Examining the Factors That Govern the Regioselectivity in Rhodium-Catalyzed Alkyne Cyclotrimerization

Article abstract of DOI:10.1021/acs.organomet.9b00347

The electronic and steric factors that favor the formation of 1,2,4- and 1,3,5-regioisomers in the intermolecular [2 + 2 + 2] cyclotrimerization of terminal alkynes are not well understood. In this work, this problem was analyzed from a theoretical and ex

Full text of DOI:10.1021/acs.organomet.9b00347

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pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Examining the Factors That Govern the Regioselectivity in Rhodium-
Catalyzed Alkyne Cyclotrimerization
̀
̀
̀
́
Oscar Torres, Martí Fernandez, Alex Díaz-Jimenez, Anna Pla-Quintana,* Anna Roglans,
̀
and Miquel Sola*
̀
̀
Institut de Química Computacional i Catalisi (IQCC) and Departament de Química, Universitat de Girona, C/Maria Aurelia
Capmany, 69, E-17003 Girona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: The electronic and steric factors that favor the formation of 1,2,4- and
1,3,5-regioisomers in the intermolecular [2 + 2 + 2] cyclotrimerization of terminal
alkynes are not well understood. In this work, this problem was analyzed from a
theoretical and experimental point of view. Density functional theory (DFT)
calculations of the [2 + 2 + 2] cyclotrimerization of p-X-substituted phenylacetylenes
(X = H, NO2, NH2) catalyzed by [Rh(BIPHEP)]+ were carried out to determine the
reaction mechanism in each case and analyze the effect that the electronic character of
the substituents has on the regioselectivity. For the rate-determining step
corresponding to the oxidative coupling leading to the rhodacyclopentadiene
intermediate, we have taken into account two reaction pathways: the reaction
pathway with the lowest energy barrier and the reaction pathway through the most
stable transition state (Curtin−Hammett pathway). Our results show that the
theoretical results conform to experimental outcomes for different p-X-substituted
t
phenylacetylenes (X = NO2, F, H, Me, Bu, OMe, NMe2) only when the Curtin−Hammett reaction pathway is considered. A
fairly good correlation has been obtained between the electronic nature of the substituents (as expressed by the Hammett σpara
constant values) and the regioisomeric ratios experimentally obtained and computationally predicted.
Scheme 1. Generally Accepted Mechanism for the [2 + 2 +
2] Cyclotrimerization Reaction of Three Alkynes
INTRODUCTION
■
a
Polysubstituted benzenes are extremely useful compounds that
are widely used both in industry and in academia. Since Reppe
et al. discovered in 1948 that nickel catalyzed the [2 + 2 + 2]
cyclotrimerization of three alkynes,1 this process has evolved
into an elegant preparative route to polysubstituted benzenes.2
A simplified picture of the most generally accepted
mechanism of the [2 + 2 + 2] cyclotrimerization, supported
by experimental evidence3 and computational studies,4−7 is
shown in Scheme 1. The reaction begins via a pair of ligand−
alkyne substitution reactions. The oxidative coupling of the
two alkyne ligands then generates the metallacyclopentadiene
IIIa or the metallacyclopentatriene IIIb with a bis-carbene
structure. Subsequent coordination of a third alkyne ligand to
the intermediate IIIa or IIIb is followed by either alkyne
insertion to form the metallacycloheptatriene V (the so-called
Schore mechanism)8 or metal-mediated [4 + 2] cycloaddition
to yield the metallanorbornadiene VI or [2 + 2] cycloaddition
to give the metallabicyclo[3.2.0]heptatriene VII. Finally, the
arene VIII is formed by reductive elimination of the metal.
A successful control of the regioselectivity in the intra-
molecular version of the [2 + 2 + 2] cycloaddition reactions is
generally accomplished by altering the positions of the alkynes
in the linear substrate and/or by modulating the strain in the
intermediates or products. On the other hand, successful
regiocontrol in a fully intermolecular reaction is much more
challenging.9 In the intermolecular [2 + 2 + 2] cyclo-
a
[M] = transition metal.
trimerization of three identical monosubstituted alkynes,
there is no chemoselectivity but regioselectivity remains a
problem. Scheme 2 shows the two possible regioisomers, 1,2,4-
trisubstituted benzene and 1,3,5-trisubstituted benzene, that
can be formed in the cycloaddition process.
The formation of the two regioisomers of Scheme 2 can be
understood by following the postulated general mechanism for
Received: May 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00347
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head, tail to tail, tail to head, and head to tail, giving the 1,4,
2,3, and 1,3/2,4 regioisomeric metallacyclopentadienes
(Scheme 2). In this notation, we consider the phenyl group
as the tail of the phenylacetylene molecule. In the subsequent
insertion of the third alkyne and posterior reductive
elimination, intermediates 1,4 and 2,3 only afford regioisomer
1,2,4, and only intermediates 1,3/2,4 can give regioisomers
1,2,4 or 1,3,5. As can be seen in Scheme 2, regioisomer 1,2,4 is
more likely to form than regioisomer 1,3,5, if we suppose
similar energy barriers for the formation of all intermediates. It
can be concluded that there are two crucial steps in obtaining
high selectivity in the formation of one of the regioisomers: (i)
the selective formation of a metallacyclopentadiene inter-
mediate and (ii) in the case of intermediate 1,3/2,4 the
regioselective insertion of the third alkyne. This second aspect
is crucial for the formation of the 1,3,5 regioisomer.
Scheme 2. Possible Regioisomers in the [2 + 2 + 2]
Cyclotrimerization of Three Identical Terminal Alkynes and
Their Mechanism of Formation
Substantial research efforts have been devoted to the
development of reaction conditions and catalytic systems
that allow the regioselective synthesis of polysubstituted
benzenes.10 The regioselectivity ratios obtained have been
rationalized mainly on the basis of steric grounds but also on
the basis of electronic effects in some examples,11 but there is
not a clear consensus on how the steric and electronic effects
govern the process; thus, there is a lack of predictive criteria.
To gain insight into the factors that govern the
regioselectivity in the [2 + 2 + 2] cycloaddition reactions,
we decided to study the cyclotrimerization of differently p-X-
substituted phenylacetylenes both by experiments and by
this reaction. In the case of the rhodium(I)-catalyzed
cyclotrimerization reactions, in the formation of the
rhodacyclopentadiene III, the two alkynes can be coupled
oxidatively to the rhodium(I) in three or four (depending on
the symmetry of the catalyst) different ways: namely, head to
Scheme 3. Gibbs Energy Profile (in kcal/mol) for the [2 + 2 + 2] Cycloaddition Reaction of Three Phenylacetylenes Catalyzed
a
by [Rh(BIPHEP)]+
a
Four possible oxidative coupling pathways have been explored, but from A3 only two paths have been followed, the lowest energy barrier path (in
green) leading to the 1,3,5-isomer and the Curtin−Hammett-favored path (in gray) leading to the 1,2,4-isomer.
B
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means of density functional theory (DFT) calculations. We
selected the cases X = H, NO2, NR2 (R = H in the
computational study and R = CH3 in experiments) with the
aim of discussing electronic effects in this cyclotrimerization.
Rhodium has been chosen as the transition metal in the
catalytic system, since it is one of the most often used catalysts.
In particular, we considered the cationic catalyst [Rh-
(BIPHEP)]+ (BIPHEP = 2,2-bis(diphenylphosphino)-1,1-
biphenyl), as it has been widely used for these [2 + 2 + 2]
cycloaddition reactions.2
are unimportant, the oxidative coupling places the C atom with
electron-withdrawing substituents next to the metal. Thus,
from an electronic point of view, the 1,4-coupling should be
favored and the 2,3-coupling should have the largest energy
barrier. One can expect the same ordering on taking into
account steric effects among phenylacetylenes. Indeed, when
substituents of terminal alkynes are bulky, the steric factor is
the one that controls the selectivity of the oxidative coupling.16
In our particular case, steric and electronic effects point to the
same conclusion for the oxidative coupling of two phenyl-
acetylenes.
RESULTS AND DISCUSSION
The results in Scheme 3 show that, as predicted on the basis
of electronic and steric effects, the 2,3-coupling is the one
having the less stable transition state (TS) for the oxidative
coupling. On the other hand, TSs for the 1,4- and 2,4-coupling
have the lowest energies (Scheme 3), but because the A2
intermediate in the 1,3-coupling is less stable than those of the
1,4- and 2,4-couplings, the oxidative coupling with the lowest
energy barrier corresponds to the tail to head 1,3-attack
(A2_1,3 in green in Scheme 3). The Gibbs energy barrier for
this 1,3-oxidative coupling through TS(A2,A3) is 17.4 kcal/
mol, about 2 kcal/mol less than for any of the other couplings
(see Table 1). This is the highest energy barrier throughout the
■
Let us start the discussion by analyzing the [2 + 2 + 2]
cyclotrimerization of unsubstituted phenylacetylene to yield
1,2,4- and 1,3,5-triphenylbenzene. The phenyl group has a
weak π donor and inductive withdrawing character12 that
makes phenylacetylene a mildly electron deficient alkyne.13
The Gibbs energy profile obtained for the [2 + 2 + 2]
cyclotrimerization of phenylacetylene catalyzed by [Rh-
(BIPHEP)]+ is shown in Scheme 3. There is a preactivation
scenario that transforms A0 to A2 in an exergonic process by
ca. 40−50 kcal/mol. On the other hand, the catalytic cycle that
involves A2 to A6 species is very exergonic by about 130−145
kcal/mol. This huge thermodynamic driving force is generated
by the formation of three new C−C σ bonds and a gain in
aromatic stabilization energy. Somewhat unexpectedly, 1,3,5-
triphenylbenzene is 1.6 kcal/mol less stable than 1,2,4-
triphenylbenzene. π−π stacking interactions between adjacent
phenyl groups in 1,2,4-triphenylbenzene make this compound
more stable than its 1,3,5-regioisomer. Formation of 1,3,5-
triphenylbenzene is, therefore, statistically (only 25% of the
possible reaction paths lead to its formation; Scheme 2) and
thermodynamically disfavored.
Table 1. Gibbs Energy Barriers (in kcal/mol) for the
Oxidative Coupling Step in the [2 + 2 + 2]
Cyclotrimerization Reaction of p-X-Substituted
Phenylacetylenes Catalyzed by Rh[BIPHEP]+ (TS(A2,A3))
coupling
X = H
X = NO2
X = NH2
regioisomer
1,4
2,4
2,3
1,3
23.4
19.5
19.2
17.4
16.6
17.4
21.5
21.9
18.8
16.8
18.5
13.9
1,2,4
1,2,4 or 1,3,5
1,2,4
1,2,4 or 1,3,5
To discuss the kinetic preferences of the two isomers, we
have to analyze the entire reaction mechanism. In the first step,
the interaction of one phenylacetylene with the [Rh-
(BIPHEP)]+ catalyst yields 14-electron intermediate A1 and
stabilizes the system by 31.3 kcal/mol. In the second step, a
second phenylacetylene molecule coordinates to the metal
center to form A2. This interaction can occur in four different
ways: namely, tail to tail (A2_2,3), head to head (A2_1,4), tail
to head (A2_1,3), and head to tail (A2_2,4, see Scheme 3).
Depending on the orientation of the two phenylacetylenes, the
stabilization energy of A2 with respect to A1 and a free
phenylacetylene ranges from 10.0 to 19.0 kcal/mol, the most
stable A2 intermediates being the head to head A2_1,4 and the
head to tail A2_2,4 isomers. Unsurprisingly, for steric reasons,
the tail to tail A2_2,3 disposition of the two ligands leads to
the less stable A2 intermediate. On the other hand, the tail to
head A2_1,3 isomer is 6.1 kcal/mol less stable than the head
to tail A2_2,4 intermediate because in the former there is some
steric repulsion between one of the phenyl groups of the
BIPHEP ligand and the triple bond of one phenylacetylene
(HBIPHEP−Cphenylacetylene distance of 2.533 Å). It is likely that the
different A2 species may reach equilibrium. Given that the
transformation between A2 species, which require turning back
to A1, is feasible, Curtin−Hammett14 conditions are
applicable. For this reason, we have decided to study both
the reaction path with the lowest energy barrier and the
Curtin−Hammett predicted path.
catalytic cycle and, therefore, is the rate-determining step (rds)
as found in some other [2 + 2 + 2] cyclotrimeriza-
tions.4a,5a,6b,c,e,7a,17 Given that for our system Curtin−
Hammett conditions are applicable, the reaction can also
evolve from A3_2,4 (in gray in Scheme 3) that has the
transition state lowest in energy. Under Curtin−Hammett
conditions, the barrier has to be computed with respect to the
intermediate lowest in energy, and therefore, formation of
A3_2,4 through TS(A2,A3) has an energy barrier of 22.2 kcal/
mol. It is important to note that both intermediates, which
differ in the relative orientation of the BIPHEP moiety and the
rhodacyclopentadiene, can provide either the 1,2,4- or the
1,3,5-triphenylbenzene depending on the insertion step.
The rhodacyclopentadiene ring in the intermediate A3_1,3
has a short−long−short Cα−Cβ−Cβ−Cα sequence (1.347,
1.477, and 1.353 Å), indicating that the π bonds are quite
localized and there is no aromaticity in this five-membered
ring.6b,7c The same pattern is observed in all of the
rhodacyclopentadiene intermediates studied.
It is worth comparing the Gibbs energy profile of the [2 + 2
+ 2] cyclotrimerization catalyzed by [Rh(BIPHEP)]+ of
phenylacetylene with that of acetylene. The latter can be
found in the Supporting Information. The energy barrier of the
oxidative coupling of two acetylenes is 3.1 kcal/mol lower than
that found for the 1,3-oxidative coupling of two phenyl-
acetylenes. This result is somewhat unexpected, since it has
been reported that electron-withdrawing groups facilitate the
oxidative coupling by lowering the LUMO of the π bond.4b,7c
From A2, the system evolves to give the rhodacyclopenta-
diene intermediate A3 through an oxidative coupling. From the
work by Stockis and Hoffmann,15 we know that, if steric effects
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Scheme 4. Gibbs Energy Barriers (in kcal/mol) for the Insertion of Phenylacetylene in the 1,3- or 2,4-
a
Diphenylrhodacyclopentadiene (TS(A4,A5))
a
b
A green tick indicates the preferred pathway (insertion with the lowest barrier). Despite many attempts to fully optimize the TS for this
approach, this TS was optimized only for the forces and not for the displacements due to the very flat potential energy surface. Therefore, the
reported Gibbs energy barrier represents an estimation that we think should be close to the exact value.
It is likely that steric effects are responsible for the increase in
the energy barrier on going from acetylene to phenylacetylene.
Coming back to the [2 + 2 + 2] cyclotrimerization of
phenylacetylene catalyzed by [Rh(BIPHEP)]+, let us discuss
first the evolution of the intermediate coming from the lowest
barrier in the oxidative coupling. Once the 1,3-diphenylrho-
dacyclopentadiene A3_1,3 is formed, another phenylacetylene
molecule coordinates to Rh to yield the 16-electron
intermediate A4, releasing about 18 kcal/mol. The molecular
structure of the resulting complex is similar to the only
reported example of a metallacyclopentadiene(alkyne) spe-
cies.18 Interestingly, in this case, the addition of the new
coordinated phenylacetylene molecule to the 1,3-diphenylrho-
dacyclopentadiene occurs through an insertion into the Rh−C
bond (Schore’s mechanism). We tried to locate the
rhodanorbornadiene and rhodabicyclo[3.2.0]heptatriene inter-
mediates, but all our attempts failed; consequently, the
presence of these intermediates in the reaction mechanism
was ruled out. The insertion through the Schore mechanism
does not generate the expected rhodacycloheptatriene or the
four- and five-membered bicyclic intermediate. Instead of that,
the reaction evolves directly to the formation of A5: i.e., the
product η6-coordinated to the Rh[BIPHEP]+ with Rh−Cbenzene
distances ranging from 2.26 to 2.47 Å. For the insertion
process, we have analyzed all four possible insertions of the
phenylacetylene molecule into the rhodacyclopentadiene
complex (Scheme 4, first row). The two attacks in which the
phenylacetylene is inserted into the Rh−Cα bond of the
rhodacyclopentadiene complex with the Cα being attached to a
hydrogen (types I and II) were found to lead to intermediate
A5 with low Gibbs energy barriers. The insertions into the
Rh−Cα bond in which the Cα is attached to the phenyl (types
III and IV) were found to have barriers higher by at least 9.3
kcal/mol. Type I insertions are usually preferred for electro-
static reasons. The unsubstituted C atoms in phenylacetylene
and rhodacyclopentadiene are more negatively charged than
the C atoms with Ph substituents having electron withdrawing
character. On the basis of electrostatic grounds,19 the more
negatively charged unsubstituted C atom in phenylacetylene
interacts better with the metal and the less negatively charged
C atom in phenylacetylene prefers the unsubstituted Cα of the
rhodacyclopentadiene.
For the oxidative coupling process, in the insertion step, we
also considered the possibility that the different
metallacyclopentadiene(alkyne) complexes A4 were in equili-
brium. However, the barriers for insertion are lower than those
for the conversion of A4 into A3, and so the Curtin−Hammett
conditions are not fulfilled in this insertion process.
Now, let us move to the evolution of the intermediate
A3_2,4, which comes from the Curtin−Hammett path in the
oxidative coupling reaction (in gray in Scheme 3). We have
again analyzed all four possible insertions of the phenyl-
acetylene molecule into the rhodacyclopentadiene complex
(Scheme 4, second row). In this case, the insertion with the
lowest barrier (6.7 kcal/mol) takes place into the Rh−Cα bond
in which the Cα is attached to the phenyl (type III) and leads
to the 1,2,4-regiosiomer. The preference for this insertion in
comparison to type I seems to arise from a better π−π
interaction in the transition state of the type III insertion. A
type IV insertion from A3_2,4 yields the 1,3,5-regiosiomer
with a barrier of 10.4 kcal/mol. Using the transition state
theory, one predicts a 99:1 (1,2,4:1,3,5) ratio of regiosiomers.
As a whole, whereas the path with the lowest energy barrier
for the oxidative coupling generates preferentially the 1,3,5-
triphenylbenzene (with a predicted 1:99 1,2,4:1.3.5 regioiso-
meric ratio using the transition state theory), the pathway that
is followed under Curtin−Hammett conditions leads prefer-
entially to the 1,2,4-triphenylbenzene (99:1 ratio). If the two
pathways were operative and equally favored, we would predict
the formation of a ca. 50:50 mixture of 1,2,4- and 1,3,5-
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triphenylbenzene as a result of competing paths of similar
energy barriers. However, experimental (theoretical) results
found a 96:4 (99:1) ratio of the two regioisomers (vide infra),
the 1,2,4-triphenylbenzene being clearly favored. This result
indicates that the Curtin−Hammett pathway is the preferred
one in the Rh-catalyzed alkyne cyclotrimerization.
Final release of the product from A5 is assisted by the
addition of two phenylacetylene molecules, directly regenerat-
ing intermediate A2.
Next, we increased the electron-withdrawing character of the
phenyl group by adding a nitro substituent in the para position
of the phenyl group: i.e., we studied the cyclotrimerization of
p-nitrophenylacetylene catalyzed by [Rh(BIPHEP)]+. The
Gibbs energy profile for this [2 + 2 + 2] cyclotrimerization
is given in Scheme S1 in the Supporting Information. The
electron-withdrawing effects of the p-nitrophenyl group are
now enhanced and, as a result, the barrier for the 2,3-attack
increases and that of the 1,4-oxidative coupling decreases
(Table 1). Therefore, this 1,4-transition state is now the most
stable and also it is the oxidative coupling with the lowest
energy barrier. Consequently, calculations predict the for-
mation of only the 1,2,4-regioisomer. For 1,4-di-p-nitro-
phenylrhodacyclopentadiene, the type V insertion (Scheme
5) has the lowest energy barrier (4.0 kcal/mol) and the
in the [2 + 2 + 2] cyclotrimerization of p-nitrophenylacetylene
is the one corresponding to the 1,4-oxidative coupling, always
leading exclusively to the 1,2,4-tri-p-nitrophenylbenzene.
Finally, we reduced the electron-withdrawing character of
the phenyl group by adding an amino substituent in the para
position of the phenyl group: i.e., we studied the cycloaddition
of p-aminophenylacetylene catalyzed by [Rh(BIPHEP)]+. The
Gibbs energy profile for this [2 + 2 + 2] cyclotrimerization is
given in Scheme S2 in the Supporting Information. The
electron-donating effects of the amino group result in a
decrease in the barrier for the 2,3-attack and in an increase in
the 1,4-oxidative coupling in comparison to those of the p-
nitrophenylacetylene (Table 1). For steric reasons, the tail to
head (A2_1,3) disposition of the two ligands leads to the less
stable intermediate A2. This intermediate is connected to the
TS(A2,A3) of the 1,3-oxidative coupling that has the lowest
Gibbs energy barrier (13.9 kcal/mol). The Gibbs energy
barriers of the rest of the possible oxidative couplings are, at
least, 2.9 kcal/mol higher in energy. We also considered the
pathways that start with the head to head (A2_1,4) and head
to tail (A2_2,4) dispositions of the two p-aminophenylacety-
lenes that correspond to the transition states lowest in energy
(Curtin−Hammett pathways). These two transition states
differ by only 0.1 kcal/mol, and for this reason we analyzed
two Curtin−Hammett paths for this cyclotrimerization. This
0.1 kcal/mol energy difference corresponds to a product ratio
of 54:46 in favor of the 1,2,4-regioisomer (considering that
A2_1,4 leads to the 1,2,4- regioisomer and that A2_2,4 evolves
to the 1,3,5-regioisomer, vide infra). Once the 1,3-, 1,4-, or 2,4-
di-p-aminophenylrhodacyclopentadiene intermediate A3 is
formed, another p-aminophenylacetylene molecule coordinates
to Rh to yield the 16-electron intermediate A4 and release
about 20 kcal/mol, depending on the orientation of the
incoming molecule. For the path through the lowest energy
barrier for the phenylacetylene, type I insertions into 1,3- and
2,4-di-p-aminophenylrhodacyclopentadiene intermediates, in
which the p-aminophenylacetylene is inserted into the Rh−
Cα bond of the rhodacyclopentadiene complex with the
unsubstituted Cα, were found to lead to intermediate A5 with
low Gibbs energy barriers (Scheme 6). For 1,4-di-p-amino-
phenylrhodacyclopentadiene, type V insertion is preferred, as
in the case of p-nitrophenylacetylene. The Gibbs energy
barriers for the transformation of A4 into A5 are 4.4 kcal/mol
for the type I insertion in A4_1,3 leading to the 1,3,5-isomer
and 4.9 kcal/mol for the type V insertion in A4_1,4 producing
the 1,2,4-isomer, whereas the type I insertion in A4_2,4 is
barrierless and yields the 1,3,5-regioisomer (see Scheme 6 and
Scheme S2). In all cases, these paths represent the insertion
with both the lowest transition state and the lowest energy
barrier. Although formation of the 1,3,5-isomer is slightly
favored thermodynamically (by 1.5 kcal/mol), from a kinetic
point of view and given the existence of multiple paths with
relatively low Gibbs energy barriers, it is likely that,
experimentally, a mixture of 1,3,5- and 1,2,4-tri-p-amino-
phenylacetylenebenzene will be formed. In particular, the
Curtin−Hammett pathway, which is found to be the preferred
one in the Rh-catalyzed alkyne cyclotrimerization of phenyl-
acetylene, produces a mixture of the 1,2,4-isomer coming from
the A4_1,4 intermediate via type V insertion and the 1,3,5-
regioisomer generated from type I insertion in A4_2,4.
Scheme 5. Gibbs Energy Barriers (in kcal/mol) for the
Insertion of p-NO2-phenylacetylene in the 1,4-
Dinitrophenylrhodacyclopentadiene (TS(A4,A5))
a
a
A green tick indicates the preferred pathway (insertion with the
b
lowest barrier). Despite many attempts to fully optimize the TS for
this approach, this TS was optimized only for the forces and not for
the displacements due to the very flat potential energy surface.
Therefore, the reported Gibbs energy barrier represents an estimation
that we think should be close to the exact value.
transition state lowest in energy. We called these type V to
VIII insertions because, at variance with insertions in 1,3- and
2,4-diphenylrhodacyclopentadienes, in 1,4-diphenylrhodacy-
clopentadienes, the two possible Rh−Cα insertions have Cα
atoms with Ph substituents. The insertion reaction is more
favorable for the p-nitrophenylacetylene molecules than for the
phenylacetylenes. The insertion leads to intermediate A5 (the
product η6-coordinated to [Rh(BIPHEP)]+) that subsequently
releases the 1,2,4-tri-p-nitrophenylbenzene in the final
reductive elimination process. As a whole, the route followed
To check experimentally the conclusions from the
theoretical results, we conducted the rhodium-catalyzed [2 +
2 + 2] cyclotrimerization of a series of commercially available
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Scheme 6. Gibbs Energy Barriers (in kcal/mol) for the Insertion of p-Aminophenylacetylene in the 1,3-, 2,4-, or 1,4-
a
Diaminophenylrhodacyclopentadiene (TS(A4,A5))
a
A green tick indicates the preferred pathway (insertion with the lowest barrier).
p-substituted phenylacetylenes 1 (Table 2) with different
Table 2. [Rh(COD)2]BF4/BIPHEP-Catalyzed [2 + 2 + 2]
Cyclotrimerization of Phenylacetylene Derivatives 1
a
t
electronic demands (X = NO2, F, H, Me, Bu, OMe, and
NMe2), including the substrates studied theoretically.20
A
combination of the cationic rhodium complex [Rh(COD)2]-
BF4 and BIPHEP as the biphosphine was selected as the
catalytic system. Using 5 mol % of the catalytic system
[Rh(COD)2]BF4/BIPHEP in dichloroethane as the solvent,
the reaction was carried out under reflux. The results obtained
are shown in Table 2 together with the Hammett substituent
σpara constants of the different substrates.21 Every reaction was
run twice under the same reaction conditions to check the
reproducibility of the method, especially in the case of the ratio
between regioisomers. The low yields of the NO2, F, and
NMe2 cases are due to the polymerization of the para-
substituted phenylacetylenes and formation of decomposition
products.
The correlation between the ratio of 1,2,4 (2):1,3,5 (3)
regioisomers formed and the Hammett substituent σpara
constants is fairly good. The highly electron withdrawing
nitro group yielded the 1,2,4-regioisomer 2 exclusively, and no
traces of the 1,3,5-regioisomer 3 were detected (entry 1, Table
2), as was predicted with our DFT calculations. On the other
extreme, when the reaction was run with p-dimethylamino-
phenylacetylene (entry 7, Table 2), the cyclotrimerization gave
a mixture of the two regioisomers in a 59:41 ratio (in
comparison to the theoretical 54:46 prediction). When p-
aminophenylacetylene was calculated, two insertions (A3_2,4
b
c
entry
X
σpara
yield (%) (2 + 3)
ratio (2:3)
1
2
3
4
5
6
7
NO2
F
0.78
0.06
0
−0.17
−0.20
−0.27
−0.83
38
36
62
96
92
65
33
100:0
92:08
96:04
95:05
81:19
94:06
59:41
H
Me
tBu
OMe
NMe2
a
Reaction conditions: [Rh(COD)2]BF4 (0.025 mmol), BIPHEP
(0.025 mmol), alkyne (0.5 mmol), DCE (3 mL) at reflux for 3 h
t
(X = H, NO2) or reflux for 23 h (X = F, Me, Bu, OMe, NMe2).
b
c
Isolated yield. Ratio was determined by 1H NMR of the crude
mixture except in the case of p-fluorophenylacetylene, in which 19F
NMR was used.
and A3_1,4) were possible, each one leading to the formation
of one different isomer, and so a mixture of both isomers could
F
DOI: 10.1021/acs.organomet.9b00347
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
singlet state potential energy surfaces. However, we calculated the
triplet state for all reactants, intermediates, transition states, and
products, and we found that triplet states were higher in energy in all
cases and, therefore, were not considered in the reaction path. The
electronic energy was improved by performing single-point calcu-
lations with the aug-cc-pVTZ (cc-pVTZ-PP for Rh) basis set.
Analytical Hessians were computed to determine the nature of
stationary points (one and zero imaginary frequencies for TSs 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.29 These
last two terms were computed at 353.15 K (temperature of
experiments) and 1 atm to provide the reported relative Gibbs
energies (ΔG). Entropy corrections were divided by a factor of 2 to
correct for the overestimation suffered by gas-phase entropies when
they are used to determine entropies for reactions in solution.30
Finally, solvation Gibbs energies in dichloroethane were calculated
with the B3LYP-D3/cc-pVDZ-PP method using the PCM continuum
solvation model31 at the gas-phase geometries. The resulting solvation
Gibbs energies were added to the final Gibbs energies in the gas phase
to obtain Gibbs energies in solution. Standard Gibbs energies in
solution refer to a 1 M standard-state concentration for all species.
The change of conventional 1 atm standard state for gas-phase
calculations to a standard-state gas-phase concentration of 1 M
requires the introduction of a concentration change energy term of
2.36 kcal/mol at 353.15 K.32 As a summary, the hereafter reported
Gibbs energies contain electronic energies calculated at the B3LYP-
D3/aug-cc-pVTZ-PP//B3LYP-D3/cc-pVDZ-PP level together with
gas-phase thermal corrections and entropic contributions (the latter
divided by 2) at 353.15 K as well as the 2.36 kcal/mol term of
changing the standard states from 1 atm to 1 M and the solvation
energies computed with the B3LYP-D3/cc-pVDZ-PP method.
Furthermore, the connectivity between stationary points was
unambiguously established by intrinsic reaction path33 calculations.
The Cartesian coordinates of all minima and TSs located can be
found in the Supporting Information.
be expected, which is what is observed experimentally. The
remaining substrates, comprising substituents with σpara values
ranging from 0.06 to −0.27 (entries 2−6, Table 2) led to
regioisomeric mixtures ranging from 96:04 to 81:19, highly
enriched with the 1,2,4-regioisomer. In the cyclotrimerization
of phenylacetylene following the Curtin−Hammett calculated
path, the type III insertion from A3_2,4 is the most favored,
explaining why the 1,2,4-isomer was the one obtained
predominantly in the experiments, a result which we think
can be extrapolated to this entire set of substituents.
CONCLUSIONS
■
We performed density functional theory (DFT) calculations of
three p-X-substituted phenylacetylenes (X = H, NO2, NH2)
and experimental studies of seven p-X-substituted phenyl-
acetylenes (X = NO2, F, H, Me, tBu, OMe, NMe2) in the [2 +
2 + 2] cyclotrimerization catalyzed by [Rh(BIPHEP)]+ to
analyze the effect of the electronic character of the substituents
on the regioselectivity of the reaction. Our theoretical and
experimental results show that p-nitrophenylacetylene, which
has the most electron withdrawing substituent, yields
exclusively the 1,2,4-regioisomer by favoring head to head
oxidative coupling. On the other hand, when X = H, the 1,2,4-
regioisomer is formed preferentially, whereas when X = NMe2,
a 59:41 mixture of both isomers is obtained. These
experimental results provide evidence that, from the two
possible reactions pathways analyzed computationally (lowest
in energy barrier and Curtin−Hammett paths), the Curtin−
Hammett pathway is the operative one and, therefore, is the
one governing the regioselectivity.
EXPERIMENTAL SECTION
■
Representative Methods. Unless otherwise noted, materials
were obtained from commercial suppliers and used without further
purification. Reactions requiring anhydrous conditions were con-
ducted in oven-dried glassware under a dry nitrogen atmosphere.
Dichloromethane was degassed and dried under a nitrogen
atmosphere by passing through solvent purification columns
(MBraun, SPS-800). Solvents were removed under reduced pressure
with a rotary evaporator. Reaction mixtures were chromatographed on
a silica gel column (230−400 mesh) by using a gradient solvent
system as the eluent.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00347.
■
S
Characterization data for the cyclotrimerized products
and Gibbs energy profiles (in kcal/mol) for the [2 + 2 +
2] cyclotrimerization reaction catalyzed by Rh-
[BIPHEP]+ of three 4-nitrophenylacetylenes, three 4-
aminophenylacetylenes, and three acetylenes (PDF)
Cartesian coordinates of all minima and transition states
(XYZ)
General Procedure for [2 + 2 + 2] Cycloaddition Reactions
of p-Substituted Phenylacetylenes. In a 10 mL flask, a mixture of
[Rh(COD)2]BF4 (0.025 mmol) and BIPHEP (0.025 mmol) was
dissolved in CH2Cl2 (3 mL). Hydrogen gas was introduced to the
catalyst solution, and the mixture was stirred for 30 min. The resulting
mixture was then concentrated to dryness. Dichloroethane (2 mL)
was added, and the solution was stirred under a N2 atmosphere and
heated at 80 °C. A solution of phenylacetylene 1 (0.5 mmol) in
dichloroethane (1 mL) was then added to the preheated catalytic
mixture. The reaction mixture was then stirred at reflux until
completion (TLC and GC monitoring). The solvent was evaporated,
and the residue was purified by column chromatography on silica gel.
Computational Details. Geometries of the reactants, intermedi-
ates, transition states (TSs), and products were optimized using the
DFT B3LYP22 hybrid exchange-correlation functional with the
Gaussian0923 program. All geometry optimizations were performed
without symmetry constraints. In all calculations the D3 Grimme
energy correction for dispersion24 with the Becke−Johnson damping
function25 was included. The all-electron cc-pVDZ basis set26 was
employed for nonmetal atoms, and the cc-pVDZ-PP basis set
containing an effective core relativistic pseudopotential was used for
Rh.27 The same method (B3LYP-D3) with a similar double-ξ basis set
with polarized functions has been recently recommended to predict
product concentrations.28 The results reported are limited to the
AUTHOR INFORMATION
Corresponding Authors
*E-mail for A.P.-Q.: anna.plaq@udg.edu.
*E-mail for M.S.: miquel.sola@udg.edu.
■
ORCID
̀
́
Alex Díaz-Jimenez: 0000-0003-1241-8263
Anna Pla-Quintana: 0000-0003-2545-9048
Anna Roglans: 0000-0002-7943-5706
̀
Miquel Sola: 0000-0002-1917-7450
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministry of Economy and
Competitivity (MINECO) (Project No. CTQ2017-85341-P)
■
G
DOI: 10.1021/acs.organomet.9b00347
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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Scopelliti, R.; Rothlisberger, U.; Severin, K. Reactions of alkynes with
[RuCl(cyclopentadienyl)] complexes: the important first steps. Chem.
and the DIUE of the Generalitat de Catalunya (Project No.
2017SGR39 and ICREA Academia 2014 to M.S.) are
acknowledged. Thanks are due to the Generalitat de Catalunya
for FI predoctoral grants to O.T., M.F,. and A.D.-J. The EU
under the FEDER grant UNGI10-4E-801 has also funded this
research.
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