Shedding light on the use of Cu(ii)-salen complexes in the A3 coupling reaction

Article abstract of DOI:10.1039/c9dt04146j

One Cu(ii) complex, {Cu(ii)L} (1S), has been synthesised, in two high yielding steps under ambient conditions, and characterised by single-crystal X-Ray diffraction (SXRD), IR, UV-Vis, circular dichroism (CD), elemental analysis, thermogravimetric analysis (TGA) and electron spray ionization mass spectroscopy (ESI-MS). This air-stable compound enables the generation, at room temperature and in open-air, of twenty propargylamines, nine new, from secondary amines, aliphatic aldehydes and alkynes with a broad scope with yields up to 99%. Catalyst loadings can be as low as 1 mol%, while the recovered material retains its structural integrity and can be used up to 5 times without loss of its activity. Control experiments, SXRD, cyclic voltammetry and theoretical studies shed light on the mechanism revealing that the key to success is the use of phenoxido salen based ligands. These ligands orchestrate topological control permitting alkyne binding with concomitant activation of the C-H bond and simultaneously acting as a template temporarily accommodating the abstracted acetylenic proton, and continuously generating, via in situ formed radicals and a Single Electron Transfer (SET) mechanism, a transient Cu(i) active site to facilitate this transformation. The scope and limitations of this protocol are discussed and presented.

Full text of DOI:10.1039/c9dt04146j

Volume 49
Number 2
14 January 2020
Pages 243-526
Dalton
Transactions
An international journal of inorganic chemistry
rsc.li/dalton
ISSN 1477-9226
PAPER
George E. Kostakis et al.
Shedding light on the use of Cu(II)-salen complexes in the
A3 coupling reaction

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Shedding light on the use of Cu(II)-salen
complexes in the A3 coupling reaction†
Cite this: Dalton Trans., 2020, 49,
289
Stavroula I. Sampani, a Victor Zdorichenko,b Marianna Danopoulou,a
Matthew C. Leech, c Kevin Lam, c Alaa Abdul-Sada,a Brian Cox,
a,b
Graham J. Tizzard,d Simon J. Coles, d Athanassios Tsipis e and
a
George E. Kostakis
*
One Cu(II) complex, {Cu(II)L} (1S), has been synthesised, in two high yielding steps under ambient con-
ditions, and characterised by single-crystal X-Ray diffraction (SXRD), IR, UV-Vis, circular dichroism (CD),
elemental analysis, thermogravimetric analysis (TGA) and electron spray ionization mass spectroscopy
(ESI-MS). This air-stable compound enables the generation, at room temperature and in open-air, of
twenty propargylamines, nine new, from secondary amines, aliphatic aldehydes and alkynes with a broad
scope with yields up to 99%. Catalyst loadings can be as low as 1 mol%, while the recovered material
retains its structural integrity and can be used up to 5 times without loss of its activity. Control experi-
ments, SXRD, cyclic voltammetry and theoretical studies shed light on the mechanism revealing that the
key to success is the use of phenoxido salen based ligands. These ligands orchestrate topological control
permitting alkyne binding with concomitant activation of the C–H bond and simultaneously acting as a
template temporarily accommodating the abstracted acetylenic proton, and continuously generating, via
in situ formed radicals and a Single Electron Transfer (SET) mechanism, a transient Cu(I) active site to
facilitate this transformation. The scope and limitations of this protocol are discussed and presented.
Received 24th October 2019,
Accepted 14th November 2019
DOI: 10.1039/c9dt04146j
rsc.li/dalton
groups and (c) their scope and synthetic versatility. The multi-
component reaction of aldehydes, amines and alkynes, known
Introduction
The discovery of atom/energy-efficient and low-cost catalytic as the A3 coupling, is a vital route to propargyl amines.2–7
processes has been a longstanding goal for synthetic chemists; These organic scaffolds are essential intermediates in the syn-
thus, various sophisticated approaches, including multicom- thesis of biologically active nitrogen-containing compounds,
ponent reactions, have been developed.1 These methodologies such as acrylamidines, oxazoles, pyrroles, pyrrolidines and
dominate synthetic chemistry because they yield products natural products.2–4 Remarkably, few enantioselective A3 meth-
from simple starting materials, in fewer steps, and in a shorter odologies are known,8,9 and even fewer are known in which
time. However, the significant challenges of these protocols the role of the catalyst is well understood.10 From these
are to identify (a) the appropriate catalyst to promote a specific studies, it is established that the aldehyde and amine combine
transformation, (b) the suitable combination of functional to form an iminium ion, which in turn reacts with the alkyne
to yield the product. In light of this, various metal-based meth-
odologies, for example, Au(I)/Au(III),11–13 Ag(I),14–17 Cu(I),18–22
or Rh(III),23 that facilitate the formation of the corresponding
metal acetylide have been developed. However, other transition
elements such as Cu(II)24–26 and Fe(III),27–29 have also been
used, although with higher catalyst loadings and less mechan-
istic evidence.
aDepartment of Chemistry, School of Life Sciences, University of Sussex,
Brighton BN1 9QJ, UK. E-mail: G.Kostakis@sussex.ac.uk
bPhotodiversity Ltd c/o Department of Chemistry, School of Life Sciences,
University of Sussex, Brighton BN1 9QJ, UK
cSchool of Science, Department of Pharmaceutical Chemical and Environmental
Sciences, University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UK
dUK National Crystallography Service, Chemistry, University of Southampton,
SO1 71BJ, UK
Copper is abundant, of low cost, has incredibly versatile
chemistry and its oxidation state varies (I, II and III) while its
components can catalyse reactions that incorporate one and/
or two-electron (radical and bond-forming) based mecha-
nisms. Most importantly, copper easily coordinates to hetero-
atoms and forms π-bonds to organometallic intermediates,
eLaboratory of Inorganic and General Chemistry, Department of Chemistry,
University of Ioannina, 451 10 Ioannina, Greece
†Electronic supplementary information (ESI) available. CCDC 1954036–1954037.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9dt04146j
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Scheme 1 The chosen ligand (left) and the enantiomeric pure Cu(II) catalyst (1S) used in this study (right).
which may be a key step of the observed transformation.30–32
Results and discussion
Unquestionably, the A3 protocols that incorporate Cu(I)
require inert conditions. Work by Li,33 Benaglia,34 and The enantiomerically pure version of the ligand (H2LS) can be
Seidel,19 have addressed crucial catalyst, in situ formed, synthesised in one high yielding step (yields over 95%) by
design parameters including operational stability and par- refluxing the corresponding (1S,2S)-(−)-1,2-diaminocyclo-
tially saturated coordination environment. In general, the hexane and 3,5-di-tert-butyl-2-hydroxybenzaldehyde in EtOH.
designed ligands provide two or three heteroatoms for coordi- Then, the combination in open air of H2LS with
nation. Our group has recently initiated a project aimed at Cu(OTf)2·2H2O, at room temperature and under ambient con-
developing efficient methodologies to promote the A3 coup- ditions, in the presence of Et3N in MeOH, in a molar ratio
ling using Cu(II) coordination compounds.35 From these 1 : 1 : 2, afforded the air-stable compound [Cu(II)LS] (1S) in
initial studies, the optimum pre-catalyst features a Cu(II) yields over 80%; noteworthy the total yield for the synthesis of
center with octahedral {N4O2} geometry and the, retained in the catalyst is 76%. Reactions of H2LS with other Cu(II) salts,
solution, planar {N4} geometry of Cu(II) is a crucial factor that CuCl2, Cu(NO3)2·3(H2O), CuBr2, Cu(ClO4)2·6(H2O) in the pres-
a favours the coordination of the alkyne with concomitant ence of a base, yield 1S, but lower yields (<65%). The enantio-
activation of the C–H bond and the formation of the corres- meric compound was obtained as brown crystals and charac-
ponding Cu(I)-acetylide.
terised by SXRD (Fig. 1), IR, UV-Vis, Circular Dichroism (CD),
Salen36 ligands offer a {N2O2} planar coordination pocket. Elemental analysis, Thermogravimetric analysis (TGA) and
Stack demonstrated the peculiar redox potential of Cu-salen Electron Spray Ionization Mass Spectroscopy (ESI-MS). The Cu
compounds in different oxidation states revealing the non- centre is coordinated by the salen ligand, resulting in a dis-
innocent character of the salen based ligands.37–39 Depending torted square-planar geometry (Fig. 1) and there are two inde-
on various parameters (i.e. ligand substitution, temperature, pendent moieties in the asymmetric unit. The distance
solvent) oxidation or reduction can occur at the ligand or the between the two Cu(II) adjacent centres is 5.094 Å, while weak
metal centre of these species,40,41 followed by C–C bond acti- C–H⋯aryl but no aromatic interactions can be identified. The
vation across two monomeric units and thus yielding infinite Cu–O and Cu–N bond distances are typical for a Cu(II) com-
components via radical pathways.42–46 Moreover, in Cu-salen pound and following previous crystallographic characterised
derivatives reversible methanolysis of an azomethine CvN components (see Table S1†).37,42,52,54 Both compounds show
bond can be observed.47 Bearing all these in mind, we envi- one peak in the ESI-MS (positive-ion mode) at m/z 607.9719
saged that a well-characterised Cu(II)-salen derivative would be which perfectly corresponds to the fragment, in MeOH, i-PrOH
an efficient vehicle towards the A3 coupling; recent works and DCM solvents (Fig. S3†), indicating that the structure
support this hypothesis,48,49 although evidence of the mecha-
nism is uncertain. Inspired by our recent work with salen
based ligands,50 we identified that a Cu(II)-salen compound
made with the ligand (H2L) shown in Scheme 1 is an ideal can-
didate to serve this purpose.51 The substitutions on the ligand
have a twofold role; to promote the reduction of the metallic
centre from Cu(II) to Cu(I) through radical pathways, even at
room temperature and under non-inert atmospheric
conditions,37–46 and simultaneously prevent self-polymeris-
ation via C–C bond activation. To the best of our knowledge
and our surprise, this is the first crystallographic report of the
enantiomerically pure {Cu(II)L} (1S) component shown in
Scheme 1.52,53 Moreover, control experiments, SXRD, cyclic vol-
tammetry and theoretical studies shed light on the mechanism
of this reaction. The scope and limitations of this methodology
are also discussed.
Fig. 1 A projection of the asymmetric unit of 1S.
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remains intact in these solvents. Circular Dichroism studies of may coordinate to the Cu centre, thus giving the expected
1S in MeOH and DCM solvents in a concentration 0.3 M product in higher yield.
confirm the chiral nature of the complex (Fig. S4 & S5†).
Interestingly, a reaction in the absence of solvent (entry 12,
Thermogravimetric analysis of 1S, under N2 atmosphere, Table 1),57 gave 5aaa in 95%, however, to avoid unexpected
shows that the material is stable up to 288 °C, and then solidification of the final products and to take all the above
decomposition starts; the final residue corresponds to CuO notes, we chose DCM as the solvent for the subsequent reac-
(exp 13.07%, found 12.08%) (Fig. S6†). The UV-Vis spectrum of tions and the use of molecular sieves to capture by-product
1S in DCM solvent is typical of a Cu(II) chromophore with H2O molecules.
{N2O2} environments, respectively, at various concentrations
A control experiment in the absence of any catalyst, under
the above-identified conditions, failed to produce product
(Fig. S7†).55,56
With the catalyst in hand and aiming to develop a user- 5aaa. To further evaluate the catalytic efficacy of compound 1S,
friendly protocol, we performed reactions in the open air and we extended the pilot experiments varying concentration,
considered that 1S would be an ideal candidate for aliphatic loading, reaction time and other parameters. Concentration
aldehydes and secondary amines. Cyclohexanecarboxaldehyde, experiments (entries 1–3, Table 2) identify that the reaction is
pyrrolidine, and phenylacetylene were chosen as model sub- highly dependent, and the optimum performance is obtained
strates to evaluate the title reaction in a molar ratio 1 : 1.1 : 1.2 in a reaction with 0.4 M (1 mmol in 2.5 ml). Keeping the con-
(Table 1). Given that the starting component consists of Cu(II), centration to 0.4 M, the catalyst’ loading experiments (entries
prolonged reactions were performed to allow reaction comple- 4–6, Table 2) identify that a 2 mol% is ideal, while shorter reac-
teness and different solvents were used. Reactions with polar tions (entries 7 and 8, Table 2) gave 5aaa in lower yields. A
and coordinating solvents such as MeOH and EtOH (entries reaction at a higher temperature and shorter time (entry 9,
1 and 2, Table 1) gave low yields; however, the reactions in Table 2) gave 5aaa in good yield.
i-PrOH gave 5aaa in a moderate yield; this outcome is in line
The optimised protocol (2 mol% loading, room tempera-
with our previous findings.35 The reactions in CH3CN and ture, 72 hours, after that named as Methodology A) is appeal-
DCM (entries 4 & 5, Table 1), had a better performance, while ing since it operates in the absence of base and additives and
reactions in other solvents (entries 6–10, Table 1) gave 5aaa in at room temperature, however, to overcome the increased reac-
traces. The use of molecular sieves (entry 11, Table 1) in DCM tion time, we considered using the microwave approach to
increases the yield of the final product. Reactions with coordi- increase the reaction rates. Following the above protocol, all
nating solvents lower the catalytic efficacy; this behaviour may the reactions were performed in a microwave at low tempera-
be explained by solvent coordination to the metal centre, ture (80 °C), catalyst loading (2 mol%), in the open air and
which prohibits substrate binding. This finding is in line with were complete within 30 minutes see Table 2, entry 10 (named
other experiments with and without the presence of molecular after that as Methodology B). Methodology B is far more
sieves; the latter captures the released H2O byproduct which efficient when compared with other reported Cu based micro-
wave protocols that yield propargylamines. These methods
Table 1 Solvent screening
Table 2 Optimisation of reaction conditions
Entry
Solvent
Yielda,b (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
i-PrOH
CH3CN
DCM
Acetone
CHCl3
Toluene
Hexane
Ethyl acetate
DCM
16
22
64
74
Entry
Loading (mol%)
Time (h)
Yielda,b (%)
1
2
3
4
5
6
7
8
9
3
3
3
2
1
5
2
2
2
2
72
72
72
72
72
72
24
48
24
0.5
75c
84d
96e
97e
93e
87e
43e
86e
88e, f
>99g
71
No reaction
Traces
Traces
11
9
10
11
12
No reaction
74c
—
95
10
a Relative yield calculated by 1H-NMR based on the remaining 2a. a Relative yield calculated by 1H-NMR based on the remaining 2a.
b Reaction conditions, catalyst (3 mol%), 1.0 mmol aldehyde, 1.1 mmol b Reaction conditions: 1.0 mmol aldehyde, 1.1 mmol amine, 1.2 mmol
amine, 1.2 mmol alkyne, catalyst (3%), 5 mL solvent, 72 hours, room alkyne, molecular sieves, solvent DCM, room temperature.
temperature, concentration 0.1 M. c In the presence of molecular sieves c Concentration 0.2 M. d Concentration 0.3 M. e Concentration 0.4 M.
4 Å.
f 50 °C. g Microwave conditions 80 °C, 30 min.
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produces an oxonium H3O+ entity as a temporary byproduct
(1 H2O molecule from the Schiff base and the abstracted proton
from the triple bond), instead of water. After 72 hours, the
expected product is produced in low yield (35%), indicating
that modification of the catalytic system is required for 1S to
be suitable for primary amines.
Table 3 Scope of the reaction with aldehydes, secondary amines and
alkynesa,b
Reactivity – mechanistic studies
Aiming to investigate the role of 1S in the reaction and shed
light on the reaction mechanism, we performed a series of
experiments altering reaction parameters following method-
ology A. Notably, reactions under N2 (entry 1, Table 4) or Ar
(entry 2, Table 4) atmosphere gave 5aaa in 97 and 95%,
respectively. These data disfavour the incorporation of O2 in
the present catalytic cycle, that means the possible formation
of the dimeric intermediate Cu–O2–Cu with variable oxidation
states; the latter has been identified as a critical factor in other
C–C activation reactions catalysed by Cu(II) components.59–61
Moreover, the addition of 10 mol% TEMPO (entry 3, Table 4)
under these conditions had a significant impact leading to
activity cessation. This result signifies the presence of a radical
pathway containing the Cu(I)-complex species and supports
the plausible in situ formation of the Cu(I)-acetylide intermedi-
ate, that may be responsible for the catalytic cycle.
Then we performed an experiment with in situ preparation
of the catalyst (entry 4, Table 4). The one-pot reaction contain-
ing H2LS and the weakly binding metal salt Cu(OTf)2 yielded
5aaa in 96%. This data is indeed an impressive result, in line
with other reported similar studies,62 however, it is unclear if
the formation of the neutral complex 1S proceeds before cata-
lysis and/or the metal salt promotes the organic transform-
ation. In terms of operation ability, we believe that this in situ
a Isolated yields. b Reaction conditions, catalyst (2 mol%), 1.0 mmol
aldehyde, 1.1 mmol amine, 1.2 mmol alkyne, molecular sieves, solvent
DCM, concentration 0.4 M, methodology A (72 hours, room tempera-
ture), methodology B (MW, 80 °C, 30 min). c MW, 80 °C, 1 h.
require Ar atmosphere high catalyst loading (15 mol%) and
temperatures above 100 °C.58 The next step was to identify the
limitations of both methodologies, and therefore we extended
the scope of the reaction (Table 3) by employing a variety of
secondary amines, aliphatic aldehydes and alkynes and
produce in total twenty propargylamines out of which nine
scaffolds are new. In all cases, the reaction proceeded
smoothly, and we were able to isolate the corresponding pro-
ducts in good to excellent yields. For compound 5caa, follow-
ing already known chiral column HPLC protocols,19 we identi-
fied a (75/25) 50% ee for the product resulting with method-
ology A. This low level of enantioselectivity has been observed
in other systems,34 without significant improvement, whilst
the elevated temperature in methodology B removes the
enantioselective character of the system, therefore we decided
to discard the enantioselective characterisation of the remain-
ing products. For compound 5fda, the NMR data showed the
presence of two diastereoisomers with a ratio of 57 : 43 and
55 : 45, for methodology A and B, respectively.
Table 4 Various experiments to obtain mechanistic evidences
Time
(h)
Yielda,b
(%)
Entry
Atmosphere
Additives
1
2
3
4
5
6
7
8
9
72
72
72
72
72
72
72
72
72
N2
Ar
—
—
97
95
0
Open-air
Open-air
Open-air
Open-air
Open-air
Open-air
Open-air
TEMPO (10 mol%)
—
—
—
—
—
—
96c
100d
96e
95f
95g
94h
a Relative yield calculated by 1H-NMR based on the remaining 2a.
b Reaction conditions, catalyst (2 mol%), 1.0 mmol aldehyde, 1.1 mmol
amine, 1.2 mmol alkyne, molecular sieves, solvent DCM 2.5 mL, con-
centration 0.4 M, room temperature. c In situ formation of the catalyst
H2L/Cu(OTf)2·H2O. d Cu(OTf)2. e Recovered (1 cycle) catalyst.
f Recovered (2 cycles) catalyst. g Recovered (3 cycles) catalyst.
h Recovered (5 cycles) catalyst.
To further validate the suitability of 1S for the A3 coupling,
we performed control experiments using aniline (primary
instead of secondary amine), benzaldehyde and phenyl-
acetylene. The reason for this selection is that this reaction
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protocol is weak because of the following three factors. (A) Two unit and the three main differences prior and post catalysis,
protons are released from the parent organic ligand upon com- respectively, are (a) an imine CvN bond 1.255(13) Å and 1.284(10)
plexation; these may participate in the organic transformation Å, (b) one Cu–N bond 1.916(8) Å and 1.940(6) Å, (c) one Cu–O
by facilitating the formation of H2O byproduct molecules. (B) bond 1.893(7) Å and 1.910(5) Å. Interestingly, significant
The triflate is an extremely stable anion, the conjugate base of changes in the C–C bonds in both aromatic rings can be
a very strong acid; therefore it may abstract a proton, forming observed (Table S2†). Moreover, Bond Valence Sum analysis63
triflic acid which in turn may facilitate the redox Cu(II)–Cu(I) (Table S3†) for 1S prior and post catalysis signifies a slight
converse. (C) A reaction using solely Cu(OTf)2 as the catalyst, (∼3%) change in the oxidation state of the Cu centre. The crys-
under similar conditions (entry 5, Table 4) provides 5aaa tallographic datasets for 1S and 1S′ were collected in different
almost quantitatively while reactions with other Cu(II) salts instruments (see ESI†) but at the same temperature (100 K). To
discard the formation of 5aaa. These results showcase that the validate these differences, we collected a further three crystal-
hydroxide (OH−) moiety, produced from the condensation of lographic datasets for each catalyst, 1S and 1S′ at the same
aldehyde and secondary amine, is not an efficient base to temperature (100 K) and using the same diffractometer. The
facilitate acetylenic proton abstraction and/or the redox Cu(II)– data (Tables S4†) indicate that there are only minor variations
Cu(I) converse, therefore the combinatorial, or not, role of the in bond lengths and unit cell parameters between 1S and 1S′
two different bases (OH− and −OTf) and the role of Cu(OTf)2 and therefore exclude the possibility of structural change/
in this A3 catalytic cycle are questioned. We decided to investi- alteration of the oxidation state of the metal centre in the
gate this protocol in future experiments.
recovered catalyst. In these six different data, the Cu–O and
To identify the potential of our catalytic system, we Cu–N bonds vary from 1.869 Å to 1.914 Å and from 1.911 Å to
attempted to recover the catalyst. After reaction completion, 1.939 Å, respectively, whilst more considerable differences can
the crude product was placed in the fridge or left unattended be found in only one sample for the CvN bonds (1.250(13) Å,
in the open air, and well-formed needle-like brownish coloured 1.288(14) Å and 1.291(13) Å, 1.325(13) Å) but this crystal was
crystals grew within two hours or four days, respectively. The twinned and of low quality. A crystallographic dataset was col-
recovered material was tested and found to catalyse the reac- lected for the recovered catalyst after the 5th run, which con-
tion without loss of its activity (entries 6–9, Table 4); the pro- firmed that stability and integrity of the system. Moreover, the
cedure was repeated five times, without observing a loss of the UV-Vis spectrum (in DCM) and TGA analysis of 1S′ showed
catalytic efficacy. To further shed light on this performance, similar behaviour to that of 1S (Fig. S8 & 9†).
we attempted SXRD characterisation of the recovered material
To further shed light on the mechanism of this reaction the
1S′ (after one cycle). The crystal used for the structure determi- electrochemical behaviour of the ligand, 1S, 1S′ and titrations of
nation of 1S′ was twinned. Despite obtaining almost identical 1S or 1S′ with phenylacetylene (Ph–CuC–H) were studied in
unit cell parameters, slight differences in bond distances CH2Cl2 by cyclic voltammetry under N2. The ligand exhibits two
could be identified (Table 5). These were mainly associated to distinct quasi-reversible waves (Fig. S10†) that correspond to
only one of the two independent entities in the asymmetric two successive oxidations of
a phenol into a phenoxyl
radical.38,64 The cyclic voltammograms of 1S display two well-
separated one-electron reversible redox waves at E11=2 = 0.51 and
E21=2 = 0.81 V V vs. Fc+/Fc for 1S and E11=2 = 0.52 V and E12=2 = 0.81
V for 1S′ which showcase a typical behaviour with the reported
similar systems (Fig. S11†).38,64,65 In the reductive region
(Fig. 2), 1S and 1S′ both show a non-reversible reduction.
Notably, when a fresh sample of 1S and a sample of 1S′ were
titrated with Ph–CuC–H (0, 0.5, 1, 2, and 50 equivalent for 1S
and 0, 0.5, and 50 for 1S′, 50 equivalents correspond to 2% cata-
lyst loading), no significant effects on the oxidative process were
observed. However, both 1S and 1S′ show slightly different
cathodic behaviour in the presence of Ph–CuC–H. The cathodic
wave’s current slightly increases with the concentration of Ph–
CuC–H, and a new feature appears during the back scan. This
different behaviour may be attributed to the reduction of the
[Cu(II)/Ph–CuC–H] species to the [Cu(I)/Ph–CuC–H] species as
this notion has been well established in other protocols.66,67 To
further establish this notion, UV-Vis titration studies at room
temperature and in the open air of 1S and 1S′ and Ph–CuC–H
in a catalytic ratio (2 : 100) were performed (Fig. S8 and S9†),
with no noted differentiation.
Table 5 A ChemDraw diagram listing the significant structural differ-
ence in bond lengths between initial and recovered catalyst
Crystal data
1S
1S′
a (Å)
b (Å)
c (Å)
α (o)
β (o)
γ (o)
9.8740(4)
13.5904(5)
14.8719(6)
62.868(4)
73.368(3)
78.772(3)
1696.94(13)
100(2)
9.8853(2)
13.5954(3)
14.8780(2)
62.868(2)
73.374(2)
78.798(2)
1700.32(7)
100(2)
V (Å3)
T/K
Bond distances and angles with significant differences
NvC
Cu–N
Cu–O
1.255(13)
1.916(8)
1.893(7)
1.284(10)
1.940(6)
1.910(5)
It is worth noting that in the crude NMR spectra of all
the above-studied reactions, no parent organic ligand nor
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Fig. 2 CV data in the reductive region of 1S (left) and 1S’ (right) in the presence of phenylacetylene.
Scheme 2 A plausible mechanism for this reaction.
the formation of the hetero coupling (bis-adduct) product of in synthetic chemistry,71,72 especially for radical-triggered
terminal alkynes were observed, whereas precipitation of cascade reactions,73 that the Cu(I)-acetylide intermediate can
metallic Cu was not observed. Bearing in mind that (a) term- be formed by a Single Electron Transfer (SET) mechanism,
inal alkynes can reduce Cu(II) to Cu(I),66,67 (b) proton abstrac- therefore the proposed mechanism (Scheme 2) accounts all
tion from the catalyst has been noted in mononuclear parameters (oxidation states, proton abstraction, by-product
systems,68 (c) the reaction takes place in a non-coordinating formation, substrate-coordination, metal coordination geo-
solvent, in the absence of base and at room temperature and metry) and we believe that is highly likely for the mechanism
(d) the reaction rates and efficacy increase with temperature to follow a SET pathway.
or microwaves, we propose the following three-step mecha-
To further validate this notion, we synthesised the racemic
nism. Initially, the planar {N2O2} geometry of Cu(II) promotes reduced version of the organic ligand and the corresponding
alkyne binding with concomitant activation of the C–H bond. Cu(II)-salan compound (6) (Scheme 3, Fig. S12†), following an
In step II, the acetylenic proton is abstracted from one nitro- already known synthetic protocol.54 The reduced organic
gen atom of the organic framework to form the corres- scaffold provides a similar coordination environment to the
ponding Cu-acetylide, which may be stabilised by radical metal centre and may generate in situ radicals due to the pres-
pathways. This notion has been recently proposed in a ence of the phenoxide moieties. Notably, in previous results,
similar system.69 Then, the symmetrical {N2O2} plane compound 6 was found to perform poorly in oxidation and oxi-
accounts for adequate electron delocalisation to ensure the dative coupling reactions, when compared to the corres-
reduction of Cu(II) to Cu(I) which then orchestrates the break- ponding derivative of 1S.54 A reaction with 6 as the catalyst
ing of the Cu–O bond as well as positional rearrangement of under similar reaction conditions (Scheme 3) yields 5aaa in a
the acetylide group. Finally, the addition of the Cu(I)-acetylide very good yield, similar to that of 1S, supporting our reasoning
to the in situ generated iminium ion yields the corresponding for topological control which permits alkyne binding with con-
propargylamine derivative and water, and regeneration of the comitant activation of the C–H bond and simultaneous accom-
catalyst. Given the absence of an initiator and that the modation of the abstracted acetylenic proton, and continuous
reduction of Cu(II) to Cu(I) can be prolonged,70 we may envi- generation, via in situ generated radicals, of a transient Cu(I)
sage that step II is the rate-determining step. It is well known active site.
294 | Dalton Trans., 2020, 49, 289–299
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population analysis was performed using Weinhold’s method-
ology as implemented in the NBO 6.0 software.84–86 All calcu-
lations were performed in solution (CH3OH solvent) employing
the Polarizable Continuum Model (PCM) using the integral
equation formalism variant (IEFPCM) being the default self-
consistent reaction field (SCRF) method.87
The geometric and energetic reaction profile calculated at
the PBE0/Def2-TZVP level of theory in solution (CH3OH
solvent) is depicted schematically in Fig. 3, while the geometri-
cal structures of all reactants, intermediates and products
directly optimised in solution phase are given in the ESI
(Fig. S14†). It is important to note that the optimised geometry
of the catalyst in methanol solution (Fig. S14†) matches better
to the crystal structure of the recovered 1S′ and not the initial
1S catalyst.
Scheme 3 The pilot reaction that the racemic Cu(II)-salan compound
(6) was tested as a catalyst.
Mechanistic studies employing DFT computational protocols
To further understand the mechanism of the A3 coupling reac-
The course of the reaction involves initially a loose associ-
tions catalysed by 1S, we performed density functional theory ation of Ph–CuC–H to Cu(salen) complex in an orientation
(DFT) calculations to model the geometric and energetic reac- almost parallel to the coordination plane with the H atom
tion profile. All the DFT calculations throughout this work directed towards an N donor atom of the salen ligand. The
were carried out using the Gaussian09 software package.74 The estimated interaction energy in the adduct formed is only
geometries and thermal corrections for all stationary points 0.06 kcal mol−1. This orientation of Ph–CuC–H activates the
along the reaction coordinate are computed with the Perdew, C–H bond of Ph–CuC–H accompanied by the proton transfer
Burke and Ernzerhof75–81 of hybrid density functional denoted to the N-donor atom of the coordinated salen ligand and
as PBE0 (also called PBE1PBE) as implemented in the coordination of the phenylacetylide ligand to Cu(II) centre in a
Gaussian09 program suite. For the geometry optimisations, we η1-mode. The proton detachment process demands 213.4 kcal
have used the Def2-TZVP basis set.82,83 Hereafter the method mol−1 with the proton affinity of the N-donor atom of salen
used in DFT calculations is abbreviated as PBE0/Def2-TZVP. estimated to be 144.8 kcal mol−1. The proton transfer also pro-
Frequency calculations were also performed at the same level motes the rupture of one of the Cu–O bonds yielding a three-
of theory to identify whether the stationary point is a local coordinated Cu(II) complex (Fig. S14†). The three-coordinated
minimum or a transition state. The natural bond orbital (NBO) Cu(II) intermediate concomitantly is reduced to a three-co-
Fig. 3 Geometric and energetic (ΔH in kcal mol−1) reaction profile for the A3 coupling reactions catalysed by 1S calculated at the PBE0/Def2-TZVP
level of theory in a solution using methanol solvent.
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Scheme 4 Frontier molecular orbitals (FMOs) of the iminium ion and the Cu(I) intermediate.
Scheme 5 The proposed reaction mechanism for the A3 coupling reactions catalysed by 1S calculated at the PBE0/Def2-TZVP level of theory in
methanol solution.
ordinated Cu(I) intermediate by intramolecular single electron the electrophilic C atom of the iminium ion and the nucleo-
transfer (SET) from the Single Occupied Molecular Orbital philic C atom of the coordinated phenylacetylide acquire
(SOMO) localized mainly on the coordinated phenoxo moiety natural atomic charges of 0.318|e| and −0.375|e| respectively.
of the protonated salen ligand towards the Highest Occupied An inspection of the Frontier Molecular Orbitals (FMOs) of the
Molecular Orbital (HOMO) exhibiting high 3d character (cf. iminium ion and the Cu(I) intermediate (Scheme 4) reveals
HOMO−3, Scheme 4). The intramolecular Cu(II) → Cu(I) that the formation of the propargylamine product is also sup-
reduction stabilises the three-coordinated Cu(I) intermediate ported by LUMO (iminium) – HOMO−2 (Cu(I) intermediate)
by 23.43 kcal mol−1 concerning the Cu(II) congener consider- interactions.
ing an adiabatic SET. Notice that the experimentally deter-
In summary, the full catalytic cycle, supported by DFT cal-
mined reduction potential for 1S is 1.02 V (23.52 kcal mol−1). culations, is shown in Scheme 5, which is consistent with the
Next, the Cu(I)-intermediate having an open coordination proposed plausible catalytic cycle supported by experimental
sphere dispose of open channels for the in situ generated elec- measurements.
trophilic iminium ion to attack the nucleophilic C atom of the
coordinated phenylacetylide, thus affording the corresponding
propargylamine product and water and regenerating the cata-
lyst. The condensation of the cyclohexanecarboxaldehyde with
Conclusions
pyrrolidine affording the cyclohexyl(pyrrolidin-1-yl)methanol We present a Cu(II) based protocol that efficiently catalyses the
aldol is exothermic (ΔH = −4.86 kcal mol−1), while the gene- A3 coupling reaction in the open air and at room temperature.
ration of the iminium ion by the detachment of the hydroxyl Vital to the success of this is the use of the phenoxido salen-
group from the aldol demands 45.79 kcal mol−1. Notice that based ligand which orchestrates topological control permitting
296 | Dalton Trans., 2020, 49, 289–299
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alkyne binding with concomitant activation of the C–H bond 17 N. Salam, A. Sinha, A. S. Roy, P. Mondal, N. R. Jana and
and simultaneously acting as a template temporarily accom- S. M. Islam, RSC Adv., 2014, 4, 10001–10012.
modating the abstracted acetylenic proton, and continuously 18 N. Sharma, U. K. Sharma, N. M. Mishra and
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E. V. Van Der Eycken, Adv. Synth. Catal., 2014, 356, 1029–
Transfer (SET) mechanism, a transient Cu(I) active site to facili-
1037.
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ciple structural features for this well-characterised Cu(II) 4653.
system in the open air and paves the way for the future devel- 20 L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang and C.-A. Fan, Org.
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to several organic transformations and asymmetric synthesis.
Lett., 2004, 6, 1001–1003.
21 T. T. T. Trang, D. S. Ermolat’ev and E. V. Van der Eycken,
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Conflicts of interest
There are no conflicts to declare.
24 B. M. Choudary, C. Sridhar, M. L. Kantam and B. Sreedhar,
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Acknowledgements
GEK thanks Dr Ioannis Lykakis for fruitful discussions and
the EPSRC UK National Crystallography Service at the
University of Southampton for the collection of the crystallo-
graphic data for 1S and 1S′.88
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