-222; the opposite phenomena to those observed with
1a.
krxn[M+X–]0[2]t (1 – xEI
)
[2]
[1]
kobs
(eqn. 1)
≈
TOF ≈
1 + Ki1[1]t
9
krxn[M+X–]0[1]t (1 – xEI
)
[1]
[2]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
kobs
(eqn. 2)
TOF ≈
≈
1 + Ki2[2]t
The inhibitory effect of the TMSCF3 reagent 1a (Ki1; equation
1) results in very distinctive temporal concentration profiles
for the reaction, simulations of which are presented later. For
example, when the initial ratio of reactants is equal ([2]0 =
[1a]0) their ratio remains constant ([2]t/[1a]t = 1) throughout
the reaction. What arises is an apparent pseudo zero-order
consumption of the reactants (TOF = kobs) for the majority of
the reaction evolution. Conversely, when there is an excess
of ketone 2 over 1a the rate of turnover rises as a function of
conversion, becoming very rapid in the final phases of reac-
tion where [2]t/[1a]t >> 1.
19
8. Stopped-Flow F NMR Analysis of Siliconate and
Alkoxide Intermediates, Exchange Dynamics with
TMSCF , and Initiator Regeneration. By use of 4-F-benzo-
3
phenone (12; δF −107.0 ppm), which reacts slower than 2, and
reducing the reaction temperature to 275 K, the temporal
speciation of the initiator-derived species (10 mol% TBAT)
+
–
+
+
+
+
+
19
Systematic studies using M X (M = Li , Na , K , Cs ) which
induce very rapid turnover, proved more challenging. Reac-
was monitored using stopped-flow F NMR, Figure 4. The
known but unstable hypervalent bis-CF3-siliconate (D; δF
+
+
+
32-34
tions where M = Li , Na , stalled before completion and were
not reproducible. KOPh and CsOPh initiated at very low
concentrations, without an evident induction period, pro-
ceeded to completion, and provided reproducible kinetics.
Study of the initial rates suggested higher-order dependen-
cies on TMSCF3 ([1a]0, again inverse) and on [M X ]0, with the
ketone 2 remaining first-order. However, the reactions evolve
with near-identical behaviour to those initiated by TBAT
−63.3 ppm)
is generated instantly. Integration against
fluorobenzene (internal standard, δF −113.2 ppm) shows D to
be present at 10 mol%, and thus the predominant anion-spe-
ciation. A key feature in the time-series is the dynamic line-
broadening in D that is constant throughout the reaction, but
develops in the substoichiometric TMSCF3 (1a) reagent (δF
−66.6 ppm) as its concentration is depleted by the overall re-
action with ketone 12. In parallel with this is a marked accel-
eration in product generation (14OTMS, δF −72.4 and −113.7
ppm), consistent with equation 1. After 6 seconds, the
TMSCF3 (1a) is fully consumed and TBAT (δF −97.4 ppm) is
regenerated from Ph3SiF / Me3SiF. The dynamic-line broad-
ening in D / 1a can be satisfactorily simulated using a 3-spin
exchange process in which D is in rapid dissociative equilib-
+
–
59
(equation 1). The dichotomy is indicative of the presence of
exogenous inhibitor(s) in low concentration in the TMSCF3
(1a) reagent, that are not consumed during reaction. Increas-
ing the initial concentration of the reagent ([1a]0), or decreas-
+
–
ing the initiator concentration ([M X ]0), both cause a greater
59,60
mol-fraction of exogeneous inhibition (xEI), equation 1.
+
–
-1
‡
-1
Addition of [K] [(C6F5)4B] , to provide an additional soluble
K source with a non-nucleophilic counter-anion, had no im-
rium (kexch ~180 s ; DG ~13 kcal mol ) with 1a and a low
+
62
concentration of (unobserved) [Bu4N][CF3] (E). At 300 K,
pact on the kinetics of reactions initiated by KOPh, indicative
the line-broadening is very extensive and D short-lived.
that the rate is dependent on the initiating anion concentration
Analogous experiments using TIPSCF3 (1c) gave a very dif-
ferent outcome. Reactions conducted with 1c at 275 K were
slow enough to be followed using ketone 2 (δF −106.7 ppm),
61
and the counter-cation identity (but not its concentration).
Addition of potassium-binding ligands attenuated the rates
substantially, and with crypt-222, the system underwent
19
Figure 5. The F NMR signal for 1c remains sharp until 2 has
+
turnover slower than with Bu4N (a 3 orders of magnitude
been fully consumed. In contrast to reactions with 1a (Figure
4) the alkoxide (3O–; δF −118.4) is present in significant con-
centration and exhibits dynamic-line broadening (see inset to
Figure 5). The signal for ketone 2, also exhibits dynamic-line
broadening, immediately after addition of the TBAT. On
complete consumption of 2 (~120 s) the signals for remaining
1c and CF3H are broadened, presumably due to indirect ex-
+
rate-reduction compared to free K ).
The kinetics of trifluoromethylation of 4-fluorobenzaldehyde
(13) by 1a were also explored using TBAT as initiator. The
aldehyde undergoes significantly faster trifluoromethylation
than ketone 2 (kald / kket » 80, at 21 °C) requiring lower initial
TBAT concentrations, and causing the traces of exogeneous
59
–
inhibitor(s) in 1a to complicate the kinetics. Competing ke-
change involving CF3 . After a further 300 s, 1c is fully con-
19
tone 2 with aldehyde 13 (9 / 1 ratio) using stopped-flow
F
sumed and the CF3H doublet becomes sharp again.
NMR to analyze the transient substrate ratio (2/13) during
the first 5-30 seconds of reaction indicated that the relative
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Journal of the American Chemical Society
ex ∼180 s-1
1
2
3
4
5
6
7
[Bu4N]+
Me Si–
[Bu4N][CF3]
CF3
Si
CF3
k
Me
E
+
Me
(δF ≈ –18 ppm)
Me
TMSCF3
Me
CF3
OTMS
O
Me
(1a, 0.19 M)
Ph
Ph
D
CF3
1a
5.7 s
5.0 s
4.8 s
4.0 s
3.0 s
F
TBAT
(10 mol%)
F
14OTMS
12 (0.2 M)
THF, 275 K
1.7 s
0.2 s
8
9
TBAT = [Bu4N][Ph3SiF2]
ppm
–63
–64
–67
–66
14OTMS
10
11
12
13
14
15
16
17
18
19
14OTMS
12
[Ph3SiF2]
*
1a
Ph3SiF
Me3SiF
CF3H
D
8.7 s
7.7 s
6.7 s
5.7 s
4.7 s
3.7 s
2.7 s
1.7 s
0.2 s
*
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Selected spectra from stopped-flow F NMR analysis of the reaction of 4-F-benzophenone 12 (0.20 M) with 1a (0.19 M)
62
in THF at 275 K after initiation by 10 mol% TBAT. Inset: overlay of selected simulations (black) of dynamic line-shape for D /
1a with experimental spectra (red); E (δF −18 ppm) is undetected. (*) C6H5F internal standard.
TIPSCF3
OTIPS
OTIPS
O
O
3/4O–
F
(1c, 0.24 M)
Me
CF3
Me
+
2
H
F
TBAT
(10 mol%)
F
F
F
3/4O–
3OTIPS
4OTIPS
2 (0.2 M)
2
THF, 275 K
1c
3O–
3
× =
O–
3OTIPS
×
3OTIPS
4OTIPS
CF3H
TIPSF
2
*
525 s
223 s
91 s
t = 0
×
×
19
Figure 5. Selected spectra from in situ F NMR analysis (manual assembly) of the reaction of 4-F-acetophenone 2 (0.20 M) with
1c (0.2 M) in THF at 275 K after initiation by 10 mol% TBAT; (t = 0, no TBAT). Inset: line-broadening in ketone 2 and alkoxide
3O–. (*) C6H5F internal standard. (x) = 3O–. Free 4O– not located, possibly due to degenerate exchange with 2. Ph3SiF is not observed.
selectivity (3OSi/4OSi) and KIEs, by biasing one of two extremes
in a single overarching mechanism. Calculations employed
the M06L/6-31+G* level of theory, which was selected from a
range of other functionals and larger basis sets that were con-
sidered, see SI, as it provided the best quantitative agree-
ment with experiment. All calculations were performed in
Gaussian09, with THF solvation incorporated via a PCM
single point at the same level of theory, and with T = 298 K
and pressure at 24.45 atm to achieve a 1 M standard state.
Kinetic isotope effects were computed using the Kinisot pro-
9. General Mechanism for Anion-initiated CF
from R SiCF to Ketones and Aldehydes. The data out-
lined in Sections 2 to 8 above (see SI for full details) indicate
that the M X initiated trifluoromethylation of ketone 2 by
TMSCF3 (1a) involves an electrophile-nucleophile reaction,
3
Transfer
3
3
+
–
63
+
in which the CF3 transfer is accompanied by M . Enolsilane
4OTMS is also generated (≤ 2% when M = K and 7% when M
64
+
+
+
+
Bu4N ) with co-product CF3H (kH/kD = 6.1). Using TIPSCF3
(1c), approximately 50% of the product is 4OTIPS and kH/kD =
1.0. Contrasting kinetic behaviour is observed for 1a (equa-
tion 1) versus 1c (equation 2), with the roles of reactant for
turnover, and inhibitor reversed between the two systems.
These disparate sets of observations can easily be misinter-
preted as turnover for 1a versus 1c arising from different
pathways, e.g. siliconate versus carbanion. However, analy-
sis of the kinetics, KIEs, and DFT calculations of a wide range
of potential intermediates (see SI), eventually leads to the
conclusion that the two reagents elicit contrasting kinetics,
65
66
gram. Some of the TES and TIPS bearing structures re-
quired the 'loose' settings during the geometry optimization,
presumably because of the flat potential energy surface asso-
ciated with the long Si-CF3 bonds.
The calculations permitted several possible structure types
(such as hexacoordinate silicon dianions) to be excluded
from consideration, and also revealed pronounced differ-
ences between intermediates based on TMS, TES, and TIPS,
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Journal of the American Chemical Society
Page 8 of 16
where the increasing steric bulk substantially destabilizes the
pentacoordinate anions, Figure 6. Extensive calculations
were conducted to test for direct nucleophilic reactivity of
the pentacoordinate anions B and D. All calculations re-
vealed that direct transfer of CF3 from the silicon centre to an
electrophile requires concomitant inversion of the CF3, with
as observed experimentally for TMSCF3 (1a). The loose addi-
1
2
3
4
5
6
7
8
13
tion transition state leads to a negligible C KIE (carbonyl)
2
for addition, while a large primary H KIE is computed for
C–H deprotonation. Relative rates computed from activation
free energies suggest r = 2.0 for addition to acetophenones,
and a lower barrier for addition to 4-F-benzaldehyde (13)
-1
‡
a prohibitively large barrier (>100 kcal mol ; in line with the
versus 2 (DDG 2.6 kcal/mol; krel = 81). All of these computed
67
barrier for inversion of the free CF3 anion). The pentacoor-
values are in excellent agreement with experiment.
dinate siliconate anions thus act as reservoirs, not active nu-
A general mechanism for the trifluoromethylation of ketones
9
–
cleophiles, liberating free (non-silicon coordinated) CF3 via
and aldehydes by R3SiCF3 reagents (1) in the presence of a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
dissociation. The transition state for addition of the CF3 an-
+
–
catalytic quantity of initiator (M X ) can thus be assembled,
Figure 7. The one overarching mechanism, discussed below
in the context of two extremes (Vi and Vii), rationalizes why
ion(oid) to the ketone formally involves movement between
a non-classical hydrogen bonded complex and the addition
product, a process that occurs with low calculated barrier
+
–
the turnover rate (per M X initiator) for a given electrophile
-1
(7.5 kcal mol ) and well-represents the process that occurs
–
depends on the initial concentration (but not identity) of X ,
once the two species are in contact. The calculations support
+
the identity (but not concentration) of M , the identity of the
the known preference for deprotonation (kCH) in the gas
reagent (1a-c), and the electrophile / reagent ratio (2 / 1).
68
phase, and for addition (kCO) once solvation is introduced,
Ar
k12
/ k13C=O calc. 1.006
Me
Ar
CF3
C=O
1
Me
3OSi
OSiR3
O
2
O–
(obs. 1.008)
F3C
F3C
Si
R
+
–CF3
CF3
O
B
R
K3
R
1
Ar
Me
–
R
–
CF3
R
R
R
Si
Ar
+
–CF3
R
Si
Me
R
k2
kCO
D
CF3
3O–
CF3
E
E
δ–
Ba
O
‡
‡
‡
+7.5
Me
Da
Ar
Ar
kCO
CF3
1a
δ–
O
3OTMS
δ–
‡
O
+7.5
Ar
H
E
+4.1 ‡
(c)
CF3
kCH
H
+3.7
+3.9
{2 + E}
δ–
+10.5 ‡
(c)
–CF3
CF3
0.0
E
-2.0
-5.8
–CF3
(b)
(a)
3O–
-5.6
-9.2
(b)
(a)
K3
R = iPr (c)
R = Et (b)
R = Me (a)
-5.7
-8.3
-9.4
kCH / kCD calc. 5.4
3
3
-8.8
(obs. 6.1)
Figure 6. Selected structures and energies (M06L/6-31+G*; PCM (THF); standard state, 1 M; 298 K) of naked anions in the reaction
-
-1
of ketone 2 with R3SiCF3 1a-c. Energies have been normalized to [CF3 + 1 + 2] = 0.00 kcal mol . See text, Figure 9, and the SI for
discussion of the binding modes and effects of cations. The structures and energies of other potential intermediates examined,
including hexacoordinate dianions and fluoride adducts, are provided in the SI.
(cat 3/4O–
)
O– +
M
OH
O
O
3O-
k12
/ k13C=O = 1.008
2
2
2enol
C=O
Me
CF3
R3Si-CF3
Ar
Me
Ar
Ar
Me
Ar
kCH / kCD = 6.1
kOH / kOD = 1.0
(1)
kCO
k1
kCH
kOH
O– +
(+ 4O-)
E
E
E
k2
O
O
2
Me
O– +
Me
M
M
Kinit
R3Si-X
Ar
CF3 M+
–CF3
M+
Ar
M+X–
K4
R3SiCF3
+
R
Ar
R
Si–
Ar
(E)
H
(1)
3/4O–
CF3
(B)
R
+ CF3H
O
(F)
(3O-)
(4O-)
Me
K3
1
Ar CF3
Mechanism Vi
Mechanism Vii
(R = iPr)
k2’
OSiR3
Me
k2
1
1
M+
(R = Me)
CF3
3OSi
E
Ar
R
R
Si–
CF3
R
k2[X–]0[1](1-xEI
)
k1[X–]0[2](1-xEI
)
4OSi
3OSi
(+ 4OSi
)
TOF ≈
d[4OSi]/dt
d[3OSi]/dt
TOF ≈
(D)
CF3
1 + K3[1]
1 + K4[2]
= constant
Figure 7. Mechanisms Vi and Vii: two extremes of general model V for the trifluoromethylation of ketones by R3SiCF3 reagents
+
–
1a-1c, in the presence of a catalytic quantity of initiator M X , with acetophenone as a generic reactant. Turnover frequency
(TOF) equations are simplifications of a global approximation, where k1 = kCO + kCH + kOH[2enol]/[2], and the mol-fraction of active
anion quenched by unidentified exogenous inhibitor(s) in 1, is xEI. Initiation (Kinit) is not included in the rate equation. When
+
–
M X is 'TBAT', initiation is reversible using 1a. For non-enolizable ketones and aldehydes, kCH, kOH, and K4 = 0.
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is a combination of the product alkoxide (30-), the enolate an-
10. Mechanism Vi. In this regime, which describes reac-
1
2
3
4
5
6
7
8
ion (40-), and MX. Ketone (2) can reversibly H-bond (F) with
oxy-anions 3/40-, as observed by NMR, Figure 5, leading to
inhibition (K4). When [1c]0/[2]0 = 1 pseudo zero order kinetics
tions involving TMSCF3 (1a), the dominant anion speciation
32-34
is the bis(trifluoromethyl) siliconate (D),
rapid equilibrium (K3) with CF3 (E)
by NMR, Figure 4. The product-determining step (k1) in-
volves reaction of CF3 (E) with the ketone (2), (kCO + kCH), and
the reagent (1a) thus acts as a reversible inhibitor. The
stronger the association of M with CF3 (see Section 13) and
with the carbonyl oxygen, the faster the turnover rate: Bu4N
< [K(crypt-222)] < [K(18-c-6)] < K . The initial concentration
ratios of the reactant versus the reagent dictate the temporal
evolution of the reaction. When [2]0/[1a]0 = 1, pseudo zero or-
der kinetics are obtained, whereas when [2]0/[1a]0 ≥1 the rate
rises throughout the reaction, becoming very fast (asymp-
toting to k-3[D]) in the final stages. The kinetics of trifluoro-
methylation of ketone 2 by TMSCF3 (1a), can be satisfactorily
simulated, Figure 8, using a truncated form of mechanism Vi
that retains relationships required for TOF modulation as the
temporal concentration ratio [2]t/[1a]t evolves.
generated in
69
–
36,38
and 1a, as observed
are observed; reactions in which [1c]0/[2]0 >1 exhibit acceler-
–
ating rate in the last stages of reaction. The more strongly
+
bound M to [3/40-], the slower the reaction with 1c, leading
+
+
+
+
–
to rates increasing in the series: K < [K(18-c-6)] < Bu4N <
+
+
[K(crypt-222)] ; i.e. the opposite order to Vi. When the non-
9
+
+
+
enolizable ketone 4-F-benzophenone 12 is employed, the ki-
netics show clean pseudo first-order decay in 1c, see SI, with
no inhibition by 12 (i.e. Mechanism Vii, where K4 = 0; and
equation 2, where Ki2 = 0).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12. Competing Enolization. Also shown in Figure 7 is the
generation of the enol ether (4OSi) and CF3H from ketone 2,
+
for which the selectivity (4OSi / 3OSi) is dependent on M and
the reagent (1a-c), Table 1. The major pathway for generation
of 4OTMS in mechanism Vi is via C–H deprotonation (kCH) with
2
70,71
an attendant large primary H-KIE.
In contrast, for mech-
O
anism Vii, the significant concentration of [3/40-] allows keto-
72
Me
enol equilibrium (pKenol ~8) in 2 to be approached, with at-
k1K3-1 = 7.1 ± 1.2 s-1
k3 ≥ k1 ≥ 2000 M-1s-1
2
2
tendant intermolecular scrambling of H between ketone me-
F
k1
O–
thyl groups. Deprotonation (kOH) of the enol (2enol) is pre-
dicted (DFT) to be of very low barrier, and thus proceed with
a negligible H-KIE. Despite their different origins (kCH ver-
sus kOH) mechanisms Vi, and Vii both lead to 4OSi / 3OSi ratios
that are independent of the concentration of reactants (1, 2)
and constant throughout reaction, Figure 2.
1a
K3
Me
CF3
[TMS(CF3)2]–
–CF3
–
Bu4N+X–
3O
2
70
(D)
F
2 × 1a
OTMS
Me
CF3
TMSCF3 (1a)
(+ 4OTMS
3OTMS
)
F
13. Cation-CF
3
Interactions. The interactions between the
450
400
350
300
250
200
150
100
50
[2]0 / [1a]0 > 1
vi
[2]0 / [1a]0 < 1
–
+
CF3 anion (free and Si-bound) and the counter-cations K
+
+
and Me4N (as a model for Bu4N ) were explored computa-
tionally, with multidentate CF3 interactions found to be fa-
vored, e.g. Figure 9; see SI for details.
vii
v
viii
K+
K+
iv
K+
F
C
F
C
F
F
F
–
[K+][CF3
]
F
F
F
C
K+
C
F
iii
F
F
F
ix
ii
Me
Me
Me
x
i
N+
–
[Me4N+][CF3
]
N+
N+
i
xi
xii
H
H
H
H
H
H
H
H
H
F
F
F
F
F
F
F
C
C
F
C
F
xiii
0
N+
N+
0
5
10
15
20
25
30
35
40
45
R
R
time (s)
ii
H
H
H
H
H
H
O
Figure 8. Simulation of experimental data (open circles, SF-
IR; [3OTMS + 4OTMS]t) based on simplified mechanism Vi, for
reaction of ketone 2 with TMSCF3 (1a), initiated by 3.6 mM
O–
F
F
F
F
Me
Ar
C
C
Ar
F
Me
F
+
–
TBAT (Bu4N X ). For [2]0/[1a]0 >1, [2]0 = 0.40 M and [1a]0 = 144,
192, 248, 288, 336, 384 mM (i to vi). For [2]0/[1a]0 <1, [1a]0 = 0.48
M and [2]0 = 400, 320, 240, 200, 160, 120, 80 mM (vii to xiii).
Induction and turnover by 1a are set to arbitrary high values.
Figure 9. Cation binding to free CF3 anion: (i) various modes
+
+
of binding of K and Me4N cations; (ii) concept (schematic)
for enantioselective addition beneath the quinuclidinium
core of a cinchonidinium initiator. Inset: structure of TS for
59
Fitted parameters (k1, k3, k-3) as indicated; xEI = 0.
–
+
addition of [CF3 ][Me4N ] to 2, see SI, with H-bonding inter-
11. Mechanism Vii. In this regime, which describes reac-
tions involving TIPSCF3 (1c), the dominant anion speciation
actions to developing alkoxide anion.
The indirect transfer of CF3 from reagent 1a to the ketone /
aldehyde, i.e. via a silicon-free carbanion E, has implications
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for the mode by which enantioselective catalysis can be (TBAT, KOPh) required to effect >99% conversion of 2
1
2
3
4
5
6
7
8
achieved using chiral ammonium initiators, e.g. cinchoni-
dinium salts. The CF3-anion binding modes found computa-
ranged from 30 µM to 2.0 mM (0.0075 to 0.5 mol%); see SI.
E
E–
+
tionally for Me4N (Figure 9i) show how an ammonium cat-
M+
i
M+
F
inversion
–
F
C
F
ion might simultaneously interact with a CF3 anion and con-
F
C
>>50 kcal mol-1
F
F
inversion
trol a developing alkoxide anion, Figure 9ii. Mechanism Vi
Me
Me Si–
+
16de,31
16f
Me
Me
Me
CF3
contrasts most,
but not all, prior interpretations,
Me
D
Si
where mechanisms II/III (Scheme 2) involving CF3-
siliconates bearing the initiating (C) or propagating (B) an-
ion, are proposed to play key roles in the enantioselective tri-
fluoromethylation step.
1a
CF3
9
M+ ≤ 14 kcal mol-1
ii
F
E
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
F
dissociation
M+
F
M+
E–
F
F
C
C
k-3
F
F
C
14. Broader Mechanistic Aspects. The mechanistic fea-
tures elucidated in the current study extend beyond carbonyl
trifluoromethylation. A number of corollaries follow for ge-
neric anion-initiated trifluoromethylation of an electrophile
Me
Me
Me Si–
F
F
1a
F
D
M+ R–
R–H
CF3
+
H
C
F
73
(E) by 1a, or deprotonation (R–H), via pathways analogous
iii
inhibition
CF3
M+
F
CF3Z
+
+
–
F
to mechanism Vi, and where [E, R–H]0 >>[M X ]0. Thus, the
Z
LG
Me
Me Si–
C
+
–
initiator (M X ) affects the rate of reaction in a number of
Me
F
LG– M+
1a
–
LG
ways. [X ]0 sets the initial concentration of the siliconate ([D]0
(Z = H, R3Si, LG = Cl, Br, etc.)
–
60
= (1-xEI)[X ]0) which, in the absence of endogenous inhibi-
Figure 10. Generic reactivity of siliconate D towards electro-
philes (E), carbon acids (R–H), and inhibitors (Z–LG). (i) di-
rect CF3 transfer from D is strongly disfavoured. Inset: TS for
CF3-transfer to acetone, see SI; (ii) dissociative CF3 transfer,
without CF3 inversion; (iii) termination of the anionic chain
reaction by traces of exogenous inhibitor(s), or substrates
tors, is essentially constant throughout reaction. The insur-
mountable barrier for CF3 inversion means that, independ-
67
ent of the identity of the electrophile, E, or proton donor, R–
H, the siliconate is unable to effect direct anionic trifluoro-
methyl transfer, Figure 10i. In all cases, the reaction must
+
proceed via a dissociative pathway, Figure 10ii, in which M
–
that generate an unreactive anion, LG .
+
plays a key role: the stronger the association of M with CF3
the more favourable k-3. In contrast, efficient regeneration of
An major difference found between reactions involving rea-
gent 1a versus 1b,c is the impact of the persistent radical,
TEMPO, which powerfully inhibits reactions involving 1a,
Scheme 4A. The difference in behavior towards TEMPO can-
not arise from oxidation of the CF3 anion (E), as this is a com-
mon intermediate to all three reagents (1a-c), and the parti-
tioning of E between reaction with the ketone (2) versus
TEMPO will be constant across the series, i.e. independent of
the provenance of the carbanion E. Since the major difference
between reagents 1a and 1c under the conditions of the reac-
tion, is the dominant anion speciation (D; mechanism Vi, 1a,
versus alkoxides 3O– / 4O–; mechanism Vii, 1c), this suggests
that reaction of siliconate D with TEMPO is responsible for
the inhibition. We were unable to identify any products in
situ, or by quenching, arising from TEMPO under the stand-
ard reaction conditions, see SI. Whilst siliconates of type D
are also generated from 1b and 1c, they are a) only present
as low concentration or transient species, thus reducing their
net rate of reaction with TEMPO, and b) may be more re-
sistant to reaction with TEMPO due to their greater steric
bulk.
the siliconate (k2, Figure 7) is favored by weaker interactions
+
between M and the anionic co-product from trifluoromethyl
–
–
transfer (CF3–E ; R ; or products thereof). When the anion is
+
–
unable to react with 1a, stoichiometric initiation by [M X ] is
14-26
required.
15. Exogenous Inhibition. Trifluoromethylations initiated
+
–
by low concentrations of (M X ) are highly sensitive to traces
of exogenous inhibitor(s). Species that generate of an anion
–
(LG ) of insufficient reactivity towards 1a to propagate, will
terminate the anionic chain reaction, Figure 10iii. In a series
of control experiments, additives of the form Z-LG, (Z = H,
R3Si, LG = Cl, Br) were found to function as powerful inhibi-
tors for the anion-initiated reaction of 2 with 1a. For example,
the trifluoromethylation of 2 (0.4 M) initiated by 150 µM
TBAT ceases immediately on addition of 150 µM TMSCl, see
SI. Slower-onset irreversible inhibition is effected by the
more hindered TIPSCl, which is also inhibits the reaction of
TIPSCF3 (1c). Competing consumption of 1a is effected by
other species in low-concentrations, including CCl4 (Cl-
74
73b
transfer), Cl3CH (deprotonation / Cl–transfer), and TMS-
OH (deprotonation), but without significant chain termina-
CONCLUSIONS
73b
tion. There was no detectable inhibition by DCE, CH2Cl2,
TMS-O-TMS, Ph3SiF, Me3SiCF2H, or MeCN.
The trifluoromethylation of ketones and aldehydes by
73c
TMSCF3 (1a), initiated by catalytic fluoride ion, has been em-
12
ployed in synthesis for three decades. Previous mechanistic
In our experience, a diverse range of inhibitors, and compet-
itors (e.g. CCl4 and CHCl3) are present, in low concentrations
and variable proportions, in commercial samples of TMSCF3
(1a). This leads to substantial differences in reaction out-
come, depending on the supplier. For example, comparison
of the reaction of 2 (0.40 M) with five samples of freshly-dis-
tilled 1a (0.48 M) revealed that the concentration of initiator
work has focussed on stoichiometric reactions of R3SiCF3
(1a,c) with anions at low temperatures, generating unstable
32-34
trifluoromethyl siliconates (C,D)
(E),
and carbanion(oids)
36-38
depending on conditions. Which of these two path-
ways is followed in catalytic reactions at ambient tempera-
30
ture has been a long-standing mechanistic dichotomy.
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variable-ratio stopped-flow NMR/IR approach (Figure 3) has
been developed to facilitate time- and material-efficient anal-
TMSCF3 (1a) to TESCF3 (1b) is therefore to strongly inhibit
turnover of 1b until all of 1a has been consumed, Figure 1.
1
2
3
4
5
6
7
8
+
–
ysis of a wide range of initiator (M X ) and reactant concen-
trations. Change of reagent from TMSCF3 (1a) to TIPSCF3 (1c)
has a profound impact on the reaction. For example, the con-
version of 4-F-acetophenone (2, 0.4 M) to 3OTMS by equimolar
1a in THF at ambient temperature takes < 125 msec to com-
plete using 0.1 mol% KOPh initiator, and generates <2% of
silylenol ether 4OTMS, whereas with TIPSCF3 (1c) and 3.75
mol% KOPh, the reaction proceeds to just 60% conversion in
16 hours, and generates 50% 4OTIPS. The rates of reaction are
strongly affected by traces of inhibitors present in the rea-
gents (1), especially at the low concentrations of initiator
The overarching mechanism (V, Figure 7) for anion-initiated
reactions of R3SiCF3 (1) with ketones and aldehydes should
prove of utility in their application in synthesis. For example,
in the context of the design and analysis of enantioselective
16,29,30a,31
trifluoromethylation processes,
mechanism V shows
–
+
that control must be achieved by the CF3 / [M] ion pair, Fig-
ure 9ii, and not by a siliconate intermediate. Moreover, the
key mechanistic features of the anion-initiated reactions of 1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
with carbonyl compounds (Figure 7) translate to reactions of
29-31
1 with other electrophiles (E),
and proton donors (R–H to
–
73
generate R ), Figure 10. Thus, all processes in which sili-
conate D or analogous species, formally acts as a nucleo-
philic or basic source of CF3, must proceed via a dissociative
pathway (Figure 10ii). Siliconate D is inherently unstable,
+
–
(M X ) employed for the fastest reacting systems, see equa-
59,60
tions 1 and 2.
Nonetheless, whilst these render initial rate
data misleading, study of the full reaction time-course, e.g.
Figure 8, provides a coherent kinetics analysis.
and decomposes at ambient temperature to generate, inter
34,38a
A unified mechanism (V) for the reaction of R3SiCF3 reagents
alia, complex perfluorocarbanions.
The rate of anionic
(1a-c) with ketones and aldehydes under conditions of cata-
chain transfer, as dictated by the reactivity of the electrophile
+
–
29-31
73
–
lytic anionic initiator (M X ) is presented in Figure 7. The
(E)
or carbon acid (R-H) towards CF3 , as well as the
36-38
work confirms that the carbanion
mechanism prevails
presence of species able to attenuate decomposition (e.g. via
under conditions of application (Scheme 1). Mechanism V al-
lows a number of initially confusing observations to be ra-
tionalized. The main difference between use of TMSCF3 (1a)
versus TIPSCF3 (1c) reagents is an inversion in the major an-
ion speciation in the overall anionic chain reaction. This in-
version leads to opposing influences of electrophile and sili-
con reagent (mechanisms Vi and Vii), and to keto-enol equi-
libration (2 / 2enol) with 1c (Vii). When TBAT is used as initi-
CF2-capture, 4OSi ®10, Scheme 3), controls the formal lifetime
+
–
of D, and in turn the minimum loading of initiator (M X )
that will be required to achieve complete conversion of sub-
strate. Moreover, traces of exogenous inhibitor(s), (e.g. Z–
LG, Figure 10iii) ubiquitous in R3SiCF3 reagents (1), act to re-
duce the net active anion in the chain reaction, again increas-
+
–
ing the requisite loading of initiator (M X ). Compounds em-
ployed in synthetic routes to reagents 1a-c, e.g. TMSCl and
75
11
ator, TESCF3 (1b) effects the most rapid trifluoromethyla-
TIPSCl, function as powerful inhibitors. However, the iden-
tion in the series 1a-c. The increased steric bulk in 1b reduces
reagent inhibition (K3) relative to 1a, without the substantial
kinetic penalty in k2 experienced by 1c. These factors shift the
reaction with 1b closer to an 'ideal' catalytic cycle in which
the intermediates are all connected by low TS barriers, with
reduced off-cycle speciation. A consequence of adding
tity and effect of the inhibitors in reagents 1a-c vary substan-
tially from batch to batch, and between commercial suppliers
(see SI). Electrophiles or carbon acids (R–H) that react with
–
CF3 to ultimately generate an anion of inherently low reac-
tivity towards 1, require stoichiometric initiator to proceed
14-26
to completion.
Seventh Framework Programme (FP7/2007-2013) / ERC grant
agreement n° [340163]. The Carnegie Trust provided a collab-
orative research grant. C.P.J. thanks the EC for an International
Outgoing Fellowship (PIOF-GA-2013-627695).
______________________
ASSOCIATED CONTENT
Supporting Information: Additional discussion, experi-
mental procedures, further kinetic data and analysis, charac-
terization data and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We thank Veronica Forcina (Edinburgh, UK) and Prof. Du-
san Uhrin (Edinburgh, UK) for assistance with stopped-flow
NMR and dynamics, and Dr Per-Ola Norrby (AstraZeneca,
Sweden) for valuable mechanistic discussions in the early
phases of this work.
AUTHOR INFORMATION
Corresponding Author
Guy.lloyd-jones@ed.ac.uk
REFERENCES
Author contributions
ò C.P.J. and T.H.W. contributed equally to this work.
(1)
Selected reviews: a) Purser, S.; Moore, P. R.; Swallow,
S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem.
Soc. Rev. 2008, 37, 320-330; b) Gillis, E. P.; Eastman, K. J.; Hill,
M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Flu-
orine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–
8359; c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña,
J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation
Notes
The authors declare no competing financial interest.
Funding Sources
The research leading to these results has received funding from
the European Research Council under the European Union's
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19
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(60) In equations 1 and 2, and elsewhere, (1-xEI) represents
+
–
the mol-fraction of active anion relative to total anion [M X
]0. Based on a 1:1 inhibition mode, xEI = (KEI[I]/(1+KEI[I])) with
[I]0 = xi[1]0, where xi = mole fraction inhibitor in reagent 1.
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(61) This contrasts the borazine systems recent developed
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19
indicated in Figure 4 (kex = 2k-ex; where k-ex is the apparent
F
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the identity of [M].
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are again complicated by inhibitors. When initiated by 0.3
mM KOPh the reaction is pseudo zero-order throughout; this
result is consistent with a number of mechanisms, including
for example turnover and inhibition by 1b, or rate-limiting
dissociation of CF3 from dominant anion Bb. The faster rates
of reaction with Bu4N versus K as counter-ion suggest
mechanism Vii dominates.
+
+
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GRAPHICAL ABSTRACT
CF3
Si
reactants
& inhibitors
mechanism ?
R
R
R
O
OSiR3
Ar
Me
Ar
CF3
Me
cat. R4N+X–
intermediates
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