Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones

Article abstract of DOI:10.1021/acs.organomet.0c00005

The combination of [Cu(MeCN)₄]TFA·TFAH (TFA = O₂CCF₃) with Feringa's phosphoramidite ligand (L_A) provides an exceptionally active (0.75 mol %) catalyst for asymmetric conjugate additions of ZnR₂ (R = Et and Me at -40 to -80 °C) to enones. Kinetic and other studies of the addition of ZnEt₂ to cyclohex-2-en-1-one indicate a transition state stoichiometry composition of (ZnEt₂)₃(enone)₄Cu₂(L_A)₃ that is generated by transmetalation from Et₂Zn(enone)₂. Catalyst genesis is significantly slower than turnover (which has limited previous attempts to attain useful kinetic data); in the initial stages, varying populations of catalytically inactive, off-cycle, species are present. These issues are overcome by a double-dose kinetic analysis protocol. A rest state of [L_ACu(Et)(μ-TFA)(μ-{(enone)(ZnEt)₂(enolate)})CuL_A2]⁺ (through the equivalence of enolate = enone + ZnEt₂) is supported by DFT studies (ωB97X-D/SRSC). Rate-determining ZnEt₂(enone)₂ transmetalation drives the exceptionally high catalytic activity of this system.

Full text of DOI:10.1021/acs.organomet.0c00005

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Article
Mechanistic-Insight-Driven Rate Enhancement of Asymmetric
Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones
Ryan Nouch, Simon Woodward,* Darren Willcox, David Robinson, and William Lewis
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ABSTRACT: The combination of [Cu(MeCN)4]TFA·TFAH
(TFA = O2CCF3) with Feringa’s phosphoramidite ligand (LA)
provides an exceptionally active (0.75 mol %) catalyst for asymmetric
conjugate additions of ZnR2 (R = Et and Me at −40 to −80 °C) to
enones. Kinetic and other studies of the addition of ZnEt2 to
cyclohex-2-en-1-one indicate a transition state stoichiometry
composition of (ZnEt2)3(enone)4Cu2(LA)3 that is generated by
transmetalation from Et2Zn(enone)2. Catalyst genesis is significantly
slower than turnover (which has limited previous attempts to attain
useful kinetic data); in the initial stages, varying populations of
catalytically inactive, off-cycle, species are present. These issues are
overcome by a double-dose kinetic analysis protocol. A rest state of
[LACu(Et)(μ-TFA)(μ-{(enone)(ZnEt)2(enolate)})CuLA2]+ (through the equivalence of enolate = enone + ZnEt2) is supported by
DFT studies (ωB97X-D/SRSC). Rate-determining ZnEt2(enone)2 transmetalation drives the exceptionally high catalytic activity of
this system.
destabilizing the ground-state energy of precursor (1) by
anionic “X” ligand selection is much less appreciated; despite
the screening of libraries of copper salts being commonplace in
ACA reaction development. A complete understanding of the
intimate details of Scheme 12 which are responsible fast
turnover is highly desirable, as mechanism-inspired faster
catalysis would particularly benefit sluggish organozinc
additions where problematic lower reactivity (e.g., ZnMe2)
reagents are a known problem (see Table S1B and refs S17−
S95 for examples).
INTRODUCTION
■
The copper-catalyzed 1,4-addition of organometallics to
enones is typically proposed to proceed via evolution of a π-
enone complex, akin to 1, to a fleeting copper(III)
intermediate (2) whose reductive elimination to product 3 is
commonly proposed to be rate-limiting (Scheme 1).1,2 In
Scheme 1. Strategies for Increasing the Rate of
(Asymmetric) Conjugate Addition Reactions of
Organometallics (RM)
a
We speculated that the ground-state instability of unligated
Cu(O2CCF3), which has remained only scantly described since
its initial discovery in 1939,3 would lead to ligated copper
catalysts showing rapid 1,4-addition of diorganozincs to
enones. Furthermore, we postulated that its putative high
copper Lewis acidity and the presence of a 19F NMR tag would
render it more amenable to mechanistic study than traditional
copper carboxylate salts. Mechanistic kinetic study of ligand
promoted copper(I)-catalyzed ZnR2 1,4-addition to Michael
acceptors is rather limited, consisting of essentially just the
seminal work of Noyori4 and Schrader.5 The former concluded
a
Acrolein is shown as an exemplary enone.
asymmetric conjugate addition (ACA)1,2 versions of such
reactions, this latter step also defines the stereochemistry in the
1,4-product. Identifying ligands (L) which reduce the
transition state barrier to reductive elimination is a commonly
understood concept in achieving fast catalysis. Phosphoami-
dites and carbene (NHC) ligands have proved particularly
effective in this regard. However, the alternative strategy of
Received: January 6, 2020
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4 was the transition state for copper(I) sulphonamide
catalyzed additions of ZnEt2 (Zn) to cyclohex-2-en-1-one
(CX), and the latter concluded 5 was the transition state for
the same transformation catalyzed by Cu(OTf)2 in the
presence of chiral phosphoramide ligands (Scheme 2). As
observation that addition of PCy3 (2 equiv) leads to rapid
formation of Cu(TFA)(PCy3)2 (9) which is isolated in
quantitative yield. In the solid state, 7 is stable at 22 °C for
at least 1 day. Significant decomposition of solid 7 occurs
above 30 °C, even under inert atmospheres, due to MeCN
lability, while at −20 °C, 7 is stable for at least 1 month.
Demonstrating Catalytic Competence. As [Cu-
(MeCN)4]TFA·TFAH (7) had never been used as a 1,4-
catalyst precursor comparisons were made against benchmark
enones using the typical phosphoramidite (R,S,S)-LA (Fer-
inga’s ligand) in toluene (Scheme 3). Pleasingly, formation of a
Scheme 2. Published Proposals for the Transition State of
a
Copper(I)-Catalyzed 1,4-Additions of Zn to CX
Scheme 3. Benchmarking Enone Studies Demonstrating the
a b
,
High Activity of the (7)/LA Catalyst
a
Ligand LA contains a binaphthyl unit; LB contains a biphenyl.
induction periods4−6 and poor rate reproducibility7 have
frequently complicated kinetic studies of copper-based ACA
reactions, other approaches to arriving at catalytic cycle
proposals have been sought. Transition state 6 has been
proposed based on NMR studies of model complexes.8 While
no kinetic data is available for 6, combined computational and
synthetic studies also indirectly support this proposal.9
Aside from the early contributions of refs 4 and 5 and the
NMR studies of ref 8, unsupported conjecture has become the
norm for mechanistic descriptions of copper-catalyzed ZnR2
additions to enones. A quantified description of the reaction
behavior would be preferable for rational ACA Cu-catalyst
development, and such analysis is the target of this present
paper.
a
b
Full conversion is attained within 2 h at −80 °C. The lower isolated
yields reflect isolation issues for volatile products 10 associated with
toluene solvent removal, using Et2O results in yields in line with
conversion. Quantification against internal standards indicated
excellent conversion and mass balance.
RESULTS
■
Precatalyst Preparation. While unligated Cu(O2CCF3) is
stated to be intrinsically unstable,3 we reasoned [Cu-
−
(MeCN)4]TFA (TFA = F3CO2 ) would be an equivalent
catalyst precursor but an isolable salt similar to others of this
type.10 Reaction of Cu2O with 2.55 equiv of trifluoroacetic acid
(TFAH) in MeCN at room temperature leads to rapid
formation of colorless [Cu(MeCN)4]TFA·TFAH (7) in 74%
yield. All spectroscopic and analytical data are consistent with
this formulation. In solution, especially above −20 °C in the
absence of added ligands, 7 decomposes over 24−36 h to
{[Cu(MeCN)4]2[A]}∞ (8) where A is the chain-linked
polynuclear anion [Cu4(TFA)10]2− detectable by X-ray
crystallography (see Figure S1). At room temperature,
however, solutions of 7 retain their integrity for at least 60
very active catalyst system for 1,4-ZnR2 (R = Et and Me)
addition products 10 using only 0.75 mol % 7 was observed
(Scheme 3) even at rather low temperatures (−80 °C). For
comparison, of the 100 published most active and selective
(≥80% ee) literature ZnR2 Cu-catalyzed ACA reactions to CX
we could find, only four afford any conversion below −75 °C
(Table S1). For both ethyl and methyl additions to CX,
catalyst 7/LA was the highest performing catalyst in terms of
activity, with excellent stereoselectivity across this wide family.
Quantified yields of 10 against internal standards were good
to excellent, although volatile products caused isolation issues
when using toluene, an issue that could be avoided by using
Et2O as the solvent. The reactions are extremely clean, and
unexpected byproduct formation was noted only in HCl
quenching of the kinetic enolate (E). Such approaches result in
1
min allowing characterization by H, 31P (via P-ligation), and
19F NMR spectroscopy and confirming (1H NMR) the
CF3CO2H (TFAH) solvation.11 The viability of using 7 in
solution as a P-ligand catalyst precursor is indicated by the
B
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partial formation of aldol product 11 (Scheme 4) resulting
from direct reaction of liberated 10a with its own partially
to a Zn bound adduct(s). Unlike our previous work with
AlEt3,6 no significant color change is seen for these adducts.
We compared the fit of Zn (Zn) binding isotherms leading to
formation of mono and di CX adducts (12 and 13,
respectively) and for the formation of dimeric 14 (Scheme
6). Free coordination sites were assumed to be bound by
a
Scheme 4. Formation of Byproduct 11
a b
,
Scheme 6. Adduct Formation between CX and Zn
a
This was, in some cases, apparently previously erroneously attributed
to CX “double Michael addition”.
quenched enolate. This behavior could be confirmed by
independent reaction with authentic 10a giving moderate
yields (59%) of 11. The reaction is quite stereoselective and in
accord with the expected Zimmerman−Traxler control (A,
Scheme 4). Surprisingly, 11 has apparently not been reported
before, but is likely the source of at least some of the poorly
characterized “dimer” products that have been previously
noted in ACA reactions of CX.12 Byproduct 11 could,
however, be completely avoided by initial quenching of the
reaction mixture at −40 °C with methanol prior to HCl
addition.
a
Large standard deviations occur for high values of β2 attained by
such titration methods (see Figure S5 and ref S97). However, the
much poorer fit of the data to 14 indicates that formation of 12 or 13
Solvent Effects and Cyclohex-2-en-1-one (CX) Lewis
Acid Binding. Cyclohex-2-en-1-one (CX) conversion to 10a
(by low-temperature MeOH quench) after 45 min of reaction
b
is very significantly more favored. The figures in parentheses after the
equilibrium values indicate the standard deviation in the last
significant figure.
1
at −78 °C was monitored by H NMR spectroscopy as a
function of solvent (Scheme 4). The behavior of EtOAc and
THF suggests inhibition by base binding to a Lewis acidic
component of the catalyst system. However, the inhibition
trend does not follow published solvent donor abilities. As Zn
is expected to be the most Lewis acidic component within the
catalyst system, its behavior toward CX was studied by ReactIR
in toluene and Et2O. Both these solvents afford rapid catalytic
conversion, despite their very different classical donor number
ratings13 (Scheme 5).
solvent (whose bulk concentration remains unchanged). For
both toluene and Et2O formation of mono adduct (12) is
nominally the best fit, but not significantly favored over di-
coordinated (13). The fit to dimer (14) formation is poorer
but with high β2 values. The correlation of the equilibria values
of Scheme 6 (assuming that the CX substrate acts as a simple
ketone-like donor) versus classical solvent donor number
order13 indicates the inhibition of Scheme 5 is associated with
Cu(I) Lewis acid coordination, not Zn binding. The potential
for 12−14 to undergo rapid exchange is supported by
additional experiments in CH2Cl2 where a broad envelope of
signals is seen in the ReactIR spectrum (Figure S2). Potential
rapid exchange of 12−14 means that the transmetalating
species involved in reloading the Cu catalyst cannot easily be
uniquely identified or accurately quantified. For this reason we
chose to monitor catalytic reactions by formation of the
product enolate (E) (Scheme 4). Dichloromethane is the
preferred ReactIR solvent for these studies as the ν(C−O) at
1145 cm−1 of enolate E is easily detected in this solvent, while
overlaps with solvent vibrations are encountered in toluene
and Et2O solvents. A further advantage of CH2Cl2 is that the
rate of the catalytic 1,4-addition is slow enough in this solvent
to allow direct monitoring of the reaction mixture by both
multinuclear NMR and ReactIR under identical conditions.
Formation of the Active Catalyst. The 1,4-addition of
Zn to CX under 7/LA catalysis leads to 10a (after quench)
with a time- (and run)-independent ee of 96% over the ca. 700
s needed to attain complete conversion at −40 °C. This
implies a single selective copper catalyst (transition state)
delivers the enolate product (R)-E. However, replicate ReactIR
In both toluene and Et2O, two carbonyl bands at ca. 1685
and 1660 cm−1 are seen as Zn is titrated into CX (Figure S1).
The former corresponds to free CX, and the latter corresponds
Scheme 5. Relative Conversion of Cyclohex-2-en-1-one CX
a b
,
versus Reaction Solvent
a
1
Determined by H NMR spectroscopy after quench with methanol;
all reactions, except those in THF, proceeded to completion if left
b
long enough. Solvent binding energy to the “hard” Lewis acid
SbCl5.13
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studies of such first dose addition of mixtures of Zn and CX
show very poor run-to-run reproducibility with k1 = 4.3 × 10−3
to 8.6 × 10−3 s−1 varying in a stochastic manner (Figure S7)
implying the presence of competing catalytic and noncatalytic
species. Similar rate variation observations are present in the
supporting data of Pfretzschner.7 Suspecting a slow varying
induction period, lasting most of the initial reaction, was the
cause of the poor reproducibility in these first run dose
reactions we used multiple dosing experiments to probe for
this possibility (Figure 1). Addition of a second dose and then
and kinetic studies) is added to this mixture, the separate 31P
NMR signals collapse into a broad baseline signal by the end of
the 10 min needed for complete conversion of CX to the
enolate product (E). This collapse of 31P NMR signal intensity
is not due to catalyst deactivation. The NMR experiment is
under identical conditions of Figure 1 where the rates in the
second- and third-dose experiments (allowing for the dilution
caused by adding additional Zn and CX) remain constant,
inconsistent with any catalyst deactivation. The 31P NMR
behavior is, however, consistent with initial formation of off-
cycle copper species, related to those of von Rekowski8d that
evolve during conversion of CX into the true catalyst (Cu).
The slow emergence of a final, rapidly equilibrating, catalyst is
supported by the 19F NMR spectra of the initial reaction
mixture (Figure S6). Immediately after Zn addition, two new
major sharp signals appear at δF −75.7 and −76.0. The former
is at a chemical shift with experimental error for independently
prepared uncoordinated trifluoroacetate δF −75.6, the latter
that for CF3CO2H (δF −76.1).14 These signals convert to a
new species at δF −75.8. Upon addition of CX, catalysis ensues
and the 19F NMR signals collapse to a broad envelope at −75.6
ppm accounting for the vast majority of the signal. Such
behavior is expected for a trifluoroacetate anion undergoing
rapid exchange into a slowly formed final catalyst (Cu).
Reaction Component Orders for the 7/LA/Zn/CX
System. Double-dosing approaches (see Figure S8) allowed
reproducible (rate 2−4%) behavior for the true catalyst Cu
(derived from 7/LA). Preliminary studies revealed that
although the Cu-catalyzed conversion of Zn/CX into enolate
E strictly follows first-order kinetics (R2 = 0.99−0.999+ for all
runs)15 nonunitary reaction orders result. Additionally, the
preliminary studies showed that at [LA]/[Cu] ratios below 0.8
and above 2.1 the reaction homogeneity and strong reaction
inhibition respectively prevent the attainment of accurate
kinetic data. The air sensitivity of the system makes
determination of the order in Zn particularly challenging.
Within these limitations we set out to estimate the reaction
rate order dependence for all the components in the equation,
rate ∝ [Zn]a[CX]b[Cu]c[LA]d, for the ligand-accelerated
process catalyzed by 7/LA by studying the dependence of
the observed rate k1 (Table 1). By targeting [Cu]0 = 1.7 0.1
mM, [LA]0 = 3.4 0.4 mM, and [CX]0 = 220 27 mM, we
could estimate the order in Zn to be [Zn]0.217(30) for [Zn] 76−
347 mM (R2 = 0.94, Figure S9). By maintaining [Cu]0 = 1.7
0.06 mM, [LA]0 = 3.6 0.04 mM, and [Zn]0 = 285 9 mM,
the order in CX is determined to be [CX]0.272(20) for [CX] 72−
275 mM (R2 = 0.99, Figure S9). At [Zn]0 = 277 5 mM and
[CX]0 = 235 2 mM and at fixed LA/Cu = 2.00 0.08, the
order in the copper is determined as [Cu]0.123(4) for [Cu]
Figure 1. ReactIR observation of the 7/LA-catalyzed formation of
enolate (E) via its 1145 cm−1 band in a multiple-dose experiment. As
each reaction is completed, fresh Zn and CX are added, and catalysis
restarts. First-dose experiments show poor reproducibility (see Figure
S7), but the first-order rate constants derived from the second and
third doses show good reproducibility when allowing for the dilution
occurring in the reaction from the second to the third dose.
a third dose of Zn and CX after completion of the initial first-
dose reactions confirms the (concentration-corrected) first-
order rate constants of the latter two additional dose reactions
are identical and reproducible when allowing for the dilution of
the reaction (Figure 1) and are independent of the enolate
concentration. These observations indicate not only that a
variable composition of copper(I) species is present during the
initial dose reactions but also that only one of these species
(Cu) is catalytically competent for the transformation of CX
into 96% ee enolate (E).
Multinuclear NMR studies, under identical conditions to the
first-dose addition of Figure 1, support these ideas. Mixtures of
(R,S,S)-LA and 7 (2:1) show broad envelope signals at δP ∼
123.9 and δF ∼ −5.8 indicative of rapid ligand exchange at −40
°C.14 The line broadening of the associated H NMR methyl
1
signals of LA at that temperature is ∼5 Hz. (An exchange rate
of around 16 s−1 can be calculated from this via standard
approaches.5 Thus, LA exchange is >103 faster than the
catalytic conversion of CX to E) Using standard Eyring
analysis5 this corresponds to an energy barrier for LA exchange
of 12.3 kcal mol−1, similar to the value of 11.1 kcal mol−1 that
Pfretzschner measured for a related phosphoramidite ligand.5
After the addition of excess Zn (165 equiv relative to 7
present; identical concentrations to the synthetic and kinetic
studies) at −40 °C a mixture of species is formed (Figure S6)
whose major components by 31P NMR are δP 123.0, 123.8, and
124.8. These shifts are at similar values to those of the species
(LB)2Cu(μ-Et)(μ-I)CuEt (121.5 ppm), LBCuEt (124.0 ppm),
[LBCu(ZnEt2)]I (126.0 ppm), and (LB)2Cu(μ-Et)(μ-I)ZnEt
(126.1 ppm) at −103 °C in CD2Cl2 at a ratio of 46:28:19:7
characterized by von Rekowski via exquisite 2D NMR
techniques.8d However, in our case, once CX (130 equiv
relative to initial 7; identical concentrations to the synthetic
0.87−3.61 mM (R2 = 0.999, Figure S9). For [Zn]0 = 287
8
mM, [CX]0 = 231 5 mM, and with [Cu]0 = 1.75 0.08
mM, the ligand acceleration order is [LA]0.175(20) for [LA]
1.59−3.37 mM (R2 = 0.99, Figure S9). Thus, the full rate law is
o f
t h e
f o r m
r a t e
∝
[Zn]0.217(30)[CX]0.272(20)[Cu]0.123(4)[LA]0.175(20). Duplicated/re-
analyzed data are in accord with these values and error bars.
Strong ligand inhibition of the catalytic reaction, when [LA]/
[Cu] ≥ 2, limited the range of ligand concentrations that could
be employed, but using the data of Table 1, a deaccelerating
order of [LA]−0.25 could be estimated for this process.
D
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Table 1. Summary of the ReactIR Investigations Carried
Out in This Study
Scheme 7. Proposal for Catalytic Turnover in 7/LA-
Catalyzed Addition of Zn to CX
[Zn]0
run (mM)
[CX]0
(mM)
[Cu]0
(mM)
[LA]0
a
(mM) [LA]/[Cu] k1 × 103 (s−1
)
1
2
3
4
5
6
7
8
276
295
203
286
275
72.3
246
233
190
221
233
235
236
235
233
1.70
1.76
1.84
1.75
1.56
1.70
0.87
3.61
2.70
1.86
1.78
3.62
3.57
3.81
3.65
3.02
3.44
1.81
7.13
5.30
2.40
1.59
2.13
2.03
2.08
2.08
1.94
2.03
2.08
1.98
1.96
1.28
0.89
13.9(3)
9.5(1)
12.7(3)
12.9(3)
10.9(4)
15.4(3)
13.8(3)
17.5(1)
17.0(1)
14.3(5)
12.0(4)
76.2
347
282
278
272
280
296
9
10
11
a
For formation of enolate E, a k1 value of 13.9(3) equates to
0.00139(3) s−1. All rate constants refer to catalytic conversion of
second doses of Zn and CX in CH2Cl2 at −40 °C.
(see Table S1). Due to extensive exchange, it is not possible to
explicitly identify E·CX byproduct of catalytic turnover (Figure
S8). However, there is strong indirect evidence that Zn(CX)2
(13) is vital in the transmetalation. Attempted use of well-
characterized Et3Al(CX)6 as a terminal ethyl source in the 7/
LA catalytic system leads to only background reactions at low
rate strongly implying that 13 is vital for the transmetalation.
Blockage of the copper(I) Lewis acid centers in (15) leads to
complete deactivation. Either ligand LA itself [forming
(LA)2CuX, X = Et, O2CCF3, enolate type species] (see
Supporting Information, section 7) or strongly coordinating
solvents can fulfill this role. Alternative models to Scheme 7
were considered. The possibility that catalysis proceeds via a
[(LA)3Cu(CX)]+ (16) cation that is attacked by an unligated
complex cuprate (Scheme 8) is attractive as a related
phosphoamidite specie L3CuI was identified in the seminal
work of Feringa.16
DISCUSSION
■
A viable mechanistic model for the 7/LA-catalyzed trans-
formation of Zn and CX into its enolate product (E) has to
explicitly account for (i) the nonunitary orders of the reagent
dependencies and (ii) the poor “first-dose” rate reproducibility,
but consistent high enantioselectivity, observed (Figure 1).
The former dictates that equilibria15 are closely tied to the
rate-determining step that generates 96% ee E. The latter
requires either very slow catalyst genesis or that the reaction
generates a promoter, not initially present in the mixture, that
facilitates formation of the active catalyst “Cu” while
unpromoted copper species remain as off-cycle spectators
(with k1 ∼ 0 s−1). We have previously shown in related
aluminum chemistry that enolate product E can play such an
acceleration role.6
The observed rate law [Zn]0.217[CX]0.272[Cu]0.123[LA]0.175
provides an estimated stoichiometric ratio of
Zn3.5CX4.4Cu2.0LA2.9 (coefficients 0.3) for events closely
related to the transition state. One model consistent with
this result is shown in Scheme 7. Catalysis proceeds by
exchange between two C2 related species 15 (Scheme 7). The
rate determining step is asymmetric 1,4-addition driven by
transmetalation with Et2Zn(CX)2 (13). Species 15 has
stoichiometry Cu2LA3Zn2CX2 (through E  CX + Zn),
which in combination with Zn(CX)2 (13), provides the
observed Zn3CX4Cu2LA3, transition state stoichiometry for
rate-determining transmetalation (see Scheme S8).
Proposed 15 is consistent with (i) the overall first order, but
partial order, in [Cu] behavior, (ii) the need for enolate (E) to
be present for maximal reproducible reaction rates, (iii) the
optimal 2:3 Cu/LA ratio detected in previous NMR studies of
related model systems,8 and (iv) the observation that initial
mixtures of off-cycle copper-complexes8d converge to an
equilibrating highly active single catalyst. We propose the
cationic nature of 15 is critical to engendering the extremely
rapid catalytic conjugate addition and transmetalation that are
required for such rapid catalyst turnover with ZnR2 reagents
While calculated cation 16 (ωB97X-D/SRSC, see Figures
S12 and S13) does predict that the correct Si enantioface of
the CX is preferentially bound, which would provide (R)-E
[and ultimately (R)-10a] on attack by an external Cu-Et
nucleophile, inspection of the calculated structure indicates
that it is excessively cluttered, and such nucleophilic attack
would be extremely hindered. A transition state resulting from
transmetalation of 17 (Scheme 8) with Zn(CX)2 (13) would
also be in agreement with the observed rate law, and this could
not be explicitly discounted on kinetic data alone. However, on
the basis of DFT modeling, 15 is the preferred structure, as
structure 17 and species derived from it are computationally
very poorly behaved.
CONCLUSIONS
■
Study of the highly active ACA catalyst derived from
[Cu(MeCN)4]TFA·TFAH (7)/(R,S,S)-LA reveals why extrac-
tion of mechanistic information from Cu(I)-catalyzed reactions
of enones with diorganozinc species has previously proved
highly challenging.5,7 Genesis of the active catalyst is slow
compared to catalyst turnover, and the fraction of active
catalyst present early in the reaction is variable. This has not
E
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Scheme 8. Alternative but (Computationally) Disfavored Transition State Compositions in Accord with the Derived Rate Law
been appreciated before. Double-dosing kinetic experiments
point to transition state of composition
Darren Willcox − GSK Carbon Neutral Laboratories for
Sustainable Chemistry, University of Nottingham, Nottingham
NG7 2TU, United Kingdom; Department of Chemistry, The
University of Manchester, Manchester M13 9PL, United
Kingdom
David Robinson − Department of Chemistry and Forensics,
School of Science and Technology, Nottingham Trent University,
Nottingham NG11 8NS, United Kingdom; orcid.org/0000-
0003-2760-7163
a
(ZnR2)3(enone)4Cu2L3 associated with a first-order trans-
formation strongly coupled to a faster exchange processes.
Once simple picture consistent with this picture is a rate-
determining transmetalation that also triggers the ACA
reaction (Scheme 7). While the real system undoubtedly has
other competing processes, this appears to be the major
catalytic manifold. Such a picture is also broadly consistent
with the Cu2L3 model proposed by Gschwind,8 but some
modification is required to her original proposal (see 6 within
Scheme 2). Specifically, expulsion of one of the μ-X (X =
O2CCF3) units in 6 and the coordination of additional
equivalents of ZnEt2(enone)2 are required to fit the
experimental data in our own particular case. It is likely that
the cationic nature of 15 accounts for the higher catalytic
activity that is seen in ACA systems attained from copper(I)
precursors with weakly cuprophilic basic anions (pKaH ≤ 1) in
general and in the case of 7 specifically.
William Lewis − School of Chemistry, University of Nottingham,
Nottingham NG7 2RD, United Kingdom; School of Chemistry,
University of Sydney, Sydney 2006, New South Wales, Australia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00005
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the Engineering and Physical Sciences
Research Council (EPSRC) for support facilities and access
to ReactIR through awards EP/L015633/1 and EP/S022236/
1. R.N. and D.W. thank Aesica Pharmaceuticals and the
University of Nottingham respectively for partial studentship
funding respectively, supplementing EPSRC studentships.
EXPERIMENTAL SECTION
Full experimental details of all compounds and kinetic procedures are
detailed in the Supporting Information.
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00005.
■
sı
REFERENCES
■
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compounds (PDF)
Cartesian coordinates for compounds 15−17 (XYZ)
Accession Codes
CCDC 1975639 contains the supplementary crystallographic
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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