New insights into addition reactions of dialkylzinc reagents to trifluoromethyl ketones: Structural authentication of a β-hydride elimination product containing a tetranuclear zinc chain

Article abstract of DOI:10.1039/b911818g

A systematic study of the stoichiometric alkylation reactions of 2,2,2-trifluoroacetophenone 1 with [ZnR₂(TMEDA)] (R= Me, Et, ^tBu, CH₂SiMe₃; TMEDA= N,N,N′,N′- tetramethylethylenediamine) monitored by ¹

Full text of DOI:10.1039/b911818g

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www.rsc.org/dalton | Dalton Transactions
New insights into addition reactions of dialkylzinc reagents to trifluoromethyl
ketones: Structural authentication of a b-hydride elimination product
containing a tetranuclear zinc chain†
Eva Hevia,* Alan R. Kennedy, Jan Klett, Zoe Livingstone and Matthew D. McCall
Received 17th June 2009, Accepted 18th August 2009
First published as an Advance Article on the web 10th September 2009
DOI: 10.1039/b911818g
A systematic study of the stoichiometric alkylation reactions of 2,2,2-trifluoroacetophenone 1 with
[ZnR2(TMEDA)] (R= Me, Et, tBu, CH2SiMe3; TMEDA= N,N,N ¢,N¢-tetramethylethylenediamine)
monitored by 1H and 19F NMR spectroscopy is presented. For R = Me, Et the alkylation products
alkyl(alkoxides) [(TMEDA)Zn(R){OC(CF3)(R)Ph}] (R = Me, 2: Et, 3) are obtained as the single
products of the reaction. When the steric bulk of the dialkylzinc reagent is increased the alkylation
t
reaction is inhibited. Thus, for R = Bu, the reduction product [(TMEDA)Zn(tBu){OC(CF3)(H)Ph}]
is obtained as a result of b-hydride elimination from one of the tBu groups of the organometallic
reagent. 1H NMR spectroscopic monitoring of the reaction allowed the detection of isobutene as a side
product of this reduction process. For the highly sterically demanding group R = CH2SiMe3 which
lacks hydrogen atoms at the b position, no reaction is observed even under refluxing conditions.
Two important intermediates from these reactions have been structurally elucidated:
[(TMEDA)Zn(Me){OC(CF3)(Me)Ph}] (2) which could be involved in the previously reported
alkylation reaction of trifluoromethyl ketones by ZnR2 catalysed by TMEDA and unprecedented
tetranuclear [(tBu)2Zn4{OC(CF3)(H)Ph}6] (5) resulting from the reduction of 1 when reacted with
tBu2Zn, which displays a rare Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn linear chain arrangement for a zinc alkyl(alkoxide).
vant tertiary alcohols in good yields (84–99%).5,6 An asymmetric
Introduction
variant to prepare enantiomerically enriched a-trifluoromethyl
The development of new methodologies to prepare organofluorine
tertiary alcohols was also introduced by using the chiral N-
compounds, in particular trifluoromethyl-substituted molecules
has recently become a target for many synthetic chemists due
donor ligand TBOX (TBOX = 2,2¢-isopropylidenebis[(4S)-4-tert-
butyl-2-oxazoline]) as a catalyst. Structural information of the
to the unique properties, reactivities and assorted applications
metallated intermediates (existing prior to the hydrolysis step) has
of these compounds in areas such as agrochemicals, materials,
not yet been forthcoming.
and pharmaceuticals.1 This activity has included several studies
Following our success in isolating and spectroscopically and
on asymmetric alkylation reactions of trifluoromethyl ketones
crystallographically characterising organozinc intermediates for
metallation (zincation) reactions,7 we have endeavoured to probe
similarly the intermediates from Wolf-type alkylation reactions.
that yield chiral trifluoromethyl-substituted alcohols which are
important subunits in several pharmaceuticals2 including anticon-
vulsants, anaesthetics and the anti-HIV drug Efavirenz.3
1
Accordingly, herein, we report specifically a H and 19F NMR
Amongst the catalogue of main group organometallic reagents,
organozinc compounds are usually the reagents of choice in
asymmetric alkylations of ketones, due to their softer nucleophilic
character and greater functional group tolerance compared to
that of other organometallic reagents (such as orgonolithium,
RLi, or Grignard reagents, RMgX).4 However, in the context
of trifluoromethyl ketones, their use has been relatively limited
due to their tendency to undergo b-hydride elimination reactions
that afford the unwanted reduction products. Overcoming this
severe limitation, Wolf has successfully reported the addition
of diethylzinc to a wide range of trifluoromethyl ketones using
the popular chelating diamine TMEDA (TMEDA = N,N,N ¢,N¢-
tetramethylethylenediamine) as a catalyst which affords the rele-
spectroscopic investigation of the stoichiometric alkylation re-
actions of [(TMEDA)ZnR2] (R = Me, Et, tBu, CH2SiMe3)
with 2,2,2-trifluoroacetophenone (1). A putative intermediate
in the catalytic process, the addition product [(TMEDA)-
Zn(Me){OC(CF3)(Me)Ph}] (2) has been successfully isolated and
structurally characterized by X-ray crystallography. In addition
we report the synthesis and structural characterization of the
unprecedented tetranuclear cage [(tBu)2Zn4{OC(CF3)(H)Ph}6] (5)
which was obtained as the reduction product of the reaction of
tBu2Zn with ketone 1.
Results and discussion
The TMEDA-complexed dialkylzinc starting materials
[ZnR2(TMEDA)] (R = Me, Et) were prepared in situ by reaction
of the relevant dialkylzinc reagent with an equimolar amount
of TMEDA in a mixture of toluene/n-hexane solvent affording
in each case colourless solutions. 2,2,2-Trifluoroacetophenone
WestCHEM, Department of Pure and Applied Chemistry, University of
Strathclyde, Glasgow, UK G1 1XL. E-mail: eva.hevia@strath.ac.uk
† Electronic supplementary information (ESI) available: NMR spectra.
CCDC reference numbers 736434 and 736435. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b911818g
520 | Dalton Trans., 2010, 39, 520–526
This journal is
The Royal Society of Chemistry 2010
©

(1) was added at -10 ◦C giving pale yellow solutions which were
allowed to stir for 24 hours at room temperature. The resulting
solutions deposited colourless crystals of the nucleophilic addition
products [(TMEDA)Zn(R){OC(CF3)(R)Ph}] (R = Me, 2; Et, 3)
as determined by NMR spectroscopy and X-ray crystallography
(for 2)‡ in isolated yields of 54% and 61% respectively (Scheme 1).
Table 1 Selected chemical shifts in the 1H NMR spectra of 1-4 in C6D6
solution
Compound
d(1H)X
d(1H)Zn-R
d(1H)Ph
PhC(=O)CF3 (1)
7.80, 7.07, 6.92
7.98, 7.34, 7.19
2.22, 2.51 (q, CHH¢), 0.38 (q, CH2), 7.94, 7.36, 7.20
2 (R = X = Me) 1.93
-0.61
3 (R = X = Et)
0.83 (t, CH3)
1.57 (t, CH3)
1.19
t
4 (R = Bu; X = 5.47 (q, J3
=
7.67, 7.24, 7.14
H-F
H)
7.4 Hz)
that at room temperature in solution, a dynamic process must be
taking place in the molecule. This was confirmed by a variable
temperature NMR study using deuterated toluene as a solvent,10
which shows that at low temperature (-35 ◦C) the broad signal
observed at room temperature (Fig. 1b) splits into 4 singlets
(at 2.30, 2.03, 1.82 and 1.70 ppm, each of which integrates as
three hydrogens) and four multiplets (at 2.15, 1.89, 1.62 and
1.53 ppm, each of which integrates as one hydrogen) (Fig. 1c).
This spectrum indicates that at low temperature, TMEDA remains
coordinated to zinc and also that there is no symmetry in the
molecule, which makes each methyl group and each hydrogen
of the CH2 groups appear inequivalent. Thus, as a result, eight
distinct resonances are observed for the protons of the TMEDA
ligand. This lack of symmetry must be caused by the hindered
rotation at low temperature around the O-C bond in the chiral
Scheme 1 Synthesis of alkyl(alkoxide) compounds 2–4.
Multinuclear (1H, 13C and 19F) NMR spectroscopic studies
recorded in deuterated benzene solution established that the
alkylation reactions of ketone 1 by the relevant [ZnR2(TMEDA)]
(R = Me, Et) have taken place (Table 1 and Table 2). Thus,
the 1H NMR spectrum of 2 (see Table 1 and Experimental
Section) showed two distinct resonances for the (non-TMEDA)
methyl groups present in the molecule; a singlet at 1.93 ppm
corresponding to the methyl group that has added across the
=
C O bond of the ketone 1 and a further upfield singlet for
1
alkoxide ligand {OC(Me)(CF3)(Ph)}. On the other hand, a H
the one directly bonded to zinc at a chemical shift (-0.61 ppm)
similar to that found in the starting material [ZnMe2(TMEDA)]
in the same deuterated solvent (-0.52 ppm).8 For the TMEDA
ligand a single broad resonance at 1.77 ppm is observed for the
CH3 and CH2 groups which contrasts with the usual pattern
found for this ligand in deuterated benzene solution. Previously in
the literature it has been described that the relative positioning
of the distinct signals in the 1H NMR spectrum of TMEDA
denotes if the diamine is coordinated to the metal in solution
or alternatively if it is not coordinated.9 The fact that only a
broad signal is observed for the TMEDA ligand in 2 suggests
NMR spectrum of 2 at high temperature (T = 80 ◦C) shows
a completely different splitting pattern than those observed at
low temperature or ambient temperature. Instead, two singlets at
2.14 ppm (NCH3) and 2.06 ppm (NCH2) (Fig. 1a) are observed.
The relative positioning of these signals suggests that even at high
temperature TMEDA remains coordinated,9 however, now the
splitting pattern is consistent with a symmetric TMEDA, which
must be due to the fact that as the temperature is increased, the
‡ Crystal data for 2: C16H27F3N2OZn, Mr = 385.77, monoclinic, space
˚
group P21, a = 8.2967(4), b = 12.6431(4), c = 9.5096(4) A, b =
◦
109.426(5) , V = 940.73(2) A , Z = 2, rcalc = 1.362 g cm-3, CuKa radiation,
3
˚
-1
˚
l = 1.5418 A, m = 2.103 mm , T = 123 K, R(int) = 0.0369; Final
refinement to convergence on F2 gave R = 0.0454 (F, 3892 obs. data
only) and Rw = 0.1172 (F2, 4909 unique data), GOF = 0.981, 212 refined
parameters. Samples were twinned by a 180◦ rotation about 1 0 0, ratio
of twin components refined to 0.689:0.311. Residual electron density max.
-3
˚
and min. 0.727 and -0.654 e A . Estimated Flack parameter 0.09(4).
Crystal data for 5: C56H54F18O6Zn4, Mr = 1426.47, triclinic, space group
¯
˚
P1, a = 10.7331(4), b = 12.0496(4), c = 12.6837(3) A, a = 96.141(2), b =
◦
113.380(3), g = 98.272(3) , V = 1465.52(8) A , Z = 1, rcalc = 1.616 g cm-3,
3
˚
-1
˚
MoKa radiation, l = 0.71073 A, m = 1.722 mm , T = 123 K, R(int) =
0.0249; Final refinement to convergence on F2 gave R = 0.0602 (F, 5873
obs. data only) and Rw = 0.2032 (F2, 8333 unique data), GOF = 1.125,
391 refined parameters. Residual electron density max. and min. 2.741 and
Fig. 1 Selected aliphatic region showing the TMEDA resonances and Me
1
-3
˚
resonances from the alkoxide ligand {OC(CF3)(Me)Ph} in the H NMR
-1.352 e A . It is believed that the higher than expected residuals are due
to some R/S substitution. Attempting to model this disorder failed.
spectrum of 2 in deuterated toluene solution at variable temperatures.
Dalton Trans., 2010, 39, 520–526 | 521
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1
Table 2 Selected chemical shifts in the 13C{ H} NMR spectra in C6D6 solution
Compound
d(13C)Zn-R
d(13C)X
d(13C)C-O
d(13C)CF3
d(19F)
PhC(=O)CF3 (1)
2 (R = X = Me)
3 (R = X = Et)
180.3 (q, J2 = 34.8 Hz)
117.3 (q, J1C-F= 291.7 Hz)
129.2 (q, J1C-F= 290.5 Hz)
131.8(q, J1C-F= 291.7 Hz)
128.0(q, J1C-F= 287.5 Hz)
-71.48
-79.63
-79.05
-77.85
C-F
-16.7
28.7
76.4 (q, J2 = 25.1 Hz)
1.3 (CH2), 14.9 (CH3)
20.6 (C(CH3)3), 34.5 (CH3)
30.9 (CH2), 8.9 (CH3)
—
81.9(q, J2 C-F= 25.3 Hz)
C-F
t
4 (R = Bu; X= H)
78.8 (q, J2 = 27.8 Hz)
C-F
rotation around O-C bond in the alkoxide ligand becomes fast
relative to the NMR timescale.
structure where zinc occupies a distorted tetrahedral geometry
bonded to two nitrogens from the chelating ligand TMEDA, a
carbon from the methyl group and an oxygen from the chiral
tertiary alkoxide ligand {OC(CF3)(Me)Ph} resulting from the
nucleophilic addition of a methyl group to ketone 1.11 Surprisingly,
and despite several alkyl(alkoxide) zinc compounds [Zn(OR)(R¢)]n
being previously structurally defined, compound 2 represents
the first such example solvated by a molecule of TMEDA. A
closely related species to 2 is the pyridine-solvated ethylzinc-
fluoroalkoxide [(py)2Et2Zn2{OCH(CF3)2}2] prepared by reaction
of Et2Zn with the relevant fluorinated alcohol as a possible
precursor to fluorine-doped ZnO films.12 The latter exhibits a
dimeric arrangement where each zinc binds to two bridging
alkoxide ligands, a terminal ethyl group and a molecule of pyridine.
As expected, from coordination number considerations, the Zn-
The 13C NMR spectrum of 2 revealed a set of four aromatic
signals for the phenyl group and two singlets at 28.7 and -16.7 ppm
corresponding to the methyl group that has been added across
=
the C O bond of 1 and that coordinated to zinc respectively
(Table 2). In addition two quartets with remarkably different
coupling constants are observed at 129.2 and 76.4 ppm. The
former with a coupling constant of 290.5 Hz corresponds to
the CF3 group and appears significantly downfield to that of the
ketone 1 (117.3 ppm, J1 = 291.7 Hz). The remaining quartet
C-F
at 76.4 ppm (J2 = 25.1 Hz) can be assigned to the electrophilic
C-F
carbon that has experienced the alkylation reaction, which appears
considerably more deshielded than the carbonyl group of ketone
1 (d = 180.3 ppm, J2 = 34.8 Hz).
C-F
˚
The transformation of ketone 1 into the zinc alkyl(alkoxide) 2
has little effect on the 19F NMR spectra, as both compounds dis-
play a singlet at similar chemical shifts (at -71.48 and -79.63 ppm
respectively).
O bond distance in 2 [1.912(3) A] is shorter than those found in
˚
the aforementioned dimer [average Zn-O bond length, 2.032 A],
whereas the values of the Zn-C bond distances are within the same
˚
˚
range [1.972(5) A for 2, 1.980 A (average) for dimeric compound].
In order to gain a greater understanding about the formation
of compounds 2 and 3, the reactions of the dialkylzinc precursors
[ZnR2(TMEDA)] (previously prepared and isolated as crystalline
solids) with the ketone 1 in C6D6 solutions were investigated and
monitored by 1H and 19F NMR spectroscopy. The 1H NMR
spectrum revealed that in both cases, the alkylation reactions
are quantitative, which means that with [ZnEt2(TMEDA)] no
formation of the reduction product resulting from the competitive
b-hydride elimination reaction is observed. Note that in the
absence of TMEDA, the reduction product is the main species
obtained in the reaction of 1 and ZnEt2.5 Remarkably, the rate
of these alkylation reactions seems to be strongly dependent on
the nature of the alkyl group of the organozinc reagent. Thus, the
formation of 3 is almost quantitative after 10 minutes, whereas the
reaction of [ZnMe2(TMEDA)] with 1 requires 24 hours to reach
completion, and after 10 minutes it shows only a 5% conversion.
As previously mentioned, Wolf has reported the alkylation of
several trifluoromethyl ketones, including 1, via ZnEt2 catalysed by
TMEDA.5 Compounds 2 and 3 could be important intermediates
in this catalytic reaction. This catalytic process could take place
by the initial coordination of the chelating diamine to ZnR2
(Scheme 2), which would enhance the nucleophilicity of the
organometallic reagent, favouring the alkylation reaction over b-
hydride elimination, followed by the reaction with trifluoromethyl
ketone 1 to afford a zinc alkyl(alkoxide) intermediate (as 2 and
3). To allow the catalytic cycle to continue, the release of TMEDA
would be required. Thus, in the catalytic reaction, TMEDA should
depart from the alkyl(alkoxide) zinc compound, to coordinate
to more unreacted ZnR2 and regenerate the alkylating reagent
[ZnR2(TMEDA)]. The loss of TMEDA would be highly dis-
favoured on the grounds of the chelate effect, however, only a
Similar trends in the NMR spectroscopic data are observed for
the ethyl derivative 3 (Tables 1 and 2 and Experimental Section).
The main difference appears in the 1H NMR spectrum, since the
CH2 protons of the ethyl group which has added to ketone 1 are
diastereotopic, two distinct multiplets at 2.22 and 2.51 ppm, each
of them integrating as one hydrogen, are observed.
The molecular structure of 2 (Fig. 2) established by X-ray crys-
tallographic studies confirms that the addition of a methyl group
from the dialkylzinc [ZnMe2(TMEDA)] to the trifluoromethyl
ketone 1 has occurred. Methyl(alkoxide) 2 adopts a monomeric
Fig. 2 Molecular structure of 2. Hydrogen atoms have been omitted
˚
for clarity. Selected bond distances (A) and bond angles (deg): Zn1-O2
1.912(3), Zn1-C1 1.972(5), Zn1-N14 2.184(6), Zn1-N11 2.199(6), C2-O2,
1.362(6), C2-C11 1.538(7), O2-Zn1-C1 137.0(2), O2-Zn1-N11 97.1(2),
C1-Zn1-N11 117.2(2), O2-Zn1-N14 100.9(2), C1-Zn1-N14 108.1(3),
N14-Zn1-N11 82.7(3), C2-O2-Zn1 128.9(3).
522 | Dalton Trans., 2010, 39, 520–526
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The Royal Society of Chemistry 2010
©

rationalised in terms of the size of the CF3 group in ketone 1,
which in sharp contrast with the small size of fluorine (van der
Waals radius of fluorine is the next smallest after hydrogen), it
is a rather large sterically demanding substituent (intermediate
between an iPr and a tBu group).15
Attempts to grow crystals of the b-hydride elimination prod-
uct 4 were unsuccessful due to the excellent solubility of this
t
compound in n-hexane. However when the reaction of Bu2Zn
with one molar equivalent of ketone 1 was carried out in the
absence of TMEDA, colourless crystals of the reduction product
[(tBu)2Zn4{OC(CF3)(H)Ph}6] (5) were obtained in an 13% isolated
yield (Scheme 3). The identity of 5 was confirmed by 1H and 19
F
NMR spectroscopy and its molecular structure was determined
by X-ray crystallography (Fig. 3).
Scheme 2 Proposed catalytic cycle for alkylation of 1 by ZnR2 using
TMEDA as a catalyst.
small extent of ligand dissociation is required within the proposed
catalytic cycle. The unsolvated zinc alkyl(alkoxide) compound
would probably oligomerise to a higher aggregate, affording,
after the hydrolysis step, the relevant trifluoromethyl-substituted
tertiary alcohol. This proposed mechanism was strongly supported
by the fact that the reaction of ZnMe2 with one equivalent
of 1 in the presence of substoichiometric amounts of isolated
crystals of 2 (10 mol%), followed by hydrolysis afforded alcohol
PhC(Me)(CF3)(OH) in almost quantitative yields, which shows
the preference of the TMEDA ligand to coordinate to ZnMe2
over the alkyl(alkoxide) zinc compound 2.
Since the rate of the alkylation reaction seemed to be dependent
on the nature of the dialkylzinc reagent employed we also
investigated and monitored by H and 19F NMR spectroscopy
1
Scheme 3 Formation of 5 and hydrolysis reaction to yield 6.
the reaction of 1 with the much more sterically hindered reagent
[ZntBu2(TMEDA)].13 After 30 minutes, no evidence of reac-
tion was observed, however, after 24 hours, the 1H and 19F
NMR spectra revealed the formation of the reduction product
[(TMEDA)Zn(tBu){OC(CF3)(H)Ph}] (4) in an almost quantita-
tive yield (Scheme 1). Thus, the 19F NMR spectrum of the reaction
mixture showed a doublet at -77.85 ppm resulting from the
coupling of the fluorines of the CF3 group with the hydrogen
3
=
atom that has added across the C O bond in 1 (J
= 7.4 Hz).
H-F
Furthermore, the 1H NMR spectrum showed a new set of aromatic
resonances at 7.67, 7.24 and 7.14 ppm, which are modestly more
shielded than those found for 1 (Table 1), a singlet at 1.19 ppm
for the tert-butyl group which is still coordinated to zinc (slightly
more upfield than that found for [ZntBu2(TMEDA)], 1.34 ppm)
and a distinct quartet at 5.47 ppm for the hydrogen that has added
to the carbonyl group of 1, due to its coupling with fluorine.
Moreover, the formation of isobutene, the co-product of this b-
hydride elimination reaction can also be detected as indicated by
two additional singlets at 4.73 and 1.60 ppm which can be assigned
to its olefinic hydrogens and Me groups respectively (Scheme 1).
We next endeavoured to perform the reaction of 1 with
[Zn(CH2SiMe3)2(TMEDA)]14 which contains a b-hydrogen free,
highly sterically demanding trimethylsilylmethyl ligand. After
four days at room temperature or even when the reaction mixture
was refluxed for 2 hours in toluene no reaction was observed.
These results show that when the steric bulk of the alkyl group
of the organometallic reagent [ZnR2(TMEDA)] is increased, the
alkylation reaction is inhibited, favouring the reduction reaction
instead (when the alkyl group has b-hydrogens). This can be
Fig. 3 Molecular structure of 5. Hydrogen atoms, except for the alkoxide
C-H, are omitted for clarity.
Formally dimeric, new alkyl(alkoxide) 5 exhibits a tetranu-
clear Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn arrangement in which the metals
are connected through the secondary chiral alkoxide ligand
{OC(H)(CF3)Ph} (Fig. 3). The molecule in 5 is centrosymmetric,
containing three orthogonal fused {ZnOZnO} four membered-
rings (Fig. 4). These three rings are planar as evidenced by the
sum of their internal angles (358.58, 360 and 358.58◦ respec-
tively) and the arrangement of the four metals is almost linear
[Zn2 ◊ ◊ ◊ Zn1 ◊ ◊ ◊ Zn1A 167.78(6)◦]. Two distinct zinc environments
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 520–526 | 523
©

with the CF3 group, J3H-F = 7.4 Hz) and a broad signal at 2.66 ppm
for the OH group. In addition, the 19F{H} NMR spectrum showed
a single resonance at -77.87 ppm.
Conclusions
Fig. 4 Inorganic chain motif of 5.
A systematic study of the alkylation reactions of trifluoromethyl
t
ketone 1 with [ZnR2(TMEDA)] (R = Me, Et, Bu, CH2SiMe3)
are observed, thus the outer zinc atoms (Zn2, Zn2A) display a
distorted trigonal planar geometry bonded to two alkoxide ligands
and a terminal tert-butyl group whereas the remaining two zinc
atoms in the interior of the tetranuclear chain (Zn1, Zn1A), are
tetracoordinated in a distorted tetrahedral geometry, bonded to
four alkoxide oxygens. Unfortunately a large amount of motion
appears to be present within the alkoxide ligands in 5, perhaps
associated with R/S substitution disorder. This adversely affects
the accuracy of this structure and thus prevents discussion of its
bond lengths or bond angles. That notwithstanding, 5 represents
to the best of our knowledge the first example of a tetranuclear zinc
alkyl(alkoxide) with a linear chain arrangement.16 As previously
mentioned, zinc alkyl(alkoxide) compounds have attracted a con-
siderable amount of interest due to their applications in materials
science as precursors for ZnO nanoparticles.17 Depending on
the steric bulk and functionalisation of the ligands, unsolvated
[RZn(OR*)]n can display a wide range of structural motifs and
aggregation states (n = 1–6).18 For n = 4 these compounds display
a cubane structure19 which contrasts markedly with the linear
arrangement exhibited by 5. The closest structural precedent
to 5 is trimetallic arylzinc alkoxide [Ar2Zn3(OCHiPr2)4] (Ar =
p-CF3C6H4, C6F5),20 where the three metals also adopt a linear
disposition connected by bridging alkoxide ligands, with a central
pseudotetrahedral zinc atom (exclusively bonded to alkoxide
ligands) and two outer zincs, each of them bonded to two alkoxides
and a terminal aryl group. Compound 5 can be envisaged as an
intermediate in the reduction of ketone 1 to the secondary alcohol
PhC(H)(CF3)OH (6) prior to the hydrolysis stage. To the best of
our knowledge this is the first example of a structurally defined zinc
alkyl(alkoxide) compound, resulting from a b-hydride elimination
process.
has been carried out which revealed for R = Me and Et,
the alkylation reaction takes place in quantitative yields, being
considerably faster for R = Et than for R = Me. Increasing
the steric bulk on the alkylating reagent has a dramatic effect
on the final outcome of the reaction. Thus, for R = tBu,
the alkylation reaction is inhibited and instead, the reduc-
tion reaction (b-hydride elimination) is favoured, affording the
alkyl(alkoxide) compound [(TMEDA)Zn(tBu){OC(CF3)(H)Ph}]
(4) and isobutene (the formation of which can be detected
1
by monitoring the reaction by H NMR spectroscopy). When
the highly sterically demanding, but also b-hydrogen free di-
alkylzinc [Zn(CH2SiMe3)2(TMEDA)] is employed, no alkylation
of 1 is observed, indicating that these reactions are strongly
dependent on the steric bulk of the organometallic reagent. In
addition, two important intermediates of the reaction of 1 with
dialkylzinc reagents have been structurally elucidated. Monomeric
[(TMEDA)Zn(Me){OC(CF3)(Me)Ph}], resulting from the stoi-
chiometric reaction of 1 with [ZnMe2(TMEDA)], which could
be an important intermediate for the reaction of Et2Zn with 1
catalysed by TMEDA previously reported in the literature and
novel tetranuclear [(tBu)2Zn4{OC(CF3)(H)Ph}6] (5), an interme-
diate for the b-hydride elimination reaction, which represents to
the best of our knowledge the first zinc (alkyl) alkoxide compound
structurally defined, resulting from the reduction of a ketone.
The latter displays an unusual tetranuclear Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn
linear chain arrangement.
Experimental section
General
Compound 5 was also characterised in deuterated benzene
solution using multinuclear (1H and 19F) NMR spectroscopy. The
1H NMR spectrum was extremely complicated; showing a large
number of overlapping resonances, grouped in three discernible
main areas of the spectrum: 7.77 to 6.82 ppm, 5.60 to 4.29 ppm
and 1.36 to 0.57 ppm which can be assigned to the phenyl
All reactions were performed under a protective argon atmosphere
using standard Schlenk techniques. n-Hexane, THF and toluene
were dried by heating to reflux over sodium benzophenone
ketyl and distilled under nitrogen prior to use. ZnMe2 and
ZnEt2 were purchased from Aldrich Chemicals as a 1M solution
22
in heptane and 1 M solution in hexane respectively. ZntBu2
t
ring, CH group of the alkoxide ligand and the Bu ligand on
and [Zn(CH2SiMe3)2(TMEDA)]14 were prepared according to
literature methods. NMR spectra were recorded on a Bruker
DPX 400 MHz spectrometer, operating at 400.13 MHz for
the zinc respectively. The 19F{H} NMR spectrum is also very
complex, displaying a myriad of overlapping signals (from -76.13
to -78.47 ppm), which is consistent with the existence of a mixture
of species in solution. This could be rationalised assuming that
the structure of 5 in the solid state is retained in the deuterated
benzene solution. Since 5 possesses six chiral alkoxide ligands, each
of them with a stereocentre, 64 stereoisomers (36 diastereomeric
relationships) of 5 can be formed.21 This possibility was supported
when compound 5 was quenched with water, which afforded
secondary alcohol PhC(H)(CF3)OH (6) in an almost quantitative
1
1
1H, 376.36 MHz for 19F{ H} and 100.62 MHz for 13C{ H}.
Satisfactory elemental analysis of compounds 2–5 could not be
obtained due to its highly air and moisture sensitive nature.
Synthesis of [(TMEDA)Zn(R){OC(CF3)(R)Ph}]
(R = Me, 2; Et, 3)
The relevant dialkylzinc reagent (4 mL of a 1M solution in heptane
for ZnMe2 or 4 mL of a 1 M solution in hexane for ZnEt2) was
added to a solution of TMEDA (0.6 mL, 4 mmol) in toluene
(10 mL) at -10 ◦C and the resulting colourless solution was
allowed to stir for 10 min. Trifluoroacetophenone (1) (0.56 mL,
1
yield (Scheme 3). Alcohol 6 displays a considerably simpler H
NMR spectrum than organometallic precursor 5, with a single set
of well resolved multiplets for the aromatic protons (at 7.32 and
7.03 ppm), a quartet at 4.59 for the CH group (due to its coupling
524 | Dalton Trans., 2010, 39, 520–526
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The Royal Society of Chemistry 2010
©

4 mmol) was then introduced which instantaneously afforded a
yellow solution which turned colourless after 20 minutes stirring
at room temperature. This reaction mixture was ◦allowed to stirr
overnight and then placed in the freezer at (-20 C) and left for
24 hours. Colourless crystals were obtained (0.83 g, 54% for 2,
1.0 g, 61% for 3). NMR data for compound 2: 1H NMR (298 K,
C6D6) d 7.98 (2H, d, Hortho), 7.34 (2H, t, Hmeta), 7.19 (1H, t, Hpara),
1.93 (3H, s CH3), 1.77 (16H, s, broad, CH2 and CH3, TMEDA), -
under vacuum which afford 6 as a colourless oil. 1H NMR (298 K,
C6D6) d 7.32 (2H, d, Hortho), 7.03 (3H, m, Hmeta and Hpara), 4.59 (1H,
1
q (J3 = 7.4 Hz), CH), 2.66 (1H, s, broad, OH). 13C{ H} NMR
H-F
(298 K, C6D6) d 134.8, 129.3, 128.5, 127.7(Ph), 125.4 (q, (J1
=
C-F
1
292.3 Hz), CF3), 72.6 (q (J2 = 32.8 Hz), CH). 19F{ H} NMR
C-F
(298 K, C6D6): d -77.87.
1
Acknowledgements
0.61 (3H, s, Zn-CH3). 13C{ H} NMR (298 K, C6D6) d 147.8, 128.7,
127.5, 126.8 (Ph), 129.2 (q, J1C-F = 290.5 Hz, CF3), 76.4 (q, J2
=
C-F
We thank the Royal Society (University Research Fellowship to
E. H.), the Faculty of Science, University of Strathclyde (starter
grant to E. H.), and EPSRC (DTA award to M. D. M.) for their
generous sponsorship of this research.
25.1 Hz, C-O), 56.3, 46.6, 46.2 (CH3 and CH2, TMEDA), 28.7
1
(CH3), -16.7 (Zn-CH3). 19F{ H} NMR (298K, C6D6): d -79.63.
NMR data for compound 3:1H NMR (298K, C6D6) d 7.94 (2H,
d, Hortho), 7.36 (2H, t, Hmeta), 7.20 (1H, t, Hpara), 2.51, 2.22 (1H
each, m, CHH¢, Et), 2.01-1.77 (16H, m, broad, CH2 and CH3,
TMEDA), 1.57 (3H, t, CH3, Zn-Et), 0.83 (3H, t, CH3, Et), 0.38
Notes and references
1
(2H, q, CH2, Zn-Et). 13C{ H} NMR (298K, C6D6) d 147.1, 129.2,
1 (a) R. Filler, Y. Kobayashi and Y. L. Yagupolskii, Organofluo-
rine Compounds in Medicinal Chemistry and Biological Applications,
Elsevier, Amsterdam, Netherlands, 1993; (b) R. E. Banks, B. E. Smart
and J. C. Tatlow, Organofluorine Chemistry: Principles and Commercial
Applications, Plenum Press, New York, 1994; (c) R. D. Chambers, Ed,
Organofluorine Chemistry, Springer, Berlin, 1997; (d) T. Hiyama, K.
Kanie, T. Kusumoto, Y. Morizawa and M. Shimizu, Organofluorine
Compounds, Springer-Verlag, Berlinf-Heidelberg, 2000; (e) K. Mikami,
Y. Itoh and M. Yamanaka, Chem. Rev., 2004, 104, 1.
127.1, 126.4 (Ph), 129.8 (q, J1C-F = 291.7 Hz, CF3), 80.9 (q, J2
=
C-F
25.3 Hz, C-O), 57.8, 47.8, 47.1 (CH3 and CH2, TMEDA), 30.9
(CH2, Et), 14.9 (CH3, Zn-Et), 8.9 (CH3, Et), 1.3 (CH2, Zn-Et).
1
19F{ H} NMR (298 K, C6D6): d -79.05.
Synthesis of [(TMEDA)Zn(tBu){OC(CF3)(H)Ph}] (4)
ZntBu2 (0.36 g, 2 mmol) was added to a solution of TMEDA
(0.3 mL, 2 mmol) in toluene (10 mL) affording a colourless
solution. Trifluoroacetophenone (1) (0.28 mL, 2 mmol) was then
introduced affording a bright orange solution which was allowed
to stir at room temperature overnight. Volatiles were removed
under vacuum affording an orange oil which was analysed by
multinuclear NMR spectroscopy. Attempts to grow crystals of
4 using different solvent systems such as neat hexane were
unsuccessful which indicates that this compound is highly soluble
in organic solvents. 1H NMR (298 K, C6D6) d 7.67 (2H, d, Hortho),
7.24 (2H, t, Hmeta), 7.14 (1H, t, Hpara), 5.47 (1H, q (J3H-F = 7.4 Hz),
O-CH), 1.95 (16H, s, broad, CH2 and CH3, TMEDA), 1.19 (9H, s,
2 See for example: (a) M. L. P. Price and W. J. Jorgensen, J. Am. Chem.
Soc., 2000, 122, 9455; (b) F. Xu, R. A. Reamer, R. D. Tillyer, J. M.
Cummins, E. J. J. Grabowski, P. J. Reider, D. B. Collum and J. C.
Huffman, J. Am. Chem. Soc., 2000, 122, 11212; (c) B. Jiang and Y.-G.
Si, Angew. Chem., Int. Ed., 2004, 43, 216.
3 (a) M. E. Pierce, R. L. Parsons Jr., L. A. Radesca, Y. S. Lo, S. Silverman,
J. R. Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D. Nguyen,
C. Luo, S. j. Morgan, W. P. Davis, P. M. Confalone, C.-Y. Chen, R. D.
Tillyer, L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thompson and E. G.
Corley, J. Org. Chem., 1998, 63, 8536; (b) J. W. Corbettt, S. S. Ko, J. D.
Rodgers, L. A. Gearhart, N. A. Magnus, L. T. Bacheler, S. Diamond,
S. Jeffrey, R. M. Klabe, B. C. Cordova, S. Garber, K. Logue, G. L.
Trainor, P. S. Anderson and S. K. Erickson-Vittanen, J. Med. Chem.,
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4 (a) P. Knochel and P. Jones, Organozinc Reagents, Oxford University
Press, Oxford, 1999; (b) For a recent review on enantioselective addition
of zinc reagents to ketones see: D. J. Ramon, M. Yus, Angew. Chem.
Int. Ed. 2004, 43, 284.
1
tBu). 13C{ H} NMR (298 K, C6D6) d 144.2, 128.4, 127.5, 126.6
(Ph), 128.0 (q, (J1 = 287.7 Hz), CF3), 78.8 (q (J2 = 27.8),
C-F
C-F
CH), 56.8, 47.2, 46.9 (CH3 and CH2, TMEDA), 34.5 (CH3, tBu),
5 K. Yearick and C. Wolf, Org. Lett., 2008, 10, 3915.
20.6 (C, tBu). 19F NMR (298 K, C6D6): d -77.85 (d).
6 Enantioselective synthesis of tertiary alcohols by reaction of diethylzinc
to trifluoromethyl ketones using polydentate N-donor ligands has
been also reported in the form of a patent by Sasaki et al, see: K.
Higashiyama, S. Sasaki, H. Kubo, T. Yamauchi, A. Ishii, M. Kanai,
Japanese Patent 200609692, April 13, 2006.
Synthesis of [(tBu)2Zn4{OC(CF3)(H)Ph}6] (5)
ZntBu2 (0.72 g, 4 mmol) was dissolved in 10 mL of n-hexane and
ketone 1 (0.56 mL, 4 mmol) was added affording a bright orange
solution. The solution was left stirring at room temperature for
2 hours, concentrated by removing some of the solvent under
vacuum. The Schlenk tube was placed in the freezer (-20 ◦C)
and left for several days. A batch of colourless crystals was
isolated (0.18 g, 13%, note maximum possible yield 16%). 1H
NMR (298 K, C6D6) d 7.77–6.82 (30H m, broad overlapping, Ph)
5.60–4.29 (6H, m, broad overlapping, CH), 1.36–0.57 (18H, m,
7 For selected references see: (a) H. R. L. Barley, W. Clegg, S. H. Dale,
E. Hevia, G. W. Honeyman, A. R. Kennedy and R. E. Mulvey, Angew.
Chem., Int. Ed., 2005, 44, 6018; (b) W. Clegg, S. H. Dale, R. W.
Harrington, E. Hevia, G. W. Honeyman and R. E. Mulvey, Angew.
Chem., Int. Ed., 2006, 45, 2374; (c) W. Clegg, S. H. Dale, E. Hevia,
L. M. Hogg, G. W. Honeyman, R. E. Mulvey and C. T. O’Hara, Angew.
Chem., Int. Ed., 2006, 45, 6548; (d) D. R. Armstrong, W. Clegg, S. H.
Dale, E. Hevia, L. M. Hogg, G. W. Honeyman and R. E. Mulvey,
Angew. Chem., Int. Ed., 2006, 45, 3775; (e) D. R. Armstrong, W. Clegg,
S. H. Dale, D. V. Graham, E. Hevia, L. M. Hogg, G. W. Honeyman,
A. R. Kennedy and R. E. Mulvey, Chem. Commun., 2007, 598; (f) D. R.
Armstrong, J. Garcia-Alvarez, D. V. Graham, G. W. Honeyman, E.
Hevia, A. R. Kennedy and R. E. Mulvey, Chem.–Eur. J., 2009, 15,
3800; (g) W. Clegg, B. Conway, E. Hevia, M. D. McCall, L. Russo and
R. E. Mulvey, J. Am. Chem. Soc., 2009, 131, 2375; (h) E. Hevia, A. R.
Kennedy, J. Klett and M. D. McCall, Chem. Commun., 2009, 3240.
8 (a) P. O’Brien, M. B. Hursthouse, M. Montevalli and J. R. Walsh,
J. Organomet. Chem., 1993, 449, 1; (b) D. V. Graham, E. Hevia, A. R.
Kennedy and R. E. Mulvey, Organometallics, 2006, 25, 3297.
9 Thus, the 1H NMR spectrum of free TMEDA in C6D6 solution displays
two singlets at 2.13 ppm (CH2N) and 2.08 ppm (NCH3), however,
1
broad overlapping, tBu). 19F{ H} NMR (298 K, C6D6): d -76.13
to -78.47 (broad overlapping).
Synthesis of PhC(H)(CF3)OH (6)
Isolated crystals of 5 (0.71 g, 0.5 mmol) were dissolved in toluene
(20 mL) and quenched with a saturated NH4Cl solution, extracted
with CH2Cl2 and dried with MgSO4. The solvents were removed
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The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 520–526 | 525
©

when TMEDA is solvating a metal centre, this relative positioning is
reversed: P. C. Andrews, N. D. R. Barnett, R. E. Mulvey, W. Clegg,
P. A. O. O’Neil, D. Barr, L. Cowton, A. J. Dawson and B. J. Wakefield,
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Rushworth, M. A. Malik, P. O’Brien and G. W. Critchlow, J. Mater.
Chem., 1994, 4, 1249; (b) J. Hambrock, S. Rabe, K. Merz, A. Bikner,
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19 Selected examples: (a) M. Olmstead, P. P. Power and S. C. Schoner,
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10 The variable temperature NMR studies were carried out in deuterated
toluene solutions due to the wider range of temperatures that this
solvent allow to study in comparison with deuterated benzene.
11 The same monomeric structural motif was found for 3 as indicated by
a preliminary X-ray crystallographic study. However due to the poor
quality of the data acquired and the high degree of disorder observed
for the alkoxide ligand, no discussion on this structure is included here.
12 S. Suh, L. A. Mˆıinea, S. Javed and D. M. Hoffman, Polyhedron, 2008,
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´
Lewin´ski, M. Dranka, W. Bury, W. Sliwin´ski, I. Justyniak and J.
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of the reasons for the disorder found for the refinement of the alkoxide
ligands in the X-ray crystallographic study.
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16 A wider search of the CCDB established that this Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn ◊ ◊ ◊ Zn
motif rarely occurs in any area of zinc chemistry. For rare examples see:
(a) Y. Kai, M. Morita, N. Yasuaoka and N. Kasai, Bull. Chem. Soc.
526 | Dalton Trans., 2010, 39, 520–526
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The Royal Society of Chemistry 2010
©