Intermediates Formed in the Reactions of Organocuprates with α,β-Unsaturated Nitriles

Article abstract of DOI:10.1002/chem.201602451

Conjugate additions of organocuprates are of outstanding importance for organic synthesis. To improve our mechanistic understanding of these reactions, we have used electrospray ionization mass spectrometry for the identification of the ionic intermediates formed upon the treatment of LiCuR₂?LiCN (R=Me, Bu, Ph) with a series of α,β-unsaturated nitriles. Acrylonitrile, the weakest Michael acceptor included, did not afford any detectable intermediates. Fumaronitrile (FN) yielded adducts of the type Li_n?1Cu_nR_2n(FN)_n^?, n=1–3. When subjected to fragmentation in the gas phase, these adducts were not converted into the conjugate addition products, but re-dissociated into the reactants. In contrast, the reaction with 1,1-dicyanoethylene furnished the products of the conjugate addition without any observable intermediates. Tri- and tetracyanoethylene proved to be quite reactive as well. The presence of several cyano groups in these substrates opened up reaction pathways different from simple conjugate additions, however, and led to dimerization and substitution reactions. Moreover, the gas-phase fragmentation behavior of the species formed from these substrates indicated the occurrence of single-electron transfer processes. Additional quantum-chemical calculations provided insight into the structures and stabilities of the observed intermediates and their consecutive reactions.

Full text of DOI:10.1002/chem.201602451

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DOI: 10.1002/chem.201602451
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Reaction Intermediates
Intermediates Formed in the Reactions of Organocuprates with
a,b-Unsaturated Nitriles
Aliaksei Putau, Harald Brand, and Konrad Koszinowski*[a]
Abstract: Conjugate additions of organocuprates are of out-
standing importance for organic synthesis. To improve our
mechanistic understanding of these reactions, we have used
electrospray ionization mass spectrometry for the identifica-
tion of the ionic intermediates formed upon the treatment
of LiCuR2·LiCN (R=Me, Bu, Ph) with a series of a,b-unsaturat-
ed nitriles. Acrylonitrile, the weakest Michael acceptor in-
cluded, did not afford any detectable intermediates. Fumaro-
nitrile (FN) yielded adducts of the type Linꢀ1CunR2n(FN)nꢀ, n=
1–3. When subjected to fragmentation in the gas phase,
these adducts were not converted into the conjugate addi-
tion products, but re-dissociated into the reactants. In con-
trast, the reaction with 1,1-dicyanoethylene furnished the
products of the conjugate addition without any observable
intermediates. Tri- and tetracyanoethylene proved to be
quite reactive as well. The presence of several cyano groups
in these substrates opened up reaction pathways different
from simple conjugate additions, however, and led to dime-
rization and substitution reactions. Moreover, the gas-phase
fragmentation behavior of the species formed from these
substrates indicated the occurrence of single-electron trans-
fer processes. Additional quantum-chemical calculations pro-
vided insight into the structures and stabilities of the ob-
served intermediates and their consecutive reactions.
ganocuprate.[6,7,9–11] The formation of these adducts is reversi-
ble,[8,12] which suggests that the interaction between the p
electrons of the C=C double bond and the CuI center is rela-
tively weak. Accordingly, these adducts are often referred to as
p complexes and considered intermediates distinct from the b-
cuprio(III) enolates, in which the cuprate moiety forms
a s bond to the b-carbon atom. Quantum-chemical calcula-
tions suggest, however,[4,14,15] that this distinction is probably
artificial and that the p complex, the cuprio enolate, as well as
the cupracyclopropane should better be viewed as different
resonance structures describing one and the same intermedi-
ate (Scheme 1).[16] Depending on the substituents of the orga-
nocuprate and the substrate, the relative weight of these three
resonance structures will differ.[11]
Introduction
Conjugate additions of organocuprates continue to be one of
the most important methods for CꢀC bond formation in or-
ganic synthesis.[1] The mechanism of these reactions has
always aroused keen interest. Early studies suggested the oper-
ation of single-electron transfer (SET) processes between the
organocuprate and the Michael acceptor substrate.[2] As evi-
dence for such processes has not materialized, however, they
are no longer considered as likely reaction pathways, except
for the most electrophilic Michael acceptors.[3] Instead, conju-
gate additions of organocuprates are now generally believed
to proceed through addition/elimination sequences.[4] The cen-
tral intermediate of this mechanism corresponds to an adduct
of the two reactants, in which the copper center interacts with
the C=C double bond of the Michael acceptor (Scheme 1). Ex-
perimental support for such species mainly comes from low-
temperature NMR spectroscopy, which finds large upfield shifts
of the resonances of the a- and b-carbon atoms of the Michael
acceptor and a decrease in their coupling constants upon
mixing with the organocuprate.[5–13] When a,b-unsaturated car-
bonyl compounds are used as substrates, NMR spectroscopy
also points to secondary interactions between the oxygen
atom of the carbonyl group and the Li+ counterion of the or-
The transfer of one of the organyl groups from the copper
center to the b-carbon atom (often referred to as reductive
elimination) furnishes a lithium enolate in the rate-limiting
step of the overall sequence (Scheme 1).[4b] The lithium enolate
gives the final addition product after aqueous work-up or can
be trapped by another electrophile. For the adducts of a,b-un-
saturated carbonyl compounds, the activation energy of the
reductive elimination is relatively small (EA ꢁ80 kJmolꢀ1),[17]
which explains the need for low temperatures to intercept
these fleeting intermediates.
Although the main features of the mechanism of conjugate
additions of organocuprates are known, several important as-
pects require further attention. For instance, the reaction inter-
mediates have been shown to form higher aggregates in di-
ethyl ether, the solvent used most commonly for this type of
reaction.[10b] So far, only a limited number of these aggregates
have been characterized.[10] Likewise, the microscopic reactivity
[a] Dr. A. Putau, Dr. H. Brand, Prof. Dr. K. Koszinowski
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen, Tammannstr. 2
37077 Gçttingen (Germany)
E-mail: konrad.koszinowski@chemie.uni-goettingen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602451.
Chem. Eur. J. 2016, 22, 1 – 10
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Figure 1. Substrates considered in the present work.
the partial consumption of the dimethylcuprate reactant and
the formation of product ions with decreased Me/Cu ratios,
ꢀ
such as LiCu2Me3(CN)ꢀ and LiCu2Me2(CN)2 (Figure S1 in the
Scheme 1. Generally accepted mechanism for the conjugate addition of lith-
ium organocuprates to acrolein. For simplification, only a single bridging Li
center is drawn although the actual intermediates presumably contain poly-
nuclear Li bridges.
Supporting Information). No reaction intermediates could be
ꢀ
observed, however. In all other cases, only Linꢀ1CunR2n anions
characteristic of solutions of the reactant diorganylcuprates
were detected (Figures S2–S4 in the Supporting Information).
+
of the intermediates has only been studied theoretically, but
not experimentally. To shed more light on these problems, we
here turn to electrospray ionization (ESI) mass spectrometry,
which can provide information on organocuprates comple-
mentary to that obtained by NMR spectroscopy by selectively
probing the charged species present in solution. Previous work
has shown that this method is well-suited to detect and char-
acterize even highly reactive organocopper ions.[18–20] Gas-
phase experiments on mass-selected organocopper ions, more-
over, make it possible to probe their intrinsic reactivity in un-
precedented detail and without any interference from dynamic
equilibria,[19–21] which severely complicate their analysis in solu-
tion.[22]
In the positive-ion mode, exclusively Li(solv)n
and
+
Li2CN(solv)n were found (n=2, 3 for solv=THF and n=1, 2
for solv=Et2O, Figures S5 and S6 in the Supporting Informa-
tion).
Reactions of diorganylcuprates with fumaronitrile
The reactions of LiCuR2·LiCN (THF: R=Me, Bu, Ph; Et2O: Bu)
with 1 equivalent of fumaronitrile (FN) afforded dark-brown
solutions. Their analysis by negative-ion mode ESI mass spec-
trometry showed the presence of several complexes of the
type Linꢀ1CunR2n(FN)nꢀ, besides the organocuprate anions al-
ready known and mentioned above (Figure 2 and Figures S7–
S13 in the Supporting Information). The fumaronitrile-contain-
ing complexes displayed a very limited macroscopic stability,
which decreased in the order of Bu>Me>Ph. In line with
their relatively higher stability, the complexes derived from di-
butylcuprate, that is, Linꢀ1CunBu2n(FN)nꢀ, were particularly abun-
dant and formed aggregates with n=1–3 (Figure 2). Upon
changing the solvent from THF to Et2O, the signal intensity of
the largest aggregate (n=3) strongly increased, whereas that
of the medium one (n=2) remained rather small (Figure 2).
The reactions of LiCuR2·LiCN, R=Me and Ph, only produced
the mononuclear complexes CuR2(FN)ꢀ (Figures S7, S8, S12,
and S13).
As the addition of organocuprates to a,b-unsaturated car-
bonyl compounds proceeds too fast to intercept the involved
intermediates by ESI mass spectrometry, we employed the less
reactive a,b-unsaturated cyanoethylenes (C2H4ꢀn(CN)n, n=1–4;
Figure 1) as Michael acceptors. The systematic variation of the
number and position of the cyano groups in these substrates
permits us to fine-tune their electronic properties and probe
the resulting effects on their reactivity toward prototypical cya-
nocuprates LiCuR2·LiCN (R=Me, Bu, Ph) in THF as well as, for
selected cases, in Et2O. To aid in the interpretation of the ESI-
mass spectrometric data, we also performed quantum-chemi-
cal calculations. The goal of these calculations was to obtain
qualitative insight into the structures and stabilities of relevant
complexes in the gas phase, but not to model the full reaction
sequence of the probed systems.
ꢀ
Gas-phase fragmentation of the complexes Linꢀ1CunR2n(FN)n
resulted in the liberation of fumaronitrile in all cases [Figure 3
and Figures S14–S17 in the Supporting Information; Eq. (1)].
For the lithium-containing species, n=2, 3 and R=Bu, these
processes were accompanied by the hydrolysis of one or two
butyl substituents in ion–molecule reactions involving traces of
water present in the vacuum system of the mass spectrometer
[Eq. (2) with n=2, 3, x=0–n, and z=1, 2]:
Results
ESI mass spectrometry
Reactions of diorganylcuprates with acrylonitrile
Upon the addition of 1 equivalent of acrylonitrile, ethereal sol-
utions of LiCuR2·LiCN (THF: R=Me, Bu, Ph; Et2O: Bu) turned
yellow and yielded precipitates.[23] For the case of LiCu-
Me2·LiCN, negative-ion mode ESI mass spectrometry showed
ꢀ
Linꢀ1CunR2nðFNÞn ! Linꢀ1CunR2nðFNÞnꢀ1ꢀ þ FN
ð1Þ
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rates and the formation of their cyanide-containing counter-
parts (Figures S20–S24 in the Supporting Information), whereas
no anions indicative of a reaction were found in Et2O (Fig-
ure S25 in the Supporting Information). For the reaction of
LiCuBu2·LiCN in THF, we detected complexes that we assigned
as
LiCu2Bu2(C(CN)2–CH2Bu)(CN)ꢀ
and
Li2Cu2Bu2(C(CN)2–
ꢀ
CH2Bu)(CN)2 (Figures S21–S23). These assignments were based
on their gas-phase fragmentation, which led to the loss of
CuBu and Li2(C(CN)2–CH2Bu)(CN) [Eqs. (3) and (4); Figures S26
and S27 in the Supporting Information], respectively. The reac-
tion of the organocuprates with 1,1-dicyanoethylene, thus, ap-
parently proceeded all the way to the addition products with
the formation of new carbon–carbon bonds.
LiCu2Bu2ðCðCNÞ2ꢀCH2BuÞðCNÞꢀ
!
ð3Þ
ð4Þ
LiCuBuðCðCNÞ2ꢀCH2BuÞðCNÞꢀ þ CuBu
Figure 2. Negative-ion mode ESI mass spectrum of solutions of the products
formed in the reaction of LiCuBu2·LiCN with fumaronitrile (FN) in THF (front)
and Et2O (back).
ꢀ
Li2Cu2Bu2ðCðCNÞ2ꢀCH2BuÞðCNÞ2
!
Cu2Bu2ðCNÞꢀ þ Li2ðCðCNÞ2ꢀCH2BuÞðCNÞ
The inferred presence of addition products was also clear
from the positive-ion mode ESI mass spectra. Besides cations
+
of the type Li(solv)n and Li2(CN)(solv)n+, n=2, 3, these spectra
+
showed complexes of the composition Li2(C(CN)2–CH2R)(solv)2
(THF: R=Me, Bu, Ph; Et2O: R=Bu; Figure 4 and Figures S28–
S34 in the Supporting Information). The observation of these
ions unambiguously proved the occurrence of carbon–carbon
bond formation. Upon fragmentation in the gas phase, the
+
Li2(C(CN)2–CH2R)(solv)2 cations mainly lost one solvent mole-
cule or exchanged it for one water molecule (Figures S35–S38
in the Supporting Information).[24]
Figure 3. Mass spectrum of mass-selected CuBu2(FN)ꢀ (m/z 255) and its frag-
ment ion produced upon collision-induced dissociation (Vexc =0.21 V).
Linꢀ1CunBu2nðFNÞxꢀ þ z H2O ! Linꢀ1CunBu2nꢀzðOHÞzðFNÞxꢀ þ z BuH
ð2Þ
+
+
In the positive-ion mode, mainly Li(solv)n and Li2CN(solv)n
(n=2, 3 for solv=THF and n=2 for solv=Et2O, Figures S18
and S19 in the Supporting Information), but also a few organo-
+
copper
cations,
such
as
Li2CuBu(OH)(Et2O)2
and
+
Li2CuBu(CN)(Et2O)2 (Figure S19), were found.
Figure 4. Positive-ion mode ESI mass spectrum of a solution of the products
formed in the reaction of LiCuBu2·LiCN with 1,1-dicyanoethylene in THF.
Reactions of diorganylcuprates with 1,1-dicyanoethylene
When neat 1,1-dicyanoethylene was added to organocuprate
solutions in THF or Et2O, a bead of solid material was formed
instantly, thus already pointing to the high reactivity of this
substrate. To overcome this difficulty, 1,1-dicyanoethylene was
first dissolved in THF or Et2O, respectively, before its addition
to the organocuprates. Upon analysis by negative-ion mode
ESI mass spectrometry, the solutions in THF showed the com-
plete or partial consumption of the reactant organyl-rich cup-
Reactions of diorganylcuprates with tricyanoethylene
Reactions of diorganylcuprates with tricyanoethylene in THF af-
forded orange-brown solutions (the analogous experiments in
Et2O could not be performed because the corresponding
sample solutions caused immediate clogging of the ESI capilla-
ry). Analysis by negative-ion mode ESI mass spectrometry first
identified cyanide-containing organocuprates, such as
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ꢀ
Cu2R2(CN)ꢀ and LiCu2R2(CN)2 (R=Me, Bu, Ph), which indicated
the consumption of the reactant diorganylcuprates (Figur-
es S39–S45 in the Supporting Information). In addition, the re-
actions with the dialkylcuprates LiCuR2·LiCN, R=Me, Bu, afford-
ed copper-free anions XRꢀ =[HC4(CN)5R]ꢀ, which must have ori-
ginated from dimerization of the substrate. For the reaction of
LiCuBu2·LiCN, we also observed an organocuprate complex
ꢀ
ꢀ
that incorporated the XR species, namely LiCuBu(CN)XBu
.
Upon gas-phase fragmentation, this ion afforded a multitude
of fragment ions (Figure S46 in the Supporting Information).
Besides the formation of smaller cuprate(I) anions as well as
free XBuꢀ, the fragmentation also resulted in the loss of a butyl
radical [Eq. (5) with R=Bu]. To confirm this unusual type of re-
activity, we conducted control experiments with LiCuHex2·LiCN.
These experiments afforded analogous ESI mass spectra, in-
ꢀ
cluding LiCuHex(CN)XHex (Figures S47–S49 in the Supporting
Figure 5. Negative-ion mode ESI mass spectrum of a solution of the prod-
ucts formed in the reaction of LiCuBu2ꢀ·LiCN with tetracyanoethylene in THF,
a=Cu2Bu2CNꢀ, b=Li2Cu3Bu2(OH)(CN)3 (resulting from in-trap hydrolysis of
Li2Cu3Bu3(CN)3ꢀ), c=LiCu3Bu3(CN)2ꢀ, d=LiCuBu2YBuꢀ. For possible structural
assignments of YBuꢀ, see Figure 6.
Information), which also expelled a hexyl radical upon gas-
phase fragmentation [Eq. (5) with R=Hex], among other frag-
mentation channels (Figure S50 in the Supporting Informa-
tion).
ꢀ
ꢀ
C
LiCuRðCNÞXR ! LiCuðCNÞXR þ R
ð5Þ
Positive-ion mode ESI mass spectrometry of solutions of di-
organylcuprates treated with tricyanoethylene resulted in the
+
detection of Li(THF)n and Li2(CN)(THF)n+, n=2, 3 (Figure S51
in the Supporting Information).
Reactions of diorganylcuprates with tetracyanoethylene
Organocuprates dissolved in THF or Et2O reacted with tetracya-
noethylene to afford light-yellow solutions, along with precipi-
tates. Negative-ion mode ESI mass spectrometry again detect-
ed a multitude of cyanide-containing cuprate anions, indicat-
ing the consumption of the diorganylcuprate reagents
(Figure 5 and Figures S52–S60 in the Supporting Information).
ꢀ
Figure 6. Possible structures of YR
.
ꢀ
Moreover, additional ions assigned as YR (R=Me, Bu, Ph), Li-
ꢀ
ꢀ
second case, it would be brought about by a reductive elimi-
nation.
CuR(CN)YR (R=Bu, Ph), and LiCuR2YR (R=Bu in THF) were
observed. The measured m/z ratios and isotope patterns of the
ꢀ
ꢀ
The higher homologues LiCuR(CN)YR (R=Bu and Ph)
ions YR upon first sight seemed to point to their identities as
simple adducts of the organocuprate anions LiCuR2(CN)ꢀ and
tetracyanoethylene (Figure 6, top). Gas-phase fragmentation of
showed analogous reactivity and mainly produced
ꢀ
Li2Cu2R2(CN)3 upon gas-phase fragmentation [Figures S64 and
ꢀ
S65 in the Supporting Information; Eq. (7) with R=Bu or Ph,
respectively]. In the case of the butyl-containing species, the
expulsion of a butyl radical again was also observed, however,
among other decomposition channels (Figure S64 in the Sup-
porting Information). Control experiments with the analogous
hexyl-containing complex (Figures S66–S68 in the Supporting
Information) showed a very similar behavior (Figures S69 and
S70 in the Supporting Information).
YR did not result in the release of tetracyanoethylene, as one
would expect in this case, however, but instead led to the loss
of R(NC)C=C(CN)2 [Figures S61–S63 in the Supporting Informa-
tion; Eq. (6)]:
ꢀ
YR ! LiCuRðCNÞ2ꢀ þ RðNCÞC¼CðCNÞ2
ð6Þ
ꢀ
This finding suggested that the formation of YR involved
the cleavage of one of the CꢀCN bonds of the original tetra-
ꢀ
cyanoethylene. Thus, YR could be an adduct of a cuprate
ꢀ
LiCuRðCNÞYR ! Li2Cu2R2ðCNÞ3ꢀ þ RðNCÞC¼CðCNÞ2
ð7Þ
anion with a R(NC)C=C(CN)2 moiety (Figure 6, bottom left) or
the product of the insertion of the cuprate into one of the Cꢀ
CN bonds of the substrate (Figure 6, bottom right). In the first
case, the observed release of R(NC)C=C(CN)2 would simply cor-
respond to the dissociation of the adduct whereas in the
+
In the positive-ion mode, only Li(solv)n cations were detect-
ed (n=2, 3; Figures S71 and S72 in the Supporting Informa-
tion).
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