Direct detection of key intermediates in rhodium(I)-catalyzed [2+2+2] cycloadditions of alkynes by ESI-MS

Article abstract of DOI:10.1002/chem.201200880

The mechanism of the Rh-catalysed [2+2+2] cycloaddition reaction of diynes with monoynes has been examined using ESI-MS and ESI-CID-MS analysis. The catalytic system used consisted of the combination of a cationic rhodium(I) complex with bisphosphine ligands, which generates highly active complexes that can be detected by ESI(+) experiments. ESI-MS on-line monitoring has allowed the detection for the first time of all of the intermediates in the catalytic cycle, supporting the mechanistic proposal based mainly on theoretical calculations. For all ESI-MS experiments, the structural assignments of ions are supported by tandem mass spectrometry analyses. Computer model studies based on density functional theory (DFT) support the structural proposal made for the monoyne insertion intermediate. The collective studies provide new insight into the reactivity of cationic rhodacyclopentadienes, which should facilitate the design of related rhodium-catalysed C-C couplings. Detecting intermediates: The mechanism of the Rh^I-catalyzed [2+2+2] cycloaddition reaction was examined using ESI-MS (see scheme). All of the intermediates in the catalytic cycle were detected by ESI-MS for the first time and characterized by ESI-MS/MS. DFT was used to support the structural proposal made for the monoyne insertion intermediate. Copyright

Full text of DOI:10.1002/chem.201200880

FULL PAPER
DOI: 10.1002/chem.201200880
Direct Detection of Key Intermediates in Rhodium(I)-Catalysed [2+2+2]
Cycloadditions of Alkynes by ESI-MS
Magda Parera,[a] Anna Dachs,[a, b] Miquel Solꢀ,[a, b] Anna Pla-Quintana,*[a] and
Anna Roglans*[a]
Abstract: The mechanism of the Rh-
catalysed [2+2+2] cycloaddition reac-
tion of diynes with monoynes has been
examined using ESI-MS and ESI-CID-
MS analysis. The catalytic system used
consisted of the combination of a cati-
onic rhodium(I) complex with bisphos-
phine ligands, which generates highly
active complexes that can be detected
by ESI(+) experiments. ESI-MS on-
line monitoring has allowed the detec-
tion for the first time of all of the inter-
mediates in the catalytic cycle, support-
ing the mechanistic proposal based
mainly on theoretical calculations. For
all ESI-MS experiments, the structural
assignments of ions are supported by
tandem mass spectrometry analyses.
Computer model studies based on den-
sity functional theory (DFT) support
the structural proposal made for the
monoyne insertion intermediate. The
collective studies provide new insight
into the reactivity of cationic rhodacy-
clopentadienes, which should facilitate
the design of related rhodium-catalysed
Keywords: cycloaddition · density
functional calculations
· electro-
spray ionization · mass spectrome-
try · rhodium
À
C C couplings.
Introduction
tion has never been analysed in this way. The generally ac-
cepted reaction mechanism for this cycloaddition involving
three alkynes is shown in Scheme 1.
Given the importance of transition-metal-catalysed reactions
in organic synthesis, it is of great interest to understand the
reaction mechanisms to be able to improve these processes.
One of the difficulties faced in these investigations is that
due to the low concentrations and transient nature of most
of the intermediates involved, the identification of the spe-
cies is complex and limited information is obtained. There-
fore, techniques that allow the direct monitoring of these re-
active intermediates are of great interest. One such method
is electrospray ionization mass spectrometry (ESI-MS),[1]
which makes it possible to obtain detailed data by trapping
and identifying short-lived intermediates in organometallic
catalytic cycles in a relatively simple manner.[2] In addition
to revealing the molecular masses of ions for many reactive
intermediates, this technique also provides structural infor-
mation through characteristic fragmentation patterns ob-
tained by collision-induced dissociation (CID).
Scheme 1. Mechanistic proposal for [2+2+2] cycloaddition reactions of
three alkynes.
Initially, one alkyne moiety displaces a ligand on the
metal to form alkyne complex I, and then a second alkyne
coordinates to form complex II. Oxidative coupling may
occur to give a metallacyclopentadiene IIIa or a metallacy-
clopentatriene IIIb, in which the metal adopts a formal oxi-
dation state two units higher than that in the precursor II.
This has been found to be the rate-determining step, with
activation energies typically in the range of 11–14 kcalmolÀ1.
Subsequent coordination of a third alkyne ligand to the met-
allacyclopentadiene or metallacyclopentatriene intermediate
is followed either by alkyne insertion to form a metallacy-
cloheptatriene V (the so-called Schoreꢀs mechanism)[5] or
metal-mediated [4+2] cycloaddition to yield a 7-metallanor-
Although many transition-metal-catalysed reactions have
already been studied using ESI-MS,[2–4] to the best of our
knowledge the metal-catalysed [2+2+2] cycloaddition reac-
[a] M. Parera, Dr. A. Dachs, Prof. Dr. M. Solꢁ, Dr. A. Pla-Quintana,
Prof. Dr. A. Roglans
Departament de Quꢂmica, Universitat de Girona
Campus de Montilivi, s/n, 17071 Girona (Spain)
E-mail: anna.plaq@udg.edu
anna.roglans@udg.edu
bornadiene complex VI or cycloaddition to give
a
[b] Dr. A. Dachs, Prof. Dr. M. Solꢁ
metallabicyclo[3.2.0]heptatriene VII. Finally, the arene is
AHCTUNGTRENNUNG
Institut de Quꢂmica Computacional, Universitat de Girona
Campus de Montilivi, s/n, 17071 Girona (Spain)
formed by reductive elimination of the metal and the cata-
lyst (M) is recovered. Although this is the general pattern of
the reaction mechanism, the specific nature of the inter-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200880.
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mediates in each process depends on the nature of the
metal, the ligands, and even the substrate partners. The
mechanistic proposal in Scheme 1 is essentially based on
theoretical calculations[6] and only limited experimental data
are available to support the proposed overall mechanism.
Although several metallacyclopentadiene and metallacyclo-
pentatriene intermediates have been isolated, to the best of
our knowledge there are no experimental data relating to
more advanced intermediates in the catalytic cycle.
ACHTUNGTRENaNUGN nds has been shown to be an efficient catalyst for [2+2+2]
cycloaddition reactions[10] and was therefore the catalytic
system of choice. Our mechanistic study commenced with
the cycloaddition of diyne 1 and p-methylphenylacetylene
2a (Scheme 2). The reaction was first optimized in the labo-
ratory and quantitatively afforded cycloadduct 3a after 2 h
in refluxing dichloroethane.
Among the several transition metals able to catalyse the
[2+2+2] cycloaddition reaction, rhodium is becoming in-
creasingly popular, which has led to considerable interest in
studying the particularities of the mechanism for reactions
involving this metal. Several studies have dealt with the
characterization of rhodacyclopentadienes of type IIIa
(Scheme 1), the intermediate that is commonly proposed in
rhodium-catalysed [2+2+2] cycloadditions, by means of
techniques such as NMR and IR spectroscopies and X-ray
analysis.[7] ESI-MS has been used a limited number of times
to detect rhodacyclopentadienes in on-going reactions,
mainly by our group[4j,k] but also in a recent paper by Brod-
belt, Baik, Krische et al.,[8] which was concerned with the
mechanism of the hydrogen-mediated coupling of acety-
lenes, a reaction that shares the first steps of the catalytic
cycle with the [2+2+2] cycloaddition of alkynes. Further-
more, during our continuing study of [2+2+2] cycloaddition
reactions catalysed by rhodium complexes,[4j,k,9] in which a
contribution has been made to the understanding of mecha-
nistic aspects by theoretical approaches,[6k,l] we have also re-
ported kinetic data for the catalytic cycle of an [RhCl-
Scheme 2. ACTHNUTRGNE[NUG 2+2+2] Cycloaddition reaction between diyne 1 and p-meth-
ylphenylacetylene 2a studied by ESI-MS.
To determine the sensitivity of the technique towards the
species present in the reaction mixture, the first step was to
individually analyse the components of the reaction by ESI-
MS. All of the species detected in the present study were as-
signed by comparison of the experimentally obtained isotop-
ic pattern and the theoretically calculated one (see the Sup-
porting Information). The behaviours of the starting diyne 1
and final product 3 were examined, both of which afforded
peaks corresponding to the [M+H]+ and [M+Na]+ adducts.
The components of the catalytic system were then analysed.
[Rh
mass spectrometer. One peak was observed at m/z=211.0,
corresponding to the complex [Rh
(cod)]+ that had lost a
ACHTUNGTREN(UNNG cod)2]BF4 was dissolved in MeOH and injected into the
(PPh3)3]-catalysed [2+2+2] cycloaddition of bisalkynes with
ACHTUNGTRENNUNG
a monoalkyne, following the reaction by means of electro-
chemical techniques to study the successive steps separate-
ly.[4k]
In this study, we present the first ESI-MS investigation of
[2+2+2] cycloaddition reactions between several diynes and
monoalkynes catalysed by RhI. In addition, density function-
al theory (DFT) calculations have been used to help in the
identification of the structures of some of the intermediates
detected by ESI-MS.
cod ligand. Analysis of the BINAP ligand by ESI-MS gave
the molecular peak [BINAP+H]+ at m/z=623.2, but the
peak of an oxidized species [BINAP=O+H]+ was also ob-
served at m/z=639.2. This oxidized species could be formed
in the same mass spectrometer since an oxidative positive
ESI mode was used and the presence of traces of oxygen
was possible given the purity of the nebulizing nitrogen em-
ployed. The active catalytic species was then generated by
hydrogenating[11] a 1:1 mixture of [Rh
ACHTNUGTRENUNG(cod)2]BF4 and the
BINAP ligand in dichloromethane, and, following dilution
with MeOH,[12] this mixture was analysed by ESI-MS. The
Results and Discussion
spectrum showed the species [Rh
[Rh ACTHUNGETRNNUG
(cod)BINAP]+ at m/z=833.1, and [Rh(BINAP)2]+ at
(BINAP)]+ at m/z=725.1,
ACHTUNGTRENNUNG
U
Our group has previously used the Wilkinson catalyst both
in methodological studies and in the characterization of oxi-
dative addition intermediates by ESI-MS.[4k] However, the
neutral rhodium-containing species postulated to be formed
are undetectable by ESI-MS and there must be an ioniza-
tion mechanism operating in order for them to be detected.
Chloride dissociation allowed us to detect the oxidative ad-
dition intermediate when using Wilkinsonꢀs catalyst, but no
further intermediate could be detected. We therefore decid-
ed to use a cationic RhI complex to facilitate the observa-
tion of ionic species by ESI-MS. The combination of [Rh-
m/z=1347.0. The peak at m/z=833.1 was fragmented by
CID, resulting in loss of the cod ligand and leading to the
formation of [Rh
The complete reaction resulting from the addition of
diyne 1 to the mixture of hydrogenated [Rh(cod)2]BF4 and
BINAP together with 1.5 equivalents of p-methylphenyl-
acetylene 2a in dichloroethane was the next mixture to be
(BINAP)]+ at m/z=725.0.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
analysed by ESI-MS. After heating at reflux for 15 min in
an inert atmosphere, a sample was diluted in MeOH[12] and
injected into the mass spectrometer (Figure 1a). The postu-
lated catalytically active species [RhACTHNUTRGNEUNG
(BINAP)]+ was detect-
A
(cod=cyclooctadiene)
with
BINAP-type
ed at m/z=725.2. The peak observed at m/z=1000.3
corresponds to the mass of a cluster containing [Rh-
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ESI-MS Detection of Alkyne Cycloaddition Intermediates
FULL PAPER
tion of the diyne component from the metal, and the oxida-
tive addition intermediate fragmenting by tosyl loss through
À
S N bond fragmentation, a common fragmentation suffered
by aryl sulfonamides in mass spectrometry.[13] A peak was
also observed in the reaction mixture at m/z=1016.3 attrib-
utable to the species [RhACHTNUTGRNEUNG
(BINAP=O)(1)]+. MS/MS studies
of this compound (Figure 1c) indicated that it was cleaved
to release a fragment [MÀ155]+ corresponding to loss of the
tosyl group, from which we concluded that it corresponds to
the oxidized form of the oxidative addition intermediate.
The oxidative addition is thought to be the rate-determin-
ing step of the [2+2+2] cycloaddition reaction. The ensuing
intermediates might therefore be present at very low con-
centrations, such that they are likely to be detected, if at all,
as minor ions. In the search for these minor ions, spectra
were expanded paying special attention to the m/z 1110–
1120 region. We were delighted to observe a small peak at
m/z=1116.3, corresponding to the formal addition of p-
methylphenylacetylene
AHCTUNGTRENNUNG
to
the
intermediate
[Rh-
(BINAP)(1)]+. This peak may also correspond to different
intermediates: one involving p-coordination of acetylene 2a
to rhodacyclopentadiene, another resulting from alkyne in-
sertion into the same intermediate, or a third being a coordi-
nation species of the final product 3a with the catalyst.
Given the importance of the observation of the peak at
m/z=1116.3, we proceeded to further characterize the
nature of this intermediate by MS/MS (Figure 2a). If the in-
sertion step had not occurred, fragmentation would have
Figure 1. a) ESI mass spectrum of a mixture of ([RhACTHUNGTRNEUNG(cod)2]BF4 +BINAP)
(5 mol%)+2a+1 after 15 min. b) CID mass spectrum of the ion at
m/z=1000.3. c) CID mass spectrum of the ion at m/z=1016.3.
ACHTUNGTRENNUNG
(BINAP)(1)]+. Since the peak may correspond to two possi-
ble intermediates, one resulting from the coordination of the
diyne to rhodium (species of type II in Scheme 1) and the
other resulting from oxidative addition of the diyne to the
metal (species of type IIIa in Scheme 1), we further charac-
terized them by conducting an MS/MS analysis (Figure 1b).
The peak at m/z=1000.3 suffered fragmentation resulting in
a peak at m/z=725.0, corresponding to the fragment [Rh-
ACHTUNGTRENNUNG
(BINAP)]+, which was further cleaved to release a fragment
[MÀ155]+ corresponding to loss of the tosyl group. Had the
insertion step already occurred, [RhACTHNUTRGNEUNG
(BINAP)]+ would not
have been observed because the insertion step is effectively
irreversible.[8] Therefore, we assign the cluster at m/z=
1000.3 to a mixture of the two intermediates: the coordina-
Figure 2. a) CID mass spectrum of the ion at m/z=1116.3 at a collision
energy of 0.95 V. b) CID mass spectrum of the ion at m/z=1115.9 at a
collision energy of 0.95 V originating from a mixture of 3a+ Rh catalyst.
tion intermediate fragmenting to [RhACTHNUTRGNEUNG
(BINAP)]+ by dissocia-
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A. Roglans, A. Pla-Quintana et al.
caused simple p-methylphenylacetylene dissociation and the
formation of a fragment at m/z=1000.3. Since this was not
observed, a p-coordination intermediate can be ruled out.
In fact, two main fragments arose after CID of the peak at
m/z=1116.3, one at m/z=961.3 corresponding to loss of the
tosyl group, and another at m/z=725.1 corresponding to the
mass of [Rh
the loss of 391 mass units, exactly the weight of the final
product 3a. Whereas the formation of [Rh
(BINAP)]+ may
ACHTUNGTRENNUNG
(BINAP)]+. This last fragment was derived from
AHCTUNGTRENNUNG
Scheme 3.
ACHTUNGTREN[NUGN 2+2+2] Cycloaddition reactions between diyne 1 and p-X-
phenylacetylenes 2b–f studied by ESI-MS.
be the result of either reductive elimination from the inser-
tion intermediate or product
dissociation from the complex
Table 1. Electrospray mass spectral data for reactions described in Scheme 3.
formed by coordination of the
catalyst to the final product, the
tosyl group is presumably lost
from the oxidative insertion in-
termediate. Further evidence
for this was gained by injecting
into the mass spectrometer a
mixture of 3a in dichloroethane
and 5 mol% of the catalytic
mixture diluted with MeOH.
The catalytic mixture gave the
three peaks that have already
Entry
1
Monoyne 2/X
2b/OMe
MS [m/z]/identified species
MS/MS [m/z]/identified species
977.0 [Rh(BINAP)(1)
(2b)ÀTs]+
725.0 [Rh
(BINAP)]+
946.9 [Rh(BINAP)(1)
725.0 [Rh
(BINAP)]+
1003.3 [Rh(BINAP)(1)
725.1 [Rh
(BINAP)]+
964.9 [Rh(BINAP)(1)
724.9 [Rh
(BINAP)]+
1026.8 [Rh(BINAP)(1)
724.9 [Rh
(BINAP)]+
1132.2/[Rh
1101.9/[Rh
1158.3/[Rh
1120.2/[Rh
N
G
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2
3
4
5
2c/H
2d/tBu
2e/F
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2 f/Br
1180.2–1182.2/[Rh
A
E
E
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
been
(BINAP)]+ at m/z=725.1, [Rh
and [Rh
(BINAP)2]+ at m/z=1347.0) and upon addition of
the final product 3a, coordination of 3a to the catalytic spe-
cies [Rh
(BINAP)]+ was observed as a peak at m/z=1115.9.
mentioned
([Rh-
all cases, the MS/MS experiments showed both the loss of
tosyl groups and, by dissociation of the final product from
the catalyst or by the reductive elimination process from the
alkyne insertion intermediate, formation of the [Rh-
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
N
(BINAP)]+ fragment at m/z=725.0. To confirm the detec-
ACHTUNGTRENNUNG
When this peak was submitted to CID at the same collision
energy as in the previous experiment, it only gave the [Rh-
tion of the alkyne insertion intermediate and to exclude the
mere formation of a species corresponding to coordination
of the catalyst to the final product, a mixture of 3d and
ACHTUNGTRENNUNG
(BINAP)]+ fragment at m/z=725.1 without loss of the tosyl
group (compare spectra a and b, Figure 2).[14] We therefore
conclude that we have detected for the first time the addi-
tion intermediate.
The reaction was monitored at fixed time intervals by
ESI-MS. The reaction was complete after 2 h (TLC monitor-
ing) and we were able to observe the disappearance of the
ions corresponding to the intermediates at m/z=1000 (oxi-
dative addition) and m/z=1116 (insertion) and the forma-
tion of the final product 3a (see the Supporting Information
for spectra).
5 mol% [RhACTHGNUTERNNU(G cod)2]BF4 and BINAP was analysed. The spec-
trum showed a peak at m/z=1158.0 corresponding to the
coordination species, but when this peak was submitted to
MS/MS only a fragment at m/z=725.0 was observed. No
loss of the tosyl group was seen in this case either (see the
Supporting Information), confirming the observation of the
alkyne insertion intermediate in the ensuing reactions.
We then studied the effect of variation of the diyne and
performed the reaction with an NTs-tethered terminal diyne
4 and phenylacetylene 2c (Scheme 4 and Table 2).
To confirm the species detected and to test the general
applicability of the method, we studied the cycloaddition re-
action by varying the nature of the monoalkyne. Cycloaddi-
tion reactions with a series of para-substituted phenylacet-
The starting diyne 4 and the final product 5 were individu-
ally injected into the mass spectrometer for analysis. Both
were detected as protonated species or sodium adducts. In
the case of diyne 4 and cycloadduct 5, MS/MS experiments
showed Ts loss but as a neutral molecule resulting from het-
erolytic cleavage.[15] This differs from the behaviour of the
ACHTUNGTRENNUNGylenes 2b–f (Scheme 3 and Table 1) with the same tosyl-
tethered diyne 1 were analysed. The new reactions analysed
by ESI-MS, under reaction conditions previously optimized
in the laboratory, are shown in Scheme 3.
When the reactions were studied by ESI-MS following
the same methodology as before, data analogous to the re-
sults with p-methylphenylacetylene were obtained, confirm-
ing our initial assignments. In Table 1, only the clusters cor-
responding to the second intermediate and their further
characterization by MS/MS are shown in detail as the oxida-
tive addition intermediate is the same in all the examples. In
Scheme 4.
cetylene 2c studied by ESI-MS.
ACHTUNGTREN[NUNG 2+2+2] Cycloaddition reaction between diyne 4 and phenyla-
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ESI-MS Detection of Alkyne Cycloaddition Intermediates
FULL PAPER
Table 2. Electrospray mass spectral data for mixtures of reactions in Scheme 4 in MeOH.
(Figure 3). We hypothesized
that this species was a mixture
of the diyne coordinated to the
catalyst and the oxidative addi-
tion intermediate, each one
fragmenting through a charac-
teristic pathway. This was corro-
borated by the present study,
since the fragmentation of non-
covalent bonds (i.e., diyne dis-
sociation from the catalyst lead-
Sample[a]
MS [m/z]/identified species
MS/MS [m/z]/identified species
[Rh
N
972.1/[Rh
G
816.9 [Rh
725.1 [Rh
833.1 [Rh
919.1 [Rh
724.9 [Rh
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
988.1/[Rh
1074.1/[Rh
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1218.9/[Rh
1074.3/[Rh
N
1063.9 [Rh
725.1 [Rh
ACHTUNGTRENNUNG
[Rh
(cod)2]BF4 +BINAP+5
(BINAP)(5)]+
ACHTUNGTRENNUNG
[a] 5 mol% of rhodium complex and bisphosphine was used.
previously observed intrinsically ionic rhodium intermedi-
ates, in which homolytic cleavage led to the loss of radical
ing to the catalyst fragment at m/z=725) starts to take place
at lower amplitudes (A>0.15) than the fragmentation of co-
valent bonds (A>0.17) (tosyl cleavage from the oxidative
coupling intermediate leading to the fragment at m/z=817).
The breaking of coordination
Ts and the detection of
a cationic radical fragment
(Scheme 5).[13]
bonds occurs to a much greater
extent than the breaking of the
À
N Ts covalent bond throughout
the collision energy range stud-
ied. Furthermore, on increasing
the collision energy, the differ-
ence in the relative abundances
of the two fragments (725 vs.
817) is increased. We rule out
the possibility that the fragment
at m/z=817 originates from the
coordination
intermediate,
since the dissociation of non-co-
valent bonds should be much
more favourable than the
breaking of a covalent bond.
Scheme 5. Homolytic versus heterolytic cleavage of tosyl-containing species.
The solution resulting from the reaction between N-tosyl
diyne 4 and phenylacetylene 2c was injected into the mass
spectrometer after 15 min of reaction at room temperature
and dilution with MeOH. Intermediates analogous to those
detected for N-tosyl diyne 1 were observed and found to
display similar behaviour in the fragmentation experiments
with CID (Table 2; for mass spectra, see the Supporting In-
formation) with the exception of the observation of a new
cluster at m/z=1218.9 corresponding to the mass of [Rh-
Figure 3. Study of the dependence of fragment yields on the collision
energy at a reaction time of 45 min.
ACHTUNGTRENNUNG
(BINAP)(4)2]+. This cluster can be assigned either to inser-
tion of a second molecule of N-tosyl diyne 4 into the oxida-
tive addition intermediate (an intermediate that led to the
homo-coupling of N-tosyl diyne 4) or to complexation of the
catalyst with the homo-coupled product. ESI-MS/MS analy-
sis showed only a loss of the Ts group, which indicates that
it corresponds to the addition rather than the coordination
intermediate. The fact that terminal alkynes are more prone
to homo-coupling than their non-terminal counterparts may
explain why these intermediates were exclusively observed
in this set of experiments.
In line with the study of the variation of the diyne re-
agent, we performed a second experiment using a malonate-
tethered diyne to obtain a different fragmentation pattern
of the reaction products and intermediates. The reaction be-
tween diyne 6 and p-methylphenACTHNUGRTNEUNGylacetylene 2a, performed
in the laboratory, gave a 50% yield of cycloadduct 7
(Scheme 6).
Cycloadduct 7 was injected into the ESI-MS apparatus
and gave an adduct at m/z=353.0 corresponding to
[M+H]+, which underwent CID fragmentation to give a
peak at m/z=325.0 arising from a McLafferty rearrange-
To characterize in depth the nature of the species detect-
ed at m/z=972, a series of experiments was run to study the
dependence of fragment yields on the collision energy
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A. Roglans, A. Pla-Quintana et al.
analysed. A peak at m/z=1077.3 was observed, which could
be assigned to a cluster incorporating both the diyne and
(2a)]+. MS/MS analysis of this
monoyne, [RhACHTNUGTRENNUG(BINAP)(6)ACHTUGNTRENNUGN
peak was performed, as a result of which it was assigned to
monoyne coordination to the oxidative addition intermedi-
ate, the alkyne insertion intermediate, or the coordination
of the cycloadduct 7 to the catalyst. The main fragment at
Scheme 6. ACHTUNGTRENNUNG[2+2+2] Cycloaddition reaction between malonate-tethered
diyne 6 and p-methylphenylacetylene 2a studied by ESI-MS.
m/z=725.1 corresponded to [RhACHTUNGTRNEUNG
(BINAP)]+, which indicat-
ed the presence of a species involving coordination of cyclo-
adduct 7 to the catalyst, although we cannot rule out the
possibility that it was formed through reductive elimination
from the alkyne insertion intermediate. A peak attributable
ment ([7ÀC2H4]+), and another peak at m/z=325.0 result-
ing from the loss of COOEt and H. The ensuing reaction
was then analysed under the standard conditions. Apart
(2a)]+ was also observed at m/z=
to [RhACTHNUGRTENNUG(BINAP=O)(6)ACHUTNGTRENNUGN
from the species [Rh
A
G
1093.3. CID analysis revealed two main peaks (Figure 4b).
[Rh
G
The first fragment at m/z=741.1 corresponded to [Rh-
catalytic system, new signals appeared relating to intermedi-
ates in the reaction. In the m/z 960–980 region, in which
peaks due to oxidative addition intermediates were expect-
(BINAP=O)]+ and, analogously to the peak of the non-oxi-
ACHTUNGTRENNUNG
dized species, indicated the presence of the latter intermedi-
ate involving coordination of the cycloadduct 7 to the cata-
lyst, although it could possibly also have been formed from
the alkyne insertion intermediate. However, unlike the peak
of the non-oxidized species, a fragment attributable to [Rh-
ed, a peak at m/z=977.3 was assigned to [RhACTHNUTRGNEUG(N BINAP=
O)(6)]+. CID fragmentation of this compound showed the
formation of a peak at [MÀ73]+ (Figure 4a), corresponding
to the loss of a COOEt group, which indicated that the clus-
ter at m/z=977.3 corresponded to the oxidized form of the
oxidative addition intermediate and not to a coordination
species. Only a small peak was observed at m/z=961.3 cor-
AHCTUNGTRENNUNG
(BINAP=O)(6)]+ was observed at m/z=977.2. The forma-
tion of this fragment indicated the presence of an intermedi-
ate in which monoyne 2a was coordinated to the oxidative
addition intermediate, which fragmented by dissociation of
the metal from the monoyne. We can therefore conclude
that we also observed the hitherto elusive intermediate of
coordination of the monoyne to the oxidative addition inter-
mediate. Given that diyne 6 bears terminal alkyne moieties,
intermediates leading to the homo-coupled products were
also observed at m/z=1197.0, assigned to [Rh-
responding to [RhACHTUNGTRENNUNG
(BINAP)(6)]+, the low intensity of which
prevented full isolation and fragmentation. The mass region
corresponding to the alkyne insertion intermediate was then
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tion to give [Rh
tively.[16]
(BINAP)]+ and [Rh(BINAP=O)]+, respec-
ACHUTGTNRENNUG CAHTUNGTRENNUGN
After varying the monoyne and diyne reactants, a third
set of experiments was conducted on the cycloaddition of
diyne 4 and phenylacetylene 2c (reaction in Scheme 4) with
different bisphosphines, (R)-H8-BINAP (H8-BINAP=2,2’-
bis(diphenylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-bi-
naphthyl) and BIPHEP (BIPHEP=2,2’-bis(diphenylphos-
phino)-1,1’-biphenyl), to compare the behaviour of three dif-
ferent catalytic systems (see the Supporting Information for
complete data and the related discussion). The data extract-
ed from these experiments were analogous to those ob-
tained with BINAP (with the only changes in the expected
mass shifts arising from the different masses of the various
phosphines). Therefore, the presence of the proposed spe-
cies in the cycloaddition reactions was confirmed.
After the experimental detection of the intermediates, the
challenge remained as to how to draw a structure for the
monoyne insertion intermediate. To this end, we carried out
DFT calculations to determine whether this intermediate is
one of the three possible structures (V, VI, or VII) repre-
sented in the mechanistic proposal in Scheme 1. The reac-
tion mechanism involving diyne 4 and alkyne 2c with Rh/
Figure 4. a) CID mass spectrum of the ion at m/z=977.3. b) CID mass
spectrum of the ion at m/z=1093.3 showing the dissociation of the metal
from the monoyne.
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ESI-MS Detection of Alkyne Cycloaddition Intermediates
FULL PAPER
Figure 5. Gibbs energy profile (in kcalmolÀ1) for the formation of the product D from A with Z=NSO2CH3.
BIPHEP as the catalytic system was studied at the B3LYP/
cc-pVDZ-PP level of theory (see Computational details). To
reduce the computational cost, the Ts group was replaced
by an SO2CH3 substituent. Our simulations started from
complex A (the p-complex between phenylacetylene 2c and
our model of the [RhACTHNUTRGNEUNG
(BIPHEP)(4)]+ species), since this is
the first structure in the whole reaction mechanism with the
required number and type of atoms to be the experimentally
(2c)]+). Figure 5
detected (intermediate [RhACTHNUTRGNENGU(BIPHEP)(4)ACHTUNGTRENNUGN
shows the Gibbs energy profile for the transformation of
complex A into the final product D. The relative Gibbs
energy of A with respect to [RhACHTNUGRTNEUNG
(BIPHEP)]+, phenylacety-
lene 2c, and our model of diyne 4 is À44.8 kcalmolÀ1. This
represents the stabilization gain in Gibbs energy during the
initial oxidative coupling together with the p-complexation
of phenylacetylene. Subsequent formal [5+2] alkyne addi-
tion of phenylacet
rhodabicyclo[3.2.0]heptatriene complex B1 (see Figures 5
and 6). Another rhodabicyclo[3.2.0]heptatriene complex B2
ACHTUNGTRENNUNGylene 2c in the p-complex A leads to the
ACHTUNGTRENNUNG
Figure 6. Optimized structure at the B3LYP level of transition state TS-
AHCTUNGTREG(NNUN A,B1) with selected bond distances (ꢄ) and angles (8).
AHCTUNGTRENNUNG
could have been formed from an initial p-complexation of
phenylacetylene with the phenyl group of 2c pointing in the
direction of the BIPHEP group. However, complex B1 with
the phenyl group of the phenylacetylene species pointing
away from the BIPHEP substituent is more favourable than
B2 by 2.4 kcalmolÀ1 due to the lower steric repulsion and,
for this reason, the reaction through intermediate B2 was
discarded. The transition state (TS) for the conversion of A
Gibbs energy barrier of 1.7 kcalmolÀ1 (see Figures 5 and
7).[17] This process is exergonic by 11.8 kcalmolÀ1. Interest-
ingly, the molecular structure of C1 depicted in Figure 8
shows a clear bond length alternation in the rhodacyclohep-
tatriene ring.
Intermediate B2 could also have been transformed into
C2. However, C2 is 7.0 kcalmolÀ1 less stable than C1 and it
is therefore likely that the route through C2 is not operative.
In the final step, complex D is formed through a very exer-
gonic reductive elimination step (51.1 kcalmolÀ1) through
to B1, TSACHTUNGTRENNUNG
(A,B1) has a Gibbs energy barrier of 2.4 kcalmolÀ1
and the process is exergonic by 27.7 kcalmolÀ1. The most in-
teresting bond lengths and angles of the molecular structure
of TS
membered bicyclic ring B1 evolves to the cycloheptatriene
complex C1 through the transition state TS(B1,C1) with a
ACHTUNGTRENNUNG(A,B1) are depicted in Figure 6. The five- and four-
TS
(C1,D), which has a barrier of 2.2 kcalmolÀ1. Finally, the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
dissociation of product 3c and the recovery of the RhI/
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A. Roglans, A. Pla-Quintana et al.
slightly higher for C1 than for B1. The small energy differ-
ence between the two Gibbs energy barriers (just 0.5 kcal
molÀ1) prevents a definitive conclusion and the assignment
of this intermediate as the rhodabicycloACTHNUTRGNEUNG[3.2.0]heptatriene
complex VII cannot be completely excluded.
To sum up, the picture of the catalytic cycle obtained
after ESI-MS and DFT calculations of the studied reactions
is shown in Scheme 7. All intermediates were detected and
characterized, and as an example the m/z ratios for the de-
tected species together with their characteristic CID frag-
mentations are shown for the reaction between diyne 4 and
phenylacetylene 2c, using RhI/BIPHEP as the catalytic
system.
Figure 7. Optimized structure at the B3LYP level of transition state TS-
ACHTUNGTRENNUNG(B1,C1) with selected bond distances (ꢄ) and angles (8).
Scheme 7. Catalytic cycle proposed for the [2+2+2] cycloaddition of
diynes and monoynes under Rh/bisphosphine catalysis (the BIPHEP
ligand has been omitted for clarity) with detected ESI-MS species and
CID characterization.
Figure 8. Optimized structure at the B3LYP level of complex C1 with se-
lected bond distances (ꢄ) and angles (8).
BIPHEP catalyst from complex D is a slightly endergonic
process that only requires 5.8 kcalmolÀ1.
Conclusion
Our B3LYP/cc-pVDZ-PP results indicate that the overall
cycloaddition reaction of diyne 4 and alkyne 2c catalysed by
Rh/BIPHEP is exergonic by À129.7 kcalmolÀ1. Moreover,
reaction 4+2c+Rh/BIPHEP to yield D is exergonic by
À135.5 kcalmolÀ1. Most theoretical studies of [2+2+2] reac-
tion mechanisms carried out to date have yielded either the
ESI-MS offers a fruitful approach to the analysis of reaction
intermediates in the [2+2+2] cycloaddition of diynes and
monoynes. The cationic nature of the reaction intermediates
provided by the inherently cationic catalytic system used
(BINAP/[RhACHTUNTRGNEUNG(cod)2]BF4), as opposed to the neutrality of the
rhodabicyclo
[3.2.0]heptatriene or the cycloheptatriene com-
reactants and the products of the reaction, has been the key
to the observation of those intermediates present in particu-
larly low concentrations that other techniques have been
unable to characterize. This has allowed the direct detection
of the elusive intermediates resulting from the insertion of
the monoyne into the rhodacyclopentadiene for the first
time. Furthermore, this is the first time that the cationic rho-
dium catalyst has been investigated in a theoretical study of
a [2+2+2] cycloaddition reaction. Our DFT results indicate
plex. The coexistence of both in the same route is not
common, although it is not unprecedented.[6c,d,l] Our simula-
tions exclude the 7-metallanorbornadiene complex VI as the
monoyne insertion intermediate, since it has not been possi-
ble to locate such a complex on the potential energy surface.
On the other hand, our results favour the assignment of the
cycloheptatriene complex V as the insertion intermediate
since the forward barrier on the way to the products is
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ESI-MS Detection of Alkyne Cycloaddition Intermediates
FULL PAPER
ESI-MS: m/z: 392.1 [M+H]+, 414.1 [M+Na]+, 805.1 [2M+Na]+; elemen-
that the cycloheptatriene intermediate is the most likely
structure for the monoyne insertion intermediate, since it
has the highest forward barrier for the different steps of the
analysed reaction mechanism. However, the small differen-
ces in energy barriers do not allow us to rule out the possi-
bility of this insertion intermediate being the rhodabicyclo-
tal analysis calcd (%) for [C24H25NO2S·0.5
3.24; found: C 75.26, H 7.20, N 3.46.
ACHTNUGTNER(UNNG C6H14)]: C 74.96, H 6.99, N
Compound 3b: Column chromatography: hexanes/dichloromethane
(1:2). Colourless solid. M.p. 128–1308C; IR (ATR): n˜ =2921, 2851, 1347,
1161 cmÀ1 1H NMR (400 MHz, CDCl3, 258C, TMS): d=2.06 (s, 3H),
;
2.19 (s, 3H), 2.42 (s, 3H), 3.84 (s, 3H), 4.62 (s, 4H), 6.91 (d, 3J
8.8 Hz, 2H), 6.93 (s, 1H), 7.15 (d, 3J(H,H)=8.4 Hz, 2H), 7.33 (d, 3J-
(H,H)=8.8 Hz, 2H), 7.81 ppm (d, 3J(H,H)=8.4 Hz, 2H); 13C NMR
ACHTUNGTRENNUNG(H,H)=
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG[3.2.0]heptatriene complex.
A
ACHTUNGTRENNUNG
(75 MHz, CDCl3, 258C): d=16.4, 18.2, 21.5, 53.5, 53.9, 55.3, 113.6, 127.3,
127.6, 129.5, 129.8, 130.3, 130.6, 133.3, 133.6, 133.8, 135.7, 141.5, 143.6,
158.6 ppm; ESI-MS: m/z: 430.2 [M+Na]+, 446.1 [M+K]+, 837.2
[2M+Na]+; ESI-HRMS: calcd m/z for [C24H25NO3S+H]+ 408.1628,
found 408.1643; calcd m/z for [C24H25NO3S+Na]+ 430.1447, found
430.1459.
Experimental Section
General: Diynes 1[18] and 4[19] were prepared as previously described.
Compounds 3c[4j] and 5[9g] were prepared and characterized previously in
our laboratory. Reaction mixtures were subjected to column chromatog-
Compound 3d: Column chromatography: hexanes/dichloromethane
(1:1). Colourless solid. M.p. 203–2058C; IR (ATR): n˜ =2918, 1335,
1
raphy on silica gel (230–400 mesh). H and 13C NMR spectra were record-
1159 cmÀ1 1H NMR (400 MHz, CDCl3, 258C, TMS): d=1.35 (s, 9H),
;
ed on Bruker 300 or 400 MHz NMR spectrometers. 1H and 13C chemical
shifts (d) were referenced to internal solvent resonances and are reported
relative to SiMe4.
2.08 (s, 3H), 2.19 (s, 3H), 2.42 (s, 3H), 4.62 (s, 4H), 6.95 (s, 1H), 7.15 (d,
3J(H,H)=8.4 Hz, 2H), 7.33 (d, 3J(H,H)=8.4 Hz, 2H), 7.38 (d, 3J
(H,H)=
8.4 Hz, 2H), 7.81 ppm (d, 3J(H,H)=8.4 Hz, 2H); 13C NMR (75 MHz,
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ESI-MS instrument: Samples were studied in positive-ion mode with a
6000 ESI Ion Trap LC/MS (Bruker Daltonics) using nitrogen as the neb-
ulizer gas. Pure samples such as rhodium pre-catalyst, phosphines, diyne
reagents, and isolated cycloadducts were introduced as 2.5ꢅ10À3 m solu-
tions in methanol into the ESI source by means of a liquid chromato-
CDCl3, 258C): d=16.4, 18.2, 21.5, 31.4, 34.5, 53.5, 53.9, 125.0, 127.3,
127.6, 128.8, 129.4, 129.8, 130.7, 133.7, 134.0, 135.7, 137.9, 141.8, 143.6,
149.8 ppm; ESI-MS: m/z: 434.2 [M+H]+, 456.1 [M+Na]+, 472.1 [M+K]+
, 889.2 [2M+Na]+; elemental analysis calcd (%) for [C27H31NO2S·0.5-
AHCTNUGTER(GNNNU C6H14)]: C 75.91, H 7.64, N 2.95; found: C 75.68, H 7.85, N 3.34.
graphic system (HPLC P1200, Agilent) at a flow rate of 100 mLminÀ1
.
Compound 3e: Column chromatography: hexanes/dichloromethane
(6:4). Colourless solid. M.p. 138–1408C; IR (ATR): n˜ =2935, 1345, 1221,
The catalytic system and the aliquots sampled from the reaction mixture
(100 mL in dichloromethane or dichloroethane) were analysed after dilu-
tion in methanol (1 mL at room temperature) by direct infusion into the
ESI source by a syringe pump at a flow rate of 5 mLminÀ1. The time
elapsed between sampling and injection was kept below 1 min. A spray
voltage of 4.5 kV, a capillary voltage of about 40 V, a drying temperature
of 3508C, and a sheath gas flow rate of 7 LminÀ1 were adjusted to ensure
reasonably soft ionization. Using two octopoles, the ions were guided
from the source into the ion trap for storage and manipulation in the
presence of about 10À5 mbar helium as a trapping gas. For detection, the
ions were ejected from the trap to an electron multiplier. For collision-in-
duced-dissociation (CID) spectra, the ions were mass-selected in the ion
trap and then kinetically accelerated within the helium gas present in the
ion trap as the collision and cooling gas. Collision energies and window
widths were chosen to provide reasonable yields of the fragmented ions
while maintaining the parent ion as the most abundant one. The maxi-
mum accumulation time was in the range 50–100 ms. Mass spectra were
recorded from m/z 200 to 1400, and seven spectral averages were accu-
mulated to improve the signal-to-noise ratio. The isotope pattern was cal-
culated using a Bruker Daltonics program.
1163 cmÀ1 1H NMR (400 MHz, CDCl3, 258C, TMS): d=2.03 (s, 3H),
;
2.19 (s, 3H), 2.42 (s, 3H), 4.61 (s, 4H), 6.91 (s, 1H), 7.07 (dd, 3J
8.8 Hz, 3J(H,F)=8.8 Hz, 2H), 7.18 (dd, 3J(H,H)=8.8 Hz, 4J
5.6 Hz, 2H), 7.33 (d, 3J(H,H)=8.0 Hz, 2H), 7.80 ppm (d, 3J
(H,H)=
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
8.0 Hz, 2H); 13C NMR (75 MHz, CDCl3, 258C): d=16.3, 18.2, 21.5, 53.4,
53.8, 115.0 (d, 2J
G
3
4
(d, J
G
143.7, 161.9 ppm (d, 1J
ACHTUNGTRENNUNG
434.1 [M+K]+, 813.1 [2M+Na]+; ESI-HRMS: calcd m/z for
[C23H22FNO2S+H]+ 396.1428, found 396.1429; calcd m/z for
[C23H22FNO2S+Na]+ 418.1247, found 418.1246.
Compound 3 f: Column chromatography: hexanes/dichloromethane (1:1).
Colourless solid. M.p. 61–638C; IR (ATR): n˜ =2920, 1340, 1158 cmÀ1
;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=2.03 (s, 3H), 2.19 (s, 3H),
2.42 (s, 3H), 4.61 (s, 4H), 6.90 (s, 1H), 7.09 (d, 3J
(H,H)=8.5 Hz, 2H),
7.33 (d, 3J (H,H)=8.5 Hz, 2H), 7.51 (d, 3J
(H,H)=8.4 Hz, 2H), 7.81 ppm
(d, 3J(H,H)=8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3, 258C): d=16.6,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
18.5, 21.8, 53.8, 54.2, 121.5, 127.4, 127.9, 130.1, 130.2, 130.7, 131.2, 131.6,
134.3, 134.7, 136.3, 140.2, 140.9, 144.0 ppm; ESI-MS: m/z: 456–458
[M+H]+, 478–480 [M+Na]+, 494–496 [M+K]+, 935 [2M+Na]+; elemen-
General procedure for intermolecular [2+2+2] cycloaddition reactions
catalysed by RhI-BINAP formed in situ: In a 25 mL flask, a mixture of
[RhACHTUNGTRENNUNG(cod)2]BF4 (0.05 equiv) and the ligand BINAP (0.05 equiv) was dis-
tal analysis calcd (%) for [C23H22NO2SBr·
2.60; found: C 63.92, H 6.26, N 2.68.
ACHTNUGTNER(UNNG C6H14)]: C 64.68, H 5.99, N
solved in dichloromethane (3 mL). Hydrogen gas was introduced into the
catalyst solution with stirring for 30 min. The resulting mixture was then
concentrated to dryness, the residue was redissolved in dichloromethane
or dichloroethane (0.5 mL), and the solution was stirred under an N2 at-
mosphere. A solution of the alkyne (1.5 equiv) in dichloromethane or di-
chloroethane (0.5 mL) was then added at room temperature followed by
a solution of the diyne (1 equiv) in dichloromethane or dichloroethane
(1.5 mL). The reaction mixture was then stirred at room temperature or
under reflux until completion (TLC monitoring). The solvent was evapo-
rated and the residue was purified by column chromatography on silica
gel.
Compound 7: Column chromatography: hexanes/ethyl acetate (9:1).
Yellow solid. M.p. 72–748C; IR (ATR): n˜ =2922, 1729, 1241, 1185,
1067 cmÀ1 1H NMR (300 MHz, CDCl3, 258C, TMS): d=1.26 (t, J=
;
7.2 Hz, 6H), 2.38 (s, 3H), 3.62 (d, J=6 Hz, 4H), 4.21 (q, J=7.2 Hz, 4H),
7.20–7.25 (m, 3H), 7.37 (d, 3J(H,H)=8.1 Hz, 2H), 7.44 ppm (d, 3J-
(H,H)=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3, 258C): d=14.4, 21.4,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
60.8, 62.1, 123.1, 124.7, 126.3, 127.3, 129.7, 137.1, 138.7, 139.2, 140.6,
141.0, 172.0 ppm; ESI-MS: m/z: 353.2 [M+H]+, 375.2 [M+Na]+, 727.3
[2M+Na]+.
Computational details: All geometry optimizations were performed with-
out symmetry constraints using the hybrid DFT B3LYP[20] method with
the Gaussian 03[21] program package. Analytical Hessians were computed
to determine the nature of stationary points (one or zero imaginary fre-
quencies for transition states and minima, respectively) and to calculate
unscaled zero-point energies (ZPEs) as well as thermal corrections and
entropy effects using the standard statistical mechanics relationships for
an ideal gas.[22] The latter two terms were computed at 298.15 K and
1 atm to provide the reported relative Gibbs free energies (DG298). Fur-
Compound 3a: Column chromatography: hexanes/dichloromethane
(1:1). Colourless solid. M.p. 150–1528C; IR (ATR): n˜ =2918, 1340, 1159,
1098 cmÀ1 1H NMR (300 MHz, CDCl3, 258C, TMS): d=2.05 (s, 3H),
;
2.18 (s, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 4.61 (s, 4H), 6.92 (s, 1H), 7.09 (d,
3J(H,H)=8.1 Hz, 2H), 7.18 (d, 3J(H,H)=8.1 Hz, 2H), 7.32 (d, 3J
(H,H)=
8.4 Hz, 2H), 7.80 ppm (d, 3J(H,H)=8.4 Hz, 2H); 13C NMR (75 MHz,
G
T
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CDCl3, 258C): d=16.3, 18.2, 21.1, 21.5, 53.5, 53.9, 127.2, 127.6, 128.8,
129.0, 129.5, 129.8, 130.6, 133.7, 135.7, 136.6, 138.0, 141.9, 143.6 ppm;
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A. Roglans, A. Pla-Quintana et al.
thermore, the connectivity between stationary points was established by
intrinsic reaction path[23] calculations. The all-electron cc-pVDZ basis set
was used for P, O, N, C, S, and H atoms,[24] while for Rh we employed the
cc-pVDZ-PP basis set[25] containing an effective core relativistic pseudo-
potential. Relative energies were computed taking into account the total
A. Roglans, Synlett 2009, 2844–2848; k) A. Dachs, A. Torrent, A.
Pla-Quintana, A. Roglans, A. Jutand, Organometallics 2009, 28,
6036–6043; l) J. Salabert, R. M. Sebastiµn, A. Vallribera, A. Ro-
glans, C. Nµjera, Tetrahedron 2011, 67, 8659–8664.
[5] N. E. Schore, Chem. Rev. 1988, 88, 1081–1119.
À
number of molecules present. The Ar group of the Ts (SO2 Ar) moiety
present in the experimental diyne 4 was substituted by a CH3 group to
reduce the computational cost of the calculations.
[6] For a pioneering semiempirical study, see: a) C. Bianchini, K. G.
Caulton, C. Chardon, M.-L. Doublet, O. Eisenstein, S. A. Jackson,
T. J. Johnson, A. Meli, M. Peruzzini, W. E. Streib, A. Vacca, F.
Vizza, Organometallics 1994, 13, 2010–2023. For DFT studies of the
mechanism for alkyne cyclotrimerization, see: b) J. H. Hardesty, J. B.
Koerner, T. A. Albright, G.-Y. Lee, J. Am. Chem. Soc. 1999, 121,
6055–6067; c) K. Kirchner, M. J. Calhorda, R. Schmid, L. F. Veiros,
J. Am. Chem. Soc. 2003, 125, 11721–11729; d) Y. Yamamoto, T.
Arakawa, R. Ogawa, K. Itoh, J. Am. Chem. Soc. 2003, 125, 12143–
12160; e) R. Schmid, K. Kirchner, Eur. J. Inorg. Chem. 2004, 2609–
2626; f) A. A. Dahy, N. Koga, Bull. Chem. Soc. Jpn. 2005, 78, 781–
791; g) A. A. Dahy, C. H. Suresh, N. Koga, Bull. Chem. Soc. Jpn.
2005, 78, 792–803; h) N. Agenet, V. Gandon, K. P. C. Vollhardt, M.
Malacria, C. Aubert, J. Am. Chem. Soc. 2007, 129, 8860–8871; i) L.
Orian, J. N. P. van Stralen, F. M. Bickelhaupt, Organometallics 2007,
26, 3816–3830; j) K. Kirchner, Monatsh. Chem. 2008, 139, 337–348;
k) A. Dachs, A. Torrent, A. Roglans, T. Parella, S. Osuna, M. Solꢁ,
Chem. Eur. J. 2009, 15, 5289–5300; l) A. Dachs, S. Osuna, A. Ro-
glans, M. Solꢁ, Organometallics 2010, 29, 562–569; m) R. Xu, P.
Winget, T. Clark, Eur. J. Inorg. Chem. 2008, 2874–2883. For a
review, see: n) J. A. Varela, C. Saµ, J. Organomet. Chem. 2009, 694,
143–149.
[7] a) E. Müller, Synthesis 1974, 761–774; b) M. Iglesias, C. del Pino, J.
Ros, S. Garcꢂa Blanco, S. M. Carrera, J. Organomet. Chem. 1980,
338, 89–102; c) C. Bianchini, K. G. Caulton, C. Chardon, O. Eisen-
stein, K. Folting, T. J. Johnson, A. Meli, M. Peruzzini, D. J. Rausch-
er, W. E. Streib, F. Vizza, J. Am. Chem. Soc. 1991, 113, 5127–5129;
d) H. Nishiyama, E. Niwa, T. Inoue, Y. Ishima, K. Aoki, Organome-
tallics 2002, 21, 2572–2574; e) H. Uchimura, J.-i. Ito, S. Iwasa, H.
Nishiyama, J. Organomet. Chem. 2007, 692, 481–486.
[8] V. M. Williams, J. R. Kong, B. J. Ko, Y. Mantri, J. S. Brodbelt, M.-H.
Baik, M. J. Krische, J. Am. Chem. Soc. 2009, 131, 16054–16062.
[9] a) A. Pla-Quintana, A. Roglans, A. Torrent, M. Moreno-MaÇas, J.
Benet-Buchholz, Organometallics 2004, 23, 2762–2767; b) A. Tor-
rent, I. Gonzµlez, A. Pla-Quintana, A. Roglans, M. Moreno-MaÇas,
T. Parella, J. Benet-Buchholz, J. Org. Chem. 2005, 70, 2033–2041;
c) I. Gonzµlez, S. Bouquillon, A. Roglans, J. Muzart, Tetrahedron
Lett. 2007, 48, 6425–6428; d) S. Brun, L. Garcia, I. Gonzµlez, A.
Torrent, A. Dachs, A. Pla-Quintana, T. Parella, A. Roglans, Chem.
Commun. 2008, 4339–4341; e) L. Garcia, A. Pla-Quintana, A. Ro-
glans, Org. Biomol. Chem. 2009, 7, 5020–5027; f) L. Garcia, A. Pla-
Quintana, A. Roglans, T. Parella, Eur. J. Org. Chem. 2010, 3407–
3415; g) S. Brun, M. Parera, A. Pla-Quintana, A. Roglans, T. León,
T. Achard, J. Solꢁ, X. Verdaguer, A. Riera, Tetrahedron 2010, 66,
9032–9040; h) S. Brun, A. Torrent, A. Pla-Quintana, A. Roglans, X.
Fontrodona, J. Benet-Buchholz, T. Parella, Organometallics 2012,
31, 318–326.
Acknowledgements
Financial support from the Spanish Ministry of Education and Science
(MEC) (Projects Nos.: CTQ2011–23121/BQU and CTQ2011–23156/
BQU) and the DIUE of the Generalitat de Catalunya (Project No.:
2009SGR637) is gratefully acknowledged. M.P. thanks the Generalitat de
Catalunya for a predoctoral grant. We would also like to thank Anna
Costa for her technical assistance with the ESI mass spectrometer and
Jesffls Orduna for helpful discussions. Excellent service by the Centre de
Serveis Cientꢂfics i Acad›mics de Catalunya (CESCA) is gratefully ac-
knowledged. Support for the research of M.S. was received through the
ICREA Academia 2009 prize for excellence in research funded by the
DIUE of the Generalitat de Catalunya.
[1] R. B. Cole, Electrospray Ionization Mass Spectrometry - Fundamen-
tals, Instrumentation and Applications, Wiley, New York, 1997.
[2] For selected reviews and monographs, see: a) D. Plattner, Int. J.
Mass Spectrom. 2001, 207, 125–144; b) P. Chen, Angew. Chem. 2003,
115, 2938–2954; Angew. Chem. Int. Ed. 2003, 42, 2832–2847; c) L. S.
Santos, L. Knaack, J. O. Metzger, Int. J. Mass Spectrom. 2005, 246,
84–104; d) M. N. Eberlin, Eur. J. Mass Spectrom. 2007, 13, 19–28;
e) L. S. Santos, Reactive Intermediates - MS Investigations in Solu-
tion, Wiley-VCH, Weinheim, 2010; f) J. Roithovµ, Chem. Soc. Rev.
2012, 41, 547–559.
[3] For recent and selected references, see: a) H.-Y. Wang, W.-L. Yim,
T. Klüner, J. O. Metzger, Chem. Eur. J. 2009, 15, 10948–10959;
b) C. A. Müller, C. Markert, A. M. Teichert, A. Pfaltz, Chem.
Commun. 2009, 1607–1618; c) M. A. Schade, J. E. Fleckenstein, P.
Knochel, K. Koszinowski, J. Org. Chem. 2010, 75, 6848–6857;
d) T. A. Fernandes, B. G. Vaz, M. N. Eberlin, A. J. M. da Silva,
P. R. R. Costa, J. Org. Chem. 2010, 75, 7085–7091; e) C. H. Beier-
lein, B. Breit, R. A. P. Schmidt, D. A. Plattner, Organometallics
2010, 29, 2521–2532; f) D. Agrawal, D. Schrçder, C. M. Frech, Orga-
nometallics 2011, 30, 3579–3587; g) D. Agrawal, D. Schrçder, Orga-
nometallics 2011, 30, 32–35; h) M. A. Henderson, J. Luo, A. Oliver,
J. S. McIndoe, Organometallics 2011, 30, 5471–5479; i) K. L. Vikse,
Z. Ahmadi, C. C. Manning, D. A. Harrington, J. S. McIndoe, Angew.
Chem. 2011, 123, 8454–8456; Angew. Chem. Int. Ed. 2011, 50, 8304–
8306; j) H.-Y. Wang, W.-L. Yim, Y.-L. Guo, J. O. Metzger, Organo-
metallics 2012, 31, 1627–1634.
[10] For representative examples, see: a) K. Tanaka, Synlett 2007, 1977–
1993; b) K. Tanaka, Chem. Asian J. 2009, 4, 508–518; c) T. Shibata,
K. Tsuchikama, Org. Biomol. Chem. 2008, 6, 1317–1323.
[11] Hydrogenation of the catalytic mixture is a usual procedure for the
activation of the catalyst (see, for instance, the references cited in
the reviews in ref. [10]).
[12] We postulate that MeOH is not only a better suited solvent for ESI-
MS but that it also helps to stabilize the short-lived intermediates by
forming solvent adducts (see, for instance, Figure S41 in the Sup-
porting Information) or complexes which can then be split in the
ESI source, thus facilitating their detection by mass spectrometry.
Methanol has been shown not to have a deleterious effect on the re-
action since the cycloaddition of diyne 1 and phenylacetylene 2a
(Scheme 2) works satisfactorily (75% conversion in 5 h at reflux)
when run in a mixture of DCE/MeOH (1:10, v/v).
[4] For previous ESI-MS studies from our group, see: a) M. A. Aramen-
dꢂa, F. Lafont, M. Moreno-MaÇas, R. Pleixats, A. Roglans, J. Org.
Chem. 1999, 64, 3592–3594; b) M. Moreno-MaÇas, R. Pleixats, J.
Spengler, C. Chevrin, B. Estrine, S. Bouquillon, F. HØnin, J. Muzart,
A. Pla-Quintana, A. Roglans, Eur. J. Org. Chem. 2003, 274–283;
c) J. Masllorens, M. Moreno-MaÇas, A. Pla-Quintana, A. Roglans,
Org. Lett. 2003, 5, 1559–1561; d) C. Chevrin, J. Le Bras, F. HØnin, J.
Muzart, A. Pla-Quintana, A. Roglans, R. Pleixats, Organometallics
2004, 23, 4796–4799; e) J. Comelles, M. Moreno-MaÇas, E. PØrez,
A. Roglans, R. M. Sebastiµn, A. Vallribera, J. Org. Chem. 2004, 69,
6834–6842; f) A. Pla-Quintana, A. Roglans, ARKIVOC 2005, ix,
51–62; g) J. Masllorens, I. Gonzµlez, A. Roglans, Eur. J. Org. Chem.
2007, 158–166; h) J. Comelles, A. Pericas, M. Moreno-MaÇas, A.
Vallribera, G. Drudis-SolØ, A. Lledós, T. Parella, A. Roglans, S.
Garcꢂa-Granda, L. Roces-Fernµndez, J. Org. Chem. 2007, 72, 2077–
2087; i) C. Chevrin, J. Le Bras, A. Roglans, D. Harakat, J. Muzart,
New J. Chem. 2007, 31, 121–126; j) I. Gonzµlez, A. Pla-Quintana,
[13] a) N. Hu, Y.-P. Tu, K. Jiang, Y. Pan, J. Org. Chem. 2010, 75, 4244–
4250; b) G. Xu, T. Huang, J. Zhang, J. K. Huang, T. Carlson, S.
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ESI-MS Detection of Alkyne Cycloaddition Intermediates
FULL PAPER
Miao, Rapid Commun. Mass Spectrom. 2010, 24, 321–327; c) W. L.
Fitch, L. He, Y.-P. Tu, L. Alexandrova, Rapid Commun. Mass Spec-
trom. 2007, 21, 1661–1668; d) E. M. Thurman, I. Ferrer, O. J. Pozo,
J. V. Sancho, F. Hernandez, Rapid Commun. Mass Spectrom. 2007,
21, 3855–3868.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V.
Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Peters-
son, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Ha-
segawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M.
Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C.
Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Moro-
kuma, G. A. Voth, P. Salvador, J. J. Dannenberg, G. Zakrzewski, S.
Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A.
Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challa-
combe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonza-
lez, J. A. Pople in Gaussian 03, Revision C.01, Gaussian, Inc., Pitts-
burgh, PA, 2003.
[14] The alkyne insertion intermediate has been drawn as the rhodacy-
cloheptatriene in accordance with the results obtained by DFT cal-
culations.
[15] Heterolytic cleavage leading to Ts loss as a neutral molecule was
also observed for cycloadduct 3a; see the Supporting Information
for CID spectra of 3a, 4, and 5.
[16] It should be noted that the peaks of oxidized species were much
more intense in the case of the malonate-tethered diyne than for the
NTs-tethered diynes.
[17] TSACHTUNGTRENNUNG(B1,C1) has two imaginary frequencies at 30i and 11i. The first
has the expected motion for the transformation from B1 to C1. The
second corresponds to a movement of a phenyl group and is likely
to be the result of a numerical artifact of the quadrature grid used
in the DFT calculations.
[22] P. Atkins, J. De Paula, Physical Chemistry, Oxford University Press,
Oxford, 2006.
[23] C. Gonzalez, H. B. Schlegel, J. Chem. Phys. 1989, 90, 2154–2161.
[24] a) T. H. Dunning Jr., J. Chem. Phys. 1989, 90, 1007–1023; b) D. E.
Woon, T. H. Dunning Jr., J. Chem. Phys. 1993, 98, 1358–1371.
[25] K. A. Peterson, D. Figgen, M. Dolg, H. Stoll, J. Chem. Phys. 2007,
126, 124101.
[18] M. Nishida, H. Shiga, M. Mori, J. Org. Chem. 1998, 63, 8606–8608.
[19] J. E. Brumwell, N. S. Simpkins, N. K. Terrett, Tetrahedron Lett. 1993,
34, 1219–1222.
[20] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789; c) P. J. Stephens,
F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98,
11623–11627.
Received: March 15, 2012
Revised: July 3, 2012
Published online: && &&, 0000
[21] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven, K. N.
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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A. Roglans, A. Pla-Quintana et al.
Cycloaddition Reactions
M. Parera, A. Dachs, M. Solꢀ,
A. Pla-Quintana,*
A. Roglans* ................... &&&& — &&&&
Direct Detection of Key Intermediates
in Rhodium(I)-Catalysed [2+2+2]
Cycloadditions of Alkynes by ESI-MS
Detecting intermediates: The mecha-
nism of the RhI-catalysed [2+2+2]
cycloaddition reaction was examined
using ESI-MS (see scheme). All of the
intermediates in the catalytic cycle
were detected by ESI-MS for the first
time and characterized by ESI-MS/MS.
DFT was used to support the structural
proposal made for the monoyne inser-
tion intermediate.
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!