ESI-MS, DFT, and synthetic studies on the H2-mediated coupling of acetylene: Insertion of C=X bonds into rhodacyclopentadienes and Bronsted acid cocatalyzed hydrogenolysis of organorhodium intermediates

Article abstract of DOI:10.1021/ja906225n

The catalytic mechanism of the hydrogen-mediated coupling of acetylene to carbonyl compounds and imines has been examined using three techniques: (a) ESI-MS and ESI-CAD-MS analyses, (b) computational modeling, and (c) experiments wherein putative reactive

Full text of DOI:10.1021/ja906225n

Published on Web 10/21/2009
ESI-MS, DFT, and Synthetic Studies on the H2-Mediated
Coupling of Acetylene: Insertion of CdX Bonds into
Rhodacyclopentadienes and Brønsted Acid Cocatalyzed
Hydrogenolysis of Organorhodium Intermediates
Vanessa M. Williams,† Jong Rock Kong,† Byoung Joon Ko,† Yogita Mantri,‡
Jennifer S. Brodbelt,*,† Mu-Hyun Baik,*,‡ and Michael J. Krische*,†
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712,
and Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received February 25, 2009; E-mail: jbrodbelt@mail.utexas.edu; mbaik@indiana.edu;
mkrische@mail.utexas.edu
Abstract: The catalytic mechanism of the hydrogen-mediated coupling of acetylene to carbonyl compounds
and imines has been examined using three techniques: (a) ESI-MS and ESI-CAD-MS analyses, (b)
computational modeling, and (c) experiments wherein putative reactive intermediates are diverted to alternate
reaction products. ESI-MS analysis of reaction mixtures from the hydrogen-mediated reductive coupling of
acetylene to R-ketoesters or N-benzenesulfonyl aldimines corroborate a catalytic mechanism involving CdX
(X ) O, NSO2Ph) insertion into a cationic rhodacyclopentadiene obtained by way of acetylene oxidative
dimerization with subsequent Brønsted acid cocatalyzed hydrogenolysis of the resulting oxa- or azarho-
dacycloheptadiene. Hydrogenation of 1,6-diynes in the presence of R-ketoesters provides analogous coupling
products. ESI mass spectrometric analysis again corroborates a catalytic mechanism involving carbonyl
insertion into a cationic rhodacyclopentadiene. For all ESI-MS experiments, the structural assignments of
ions are supported by multistage collisional activated dissociation (CAD) analyses. Further support for the
proposed catalytic mechanism derives from experiments aimed at the interception of putative reactive
intermediates and their diversion to alternate reaction products. For example, rhodium-catalyzed coupling
of acetylene to an aldehyde in the absence of hydrogen or Brønsted acid cocatalyst provides the
corresponding (Z)-butadienyl ketone, which arises from ꢀ-hydride elimination of the proposed oxarhoda-
cycloheptadiene intermediate, as corroborated by isotopic labeling. Additionally, the putative rhodacyclo-
pentadiene intermediate obtained from the oxidative coupling of acetylene is diverted to the product of
reductive [2 + 2 + 2] cycloaddition when N-p-toluenesulfonyl-dehydroalanine ethyl ester is used as the
coupling partner. The mechanism of this transformation also is corroborated by isotopic labeling. Computer
model studies based on density functional theory (DFT) support the proposed mechanism and identify
Brønsted acid cocatalyst assisted hydrogenolysis to be the most difficult step. The collective studies provide
new insight into the reactivity of cationic rhodacyclopentadienes, which should facilitate the design of related
rhodium-catalyzed C-C couplings.
Introduction
processes, systematic efforts toward hydrogen-mediated C-C
bond formations that extend beyond carbon monoxide coupling
The Fischer-Tropsch1 reaction and alkene hydroformylation2
rank among the largest volume catalytic processes practiced in
the chemical industry3 and may be viewed as prototypical C-C
bond-forming hydrogenations. Despite the impact of these
only recently have begun to emerge.4,5 We have found that
diverse unsaturates couple to carbonyl compounds and imines
under the conditions of catalytic hydrogenation and transfer
hydrogenation, offering an alternative to stoichiometrically
† University of Texas at Austin.
(3) Baade, W. F.; Parekh, U. N.; Raman, V. S. Hydrogen. In Kirk-Othmer’s
Encyclopedia of Chemical Technology, 5th ed.; Wiley: Hoboken, NJ,
2004; Vol. 13, p 759.
(4) For recent reviews on hydrogen-mediated C-C coupling, see: (a) Ngai,
M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (b)
Iida, H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77. (c) Shibahara,
F.; Krische, M. J. Chem. Lett. 2008, 37, 1102. (d) Bower, J. F.; Kim,
I. S.; Patman, R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48,
34.
‡ Indiana University.
(1) For a review, see: (a) Cornils, B.; Herrmann, A.; Rasch, M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2144.
(2) For recent reviews on alkene hydroformylation, see: (a) Cornils, B.;
Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem., Int. Ed. Engl.
1994, 33, 2144. (b) Beller, M.; Cornils, B.; Frohning, C. D.;
Kohlpaintner, C. W. J. Mol. Catal. 1995, 104, 17. (c) Eilbracht, P.;
Barfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.;
Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A. Chem.
ReV. 1999, 99, 3329. (d) Nozaki, K. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 1, p 381. (e) Breit, B. Acc. Chem. Res.
2003, 36, 264.
(5) Prior to systematic studies from our laboratory, two isolated examples
of hydrogen-mediated C-C bond formation not involving the cou-
plings of carbon monoxide were reported: (a) Molander, G. A.; Hoberg,
J. O. J. Am. Chem. Soc. 1992, 114, 3123. (b) Kokubo, K.; Miura, M.;
Nomura, M. Organometallics 1995, 14, 4521.
9
16054 J. AM. CHEM. SOC. 2009, 131, 16054–16062
10.1021/ja906225n CCC: $40.75  2009 American Chemical Society

Studies on the H2-Mediated Coupling of Acetylene
A R T I C L E S
preformed organometallics in a range of classical CdX (X )
O, NR) addition processes, including aldol and Mannich
addition,6 carbonyl allylation,7 and carbonyl and imine viny-
lation.8 Remarkably, under transfer hydrogenation conditions,
an alcohol serves dually as hydrogen donor and precursor to
the carbonyl electrophile, enabling carbonyl addition from the
that corroborate a catalytic mechanism involving oxidative
coupling of acetylene to generate a cationic rhodacyclopenta-
diene, which engages in carbonyl or imine insertion, followed
by Brønsted acid assisted hydrogenolysis of the resulting oxa-
or aza-rhodacycloheptadienes to furnish the products of (Z)-
butadienylation. Structural assignments of ions observed in the
ESI-mass spectra are supported by multistage collisional
activated dissociation (CAD). Intervention of the purported
rhodacyclopentadiene and the purported oxa- and azarhodacy-
cloheptadiene as reactive intermediates is supported further
through the design of related processes in which these transient
species are diverted to products of [2 + 2 + 2] cycloaddition
and ꢀ-hydride elimination, respectively. The collective studies
demonstrate that cationic rhodacyclopentadienes engage in
carbonyl and imine insertion, providing a foundation for the
development of related rhodium-catalyzed C-C couplings.13
alcohol oxidation level,
a formal hydrohydroxyalkyla-
tion.7b-d,f,g,8n,9
A broad goal of these investigations resides in the develop-
ment of hydrogen-mediated couplings applicable to basic
chemical feedstocks. Accordingly, it was found that rhodium-
catalyzed hydrogenation of acetylene (2 cents/mol, annual US
production >500 metric kilotons)10 in the presence of carbonyl
compounds or imines promotes formation of (Z)-butadienyl
allylic alcohols and (Z)-butadienyl allylic amines, respectively
(eq 1).11 In these multicomponent couplings, two molecules of
acetylene combine with elemental hydrogen and a molecule of
carbonyl compound or imine.
Results and Discussion
In our initial studies on the hydrogen-mediated reductive
coupling of acetylene to carbonyl compounds,11a a catalytic
mechanism was proposed involving carbonyl insertion into a
cationic rhodacyclopentadiene obtained upon oxidative dimer-
ization of acetylene, followed by Brønsted acid assisted hydro-
genolysis of the resulting oxarhodacycloheptadiene,14 as shown
in Cycle A (Scheme 1). This interpretation of the catalytic
mechanism is consistent with the results of isotopic labeling
studies. Rhodium-catalyzed reductive coupling of R-ketoester
1a and acetylene under an atmosphere of elemental deuterium
provides deuterio-1b, which incorporates a single deuterium
atom at the diene terminus as the (Z)-stereoisomer. Rhodacy-
clopentadienes that are catalytically competent species in
acetylene cyclotrimerization to form benzene have been isolated
and characterized by single crystal X-ray diffraction analysis.15
Further, carbonyl insertion into a Rh-C bond followed by
In the present account, we disclose ESI-mass spectrometric12
and computational modeling studies of these transformations
(6) For hydrogen-mediated reductive aldol and Mannich couplings, see:
(a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc.
2002, 124, 15156. (b) Huddleston, R. R.; Krische, M. J. Org. Lett.
2003, 5, 1143. (c) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6,
691. (d) Marriner, G. A.; Garner, S. A.; Jang, H.-Y.; Krische, M. J. J.
Org. Chem. 2004, 69, 1380. (e) Jung, C.-K.; Garner, S. A.; Krische,
M. J. Org. Lett. 2006, 8, 519. (f) Han, S. B.; Krische, M. J. Org. Lett.
2006, 8, 5657. (g) Jung, C.-K.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 17051. (h) Garner, S. A.; Krische, M. J. J. Org. Chem. 2007, 72,
5843. (i) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 2747.
(10) Gannon, R. E.; Manyik, R. M.; Dietz, C. M., Sargent, H. B.; Schaffer,
R. P.; Thribolet, R. O. In Kirk-Othmer’s Encyclopedia of Chemical
Technology, 5th ed.; Wiley: Hoboken, NJ, 2004; Vol. 1, p 216.
(11) For hydrogen-mediated couplings of acetylene to carbonyl compounds
and imines, see: (a) Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 16040. (b) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 7242. (c) Han, S. B.; Kong, J.-R.; Krische,
M. J. Org. Lett. 2008, 10, 4133.
(12) For reviews covering use of ESI mass spectrometric analysis as applied
to the characterization of catalytic reaction mechanisms, see: (a)
Plattner, D. Int. J. Mass. Specrom. 2001, 207, 125. (b) Chen, P. Angew.
Chem., Int. Ed. 2003, 42, 2832.
(13) Following disclosure of our work (ref 11), other rhodium catalyzed
C-C bond formations believed to proceed by way of carbonyl insertion
into transient rhodacyclopentadienes were reported: (a) Tanaka, K.;
Otake, Y.; Wada, A.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9,
2203. (b) Tsuchikama, K.; Yoshinami, Y.; Shibata, T. Synlett 2007,
1395.
(7) For hydrogen-mediated carbonyl allylation, see: (a) Skucas, E.; Bower,
J. F.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678. (b) Bower,
J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc.
2007, 129, 15134. (c) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 6340. (d) Shibahara, F.; Bower, J. F.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 6338. (e) Ngai, M.-Y.; Skucas,
E.; Krische, M. J. Org. Lett. 2008, 10, 2705. (f) Kim, I. S.; Ngai,
M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14891. (g) Kim,
I. S.; Han, S.-B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514.
(8) For hydrogen-mediated vinylation of carbonyl compounds and imines,
see: (a) Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2003, 125, 11488. (b) Jang, H.-Y.; Huddleston, R. R.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 4664. (c) Kong, J.-R.; Cho, C.-
W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269. (d) Cho,
C.-W.; Krische, M. J. Org. Lett. 2006, 8, 891. (e) Kong, J.-R.; Ngai,
M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718. (f) Cho,
C.-W.; Krische, M. J. Org. Lett. 2006, 8, 3873. (g) Rhee, J.-U.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 10674. (h) Komanduri, V.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 16448. (i) Ngai, M.-Y.; Barchuk,
A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 280. (j) Barchuk, A.;
Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432. (k)
Cho, C.-W.; Skucas, E.; Krische, M. J. Organometallics 2007, 26,
3860. (l) Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org.
Lett. 2007, 9, 3745. (m) Barchuk, A.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 12644. (n) Patman, R. L.; Chaulagain,
M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
2066.
(14) As previously observed (see refs 8e,g,h), carboxylic acid cocatalysts
enhance rate and conversion, presumably by circumventing highly
energetic 4-centered transition structures for σ-bond metathesis, as
required for direct hydrogenolysis of oxametallacyclic intermediates,
with 6-centered transition structures for hydrogenolysis of iridium
carboxylates derived upon protonolytic cleavage of the nitrogen-iridium
bond. This interpretation finds support in recent theoretical studies on
the hydrogenolysis of rhodium formates: Musashi, Y.; Sakaki, S. J. Am.
Chem. Soc. 2002, 124, 7588.
(15) Bianchini, C.; Caulton, K. G.; Chardon, C.; Eisenstein, O.; Folting,
K.; Johnson, T. J.; Meli, A.; Peruzzini, M.; Rauscher, D. J.; Streib,
W. E.; Vizza, F. J. Am. Chem. Soc. 1991, 113, 5127, and references
cited therein.
(9) For related hydroaminoalkylations (amine-unsaturate C-C coupling),
see: (a) Maspero, F.; Clerici, M. G. Synthesis 1980, 305. (b) Nugent,
W. A.; Ovenall, D. W.; Homes, S. J. Organometallics 1983, 2, 161.
(c) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 6690.
(d) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 14940.
(e) Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009,
48, 1153. (f) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne,
P. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116.
(16) For insertion of carbonyl moieties into Rh-C bonds followed by
protonolytic cleavage or ꢀ-hydride elimination of the incipient rhodium
alkoxide, see: (a) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 1674. (b) Fujii, T.; Koike, T.; Mori, A.; Osakada, K. Synlett 2002,
298.
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A R T I C L E S
Williams et al.
Scheme 1. Hydrogen-Mediated Coupling of Acetylene to Pyruvate 1a (TPAA ) Ph3CCO2H) and Plausible Catalytic Cycles A and B
Consistent with the Results of Deuterium Labeling
protonolytic cleavage or ꢀ-hydride elimination of the resulting
rhodium alkoxide also has been documented.16 Nevertheless, a
related catalytic mechanism Cycle B (Scheme 1) involving
acetylene-carbonyl oxidative coupling followed by insertion
of a second acetylene molecule to form an identical oxarhoda-
cycloheptadiene cannot be excluded.
support for Cycle B. The penultimate intermediate postulated
in both Cycles A and B, the vinyl hydride, is likewise not
observed. Our computer model indicates that the hydride species
should have a short lifetime due to rapid C-H reductive
elimination, as discussed in greater detail below. The key ion
of m/z 1188 was subjected to CAD (Figure 1B). This ion
dissociates by loss of 288 Da, consistent with the elimination
of triphenylacetic acid to regenerate the oxarhodacyclohepta-
diene intermediate (m/z 900). When the latter species is
subjected to a second stage of CAD (data not shown), it
dissociates to an ion of m/z 677 which again matches the
molecular weight of the rhodacyclopentadiene species shown
in Cycle A, suggesting a retro-carbonyl insertion process.
We began our mechanistic investigation using ESI-MS to
analyze the products observed for various combinations of
reactants, in addition to analyzing the individual reactants.
Supplemental experiments in which individual reactants were
replaced by other analogs or excluded entirely were also
conducted. Multistage CAD experiments were used to provide
corroborating fragmentation fingerprints of the resulting prod-
ucts. For example, in an effort to discriminate between cycles
A and B, an aliquot of the crude reaction mixture from the
hydrogenative coupling of gaseous acetylene to R-ketoester 2a
(Figure 1) was diluted in methanol prior to ESI-MS analysis.
The observation of ions consistent with the masses of putative
reactive intermediates corroborates their intervention, and while
the composition of transient species in solution and in the gas
phase may differ, good correlation has been documented using
soft ionization mass spectrometric techniques such as ESI.17
Although these MS techniques are capable of providing invalu-
able mechanistic clues, it is always difficult to assign a
mechanistic role to a detectable species with confidence.
Mechanistic computational molecular modeling is a powerful
complement to these experimental techniques, as will be
highlighted below.
A representative ESI-mass spectrum of the reaction mixture
sampled at one hour (Figure 1A) shows that the most abundant
ion matches the molecular weight of Rh(BIPHEP) (m/z 625).
Of particular interest is the ion that matches the molecular
weight of the rhodacyclopentadiene of Cycle A (m/z 677). This
key intermediate of cycle A also is identified to be a stable
intermediate by computational modeling (Vide infra). Ions
matching the molecular weights of the oxarhodacycloheptadiene
(m/z 900) and the corresponding chloride adduct (ion of m/z
935, assigned based on theoretical isotope ratio) were observed,
as well as an ion matching the molecular weight of the
intermediate postulated to arise upon protonolytic cleavage of
the oxarhodacycloheptadiene by triphenylacetic acid (m/z 1188).
Finally, an ion corresponding to the molecular weight of
Rh(BIPHEP)2(C4H4) was observed (m/z 1199). In contrast, ions
corresponding to neither the oxarhodacyclopentene (calculated
M.W. ) 874 Da) of Cycle B nor the monohydride, vinyl- or
dienylrhodium species are observed, thus offering no direct
These MS/MS/MS data offer support for catalytic cycle A.
Nevertheless, the structural assignments of the ions observed
using ESI-MS must be considered tentative, as constitutionally
isomeric species cannot be excluded on the basis of this data
alone. Therefore, we turned to quantum chemical modeling in
pursuit of a more complete assessment of the energetics and
structures of species in the proposed catalytic mechanism.
Whereas highly efficient quantum chemical methods, such as
density functional theory,21 have allowed computational models
to become relatively large in size, the current systems are too
large to be treated without structural simplifications. Potential
simplifications were explored and it was found that the BIPHEP
ligand cannot be truncated without introducing significant
artificial effects, although the general mechanistic pattern can
be qualitatively reproduced with a smaller model. These model
calculations are presented in the Supporting Information and
we limit our discussion here to the model that utilizes the
untruncated BIPHEP ligand. The R-ketoester 1a was modeled
as methyl-2-oxoacetate and the acid cocatalyst triphenylacetic
acid, TPAA, was represented as acetic acid. While these
simplifications are significant and, hence, the present model is
not anticipated to be quantitatively reliable, there is strong
evidence that this model captures the main features of the
(18) (a) Mu¨ller, E.; Thomas, R.; Zountsas, G. Liebigs Ann. Chem. 1972,
16. (b) Mu¨ller, E.; Winter, W. Chem. Ber. 1972, 105, 2523. (c) Mu¨ller,
E.; Winter, W. Liebigs Ann. Chem. 1975, 41. (d) Scheller, A.; Winter,
W.; Mu¨ller, E. Liebigs Ann. Chem. 1976, 1448.
(19) Rhodacyclopentadienes also are believed to participate in the insertion
of substituted alkynes, as exemplified by catalytic [2 + 2 + 2]
cycloaddition processes. For reviews, see: (a) Lautens, M.; Klute, W.;
Tam, W. Chem. ReV. 1996, 96, 49. (b) Kotha, S.; Brahmachary, E.;
Lahiri, K. Eur. J. Org. Chem. 2005, 22, 4741. (c) Chopade, P. R.;
Louie, J. AdV. Synth. Catal. 2006, 348, 2307.
(20) Metal catalyzed reductive cycloadditions are highly uncommon. For
examples, see: (a) Herath, A.; Montgomery, J. J. Am. Chem. Soc. 2006,
128, 14030. (b) Chang, H.-T.; Jayanth, T. T.; Cheng, C.-H. J. Am.
Chem. Soc. 2007, 129, 4166.
(17) (a) Daniel, J. M.; Friess, S. D.; Rajagopalan, S.; Wendt, S.; Zenobi,
R. Int. J. Mass Spec. 2002, 216, 1. (b) Schrader, W.; Handayani, P. P.;
Zhou, J.; List, B. Angew. Chem., Int. Ed. 2009, 48, 1463. (c) Paz-
Schmidt, R. A.; Bonrath, W.; Plattner, D. A. Anal. Chem. 2009, 81,
3665.
(21) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989.
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Studies on the H2-Mediated Coupling of Acetylene
A R T I C L E S
Figure 1. Hydrogen-mediated coupling of gaseous acetylene to R-ketoester 2a (Ar ) p-NO2Ph) using triphenylacetic acid as cocatalyst. (A) ESI mass spectrum
with proposed structural assignment of observed ions. (B): CAD mass spectrum of the ion of m/z 1188 with proposed structural assignment of observed ions.
oxidative coupling of the two acetylene moieties to furnish the
rhodacyclopentadiene 4, which traverses the transition state 3-TS
at 15.9 kcal mol-1. This key intermediate, containing a RhIII-d6
center, is 21.6 kcal mol-1 lower in free energy than the reactant
complex and is a stable intermediate that should be accessible
to experimental detection. Formation of the rhodacyclopenta-
diene should not be reversible, as the barrier leading back to
the reactants is greater than 35 kcal/mol. This result is in good
agreement with the ESI-MS data mentioned above and assigns
a key role to this rhodacyclopentadiene complex in the catalytic
cycle. Species 4 is a 14-electron complex that can bind the
Figure 2. Computed reaction energy profile.
carbonyl substrate to deliver complex 5. The formation of this
complex is energetically uphill by only 4.8 kcal mol-1. The
mechanism and constitutes a reasonable compromise between
computational cost and accuracy.
Figures 2 and 3 summarize the salient features of the
consensus reaction mechanism determined after extensive
ketoester undergoes migratory insertion to give the ring-
expanded intermediate 6 that is lower in energy compared to 5
by 17.7 kcal mol-1 (34.5 kcal mol-1 relative to 3). The transition
state that connects these two intermediates, 5-TS, has an
sampling of Cycles A and B. Our model mechanism begins
activation barrier of 10.1 kcal mol-1 measured from the
intermediate 4 (Figure 2). Extensive exploratory calculations
reveal that intermediate 6, formally a 14-electron complex with
a RhIII-d6 center, is too electron-deficient to engage in direct
hydrogenolysis of the Rh-O bond. The Rh-O bond cleavage
must be facilitated by the carboxylic acid cocatalyst.
with the initial reactant complex 3, where the RhI-d8 center forms
a [(BIPHEP)Rh(acetylene)2]+ π-complex. The computed lowest
energy structure of 3 is shown in Figure 4. Not surprisingly,
the rhodium center adopts a square planar geometry with the
acetylene ligands aligned approximately orthogonal to the
coordination plane. The first step of the catalytic cycle is an
9
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A R T I C L E S
Williams et al.
The carboxylate moiety of the cocatalyst binds to rhodium
in a bidentate fashion and the proton adds to the oxo moiety of
the rhodacycle to furnish the 18-electron intermediate 7A (Cycle
A′ in Figure 2, blue in Figure 3). Addition of H2 to this complex
is mediated by removal of one of the arms of the carboxylate
ion, leading to a high energy intermediate 7A′, with a free energy
that is 25.2 kcal mol-1 higher than 6. From this intermediate,
the barrier for heterolytic cleavage of the H-H bond, resulting
in a hydride on the Rh center and protonation of the noncoor-
dinating oxygen atom of the carboxylate ligand, is associated
with a barrier of only 2.6 kcal mol-1 (7A′-TS). Thus, the
calculations suggest that the overall barrier for dihydrogen
activation is 27.8 kcal mol-1. This could possibly be the rate
determining step of the reaction (Figure 2, blue profile), under
the reasonable assumption that the barrier for the H2 adduct
formation is lower than or comparable to the H-H bond
cleavage step. A slightly lower pathway involves the protonation
of the oxarhodacycloheptadiene 6 after dihydrogen activation,
i.e. the binding of carboxylate to rhodium is not accompanied
by protonation, leading to the neutral complex 7 (Cycle A in
Figure 2). H2 addition furnishing this intermediate 7′ is 22.3
kcal mol-1 higher in free energy compared to 6. Despite several
attempts, we were unable to locate a transition state for H2
activation from this intermediate. We expect however, that the
barrier will be quite small, and very similar to that obtained for
H2 activation from 7A′. Adding the same barrier to the energy
of 7′ gives us an estimated overall activation free energy of
24.8 kcal mol-1 (7′-TS). Note, however, that the H-H bond
cleavage could in reality be almost barrierless if tunneling is
involved. Thus, the activation energy of 24.8 kcal mol-1 should
be considered to be the upper limit for dihydrogen activation.
Subsequent addition of a proton to the oxygen of the rhodacycle
leads to the cationic hydride intermediate 8, in which the Rh-O
bond is nearly cleaved at a distance of 2.37 Å. Whereas this
interpretation of our computed results is self-consistent and
plausible, we must be careful not to overinterpret these results.
Our explorative calculations show that the calculated energies
can shift notably with model size (see Supporting Information),
in addition to intrinsic concerns about the accuracy of DFT and
the continuum solvation models used in this work. These
concerns demonstrate the importance of combining clues from
various techniques of scientific inquiry, both experimental and
computational, as highlighted in this work. We propose that
the cocatalyst plays a dual role: (a) it acts as a Brønsted acid
and assists Rh-O bond cleavage, as previously proposed, and
(b) the conjugate base acts as a ligand, increasing the electron-
count at the Rh-center to directly assist H-H bond cleavage.14
Having completed its catalytic function, the carboxylic acid
dissociates, resulting in the formation of intermediate 9. It is
instructive to recognize that loss of the carboxylic acid decreases
the electron count at the metal center, which predisposes
complex 9 (formally a 14-electron complex) toward reductive
elimination to deliver the final product complex 10 traversing
Figure 3. Lowest energy reaction pathway depicted in Figure 2.
the transition state 9-TS with a barrier of 8.5 kcal mol-1
.
Cycle B, which involves initial acetylene-carbonyl oxidative
coupling also was explored. Calculations show that the initial
reactant complex 3A is slightly lower in energy than the bis-
alkyne adduct 3 by 3.1 kcal mol-1. The oxidative addition barrier
however, at 20.2 kcal mol-1 relative to 3, is almost 7 kcal mol-1
higher than the barrier for the coupling of two alkynes. Such a
high barrier for the initial step, combined with the inability to
detect the oxarhodacyclopentene intermediate by mass spec-
trometry (Vide supra) or infer its presence through its diversion
Figure 4. Computed structures of 3, 7, 7A′-TS, and 8. Nonessential
hydrogens are deleted for clarity. Solution phase free energies in kcal mol-1
are given in parentheses.
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Studies on the H2-Mediated Coupling of Acetylene
A R T I C L E S
Scheme 2. Proposed Catalytic Mechanism for the Hydrogen-Mediated of 1,6-Diynes 11a and 12a to R-Ketoester 2a Using Triphenylacetic
Acid As Cocatalyst
to alternate reaction products makes this pathway, which is
otherwise plausible based on the deuterium labeling experiments,
highly unlikely.
molecular weight of Rh(BIPHEP) (m/z 625), the BIPHEP ligated
rhodacyclopentadiene (m/z 677), and Rh(BIPHEP)2(C4H4) (m/z
1199) are seen (Figure 6A). Two ions are of particular interest:
that corresponding to the molecular weight of the azarhodacy-
cloheptadiene (m/z 967), which would be derived upon insertion
of imine 13a into the rhodacyclopentadiene, and the ion
matching the molecular weight of the intermediate postulated
to arise upon protonolytic cleavage of the azarhodacyclohep-
tadiene induced by triphenylacetic acid (m/z 1255). Ions
consistent with the molecular weight of Rh(BIPHEP)2 (m/z
1147) and, interestingly, Rh(BIPHEP)(Ph3CCO2H)(C2H4) (m/z
939) also are observed.
Analogous Reactions. If catalytic cycle A is operative, one
would expect related cationic rhodacyclopentadienes to display
similar reactivity and participate in carbonyl insertion processes.
It is known that 1,6-diynes react with rhodium(I) salts to furnish
isolable rhodacyclopentadienes, which have been characterized
in detail.18 Accordingly, 1,6-diyne 11a (100 mol%) was
hydrogenated in the presence of R-ketoester 2a (100 mol%)
using a cationic rhodium catalyst. The product of tandem
reductive cyclization-carbonyl coupling 11b is obtained in 58%
yield as a single alkene geometrical isomer. Thus, the cationic
rhodacyclopentadiene presumed to arise upon oxidative coupling
of 1,6-diyne 11a does display reactivity analogous to that
observed in the reductive couplings of gaseous acetylene.
Interestingly, for nonsymmetric 1,6-diyne 12a, carbonyl inser-
tion occurs such that R-ketoester 2a couples at the substituted
terminus of the rhodacyclopentadiene intermediate to furnish
12b as a single geometrical and constitutional isomer. The
modest yield of tandem reductive cyclization-carbonyl insertion
product 12b is due to competitive alkyne [2 + 2 + 2]
cycloaddition (Scheme 2).
An aliquot of the crude reaction mixture from the hydroge-
native coupling of 1,6-diyne 12a to R-ketoester 2a was diluted
5000-fold in methanol and subjected to ESI-MS analysis (Figure
5A). The two most abundant ions include one that matches the
mass of the purported cationic rhodacylcopentadiene (m/z 909)
and another that matches the mass of the purported cationic
oxarhodacycloheptadiene (m/z 1132). Analogous intermediates
are postulated in Cycle A. Upon CAD, the ion of m/z 1132
dissociates by loss of 223 Da, consistent with elimination of
2a to regenerate the rhodacyclopentadiene (m/z 909) (Figure
5B). The additional loss of 284 Da, which is consistent with
elimination of 12a, regenerates cationic Rh(BIPHEP) (m/z 625).
An ion of m/z 1195 corresponding to the mass of [Rh(BIPHEP)-
(12a)(2a)(OMe)(HOMe)] is also observed, which may cor-
respond to the methanol-methoxide adduct of the cationic
oxarhodacycloheptadiene.
The ion of m/z 1255 was subjected to multistage CAD (Figure
6B). This ion dissociates by loss of 288 Da, consistent with
elimination of triphenylacetic acid to regenerate the azarhoda-
cycloheptadiene (m/z 967). Ions corresponding to ligand deg-
radation also are observed (m/z 783, 707, and 625). Notably,
triphenylacetic acid is also eliminated upon CAD of the
analogous oxarhodacycloheptadiene in the aforementioned
coupling of acetylene to R-ketoester 2a (Figure 1).
Interception of Putative Reactive Intermediates. As described
above, compounds 11a and 12a were converted to adducts 11b
and 12b, thereby corroborating the ability of rhodacyclopenta-
dienes to engage in carbonyl insertion processes (Scheme 2).
To further test the proposed mechanism, additional experiments
were designed aimed at the interception of putative reactive
intermediates and their diversion to alternate reaction products.
In one experiment, the rhodium-catalyzed coupling of acety-
lene to aldehyde 14a was performed in the absence of both
hydrogen and the Brønsted acid cocatalyst. Here, the putative
oxarhodacycloheptadiene is potentially intercepted via ꢀ-hydride
elimination to deliver the (Z)-butadienyl ketone 14b.16 Remark-
ably, upon exposure of 14a to gaseous acetylene in the absence
of hydrogen and Brønsted acid the anticipated product of
ꢀ-hydride elimination 14b is obtained in 52% isolated yield. If
the reaction is performed under identical conditions, but using
triphenylacetic acid as cocatalyst (5 mol%), the product of
ꢀ-hydride elimination 14b is not formed, presumably due to
protonolysis of the intermediate oxarhodacycloheptadiene (Scheme
3). Additional evidence supporting the intervention of the
oxarhodacycloheptadiene intermediate is found in the conversion
of deuterio-14a to deuterio-14b. Here, the deuterium located
at the aldehydic position is stereoselectively transferred to the
vinyl terminus of deuterio-14b (eq 2).
The hydrogen-mediated coupling of acetylene to N-arylsul-
fonyl imines using chirally modified rhodium catalysts provides
optically enriched (Z)-butadienyl allylic amines.11b An analogous
mechanism involving imine insertion into a cationic rhodacy-
clopentadiene derived Via acetylene oxidative dimerization,
followed by Brønsted acid cocatalyzed hydrogenolysis of the
resulting azarhodacycloheptadiene was postulated. To probe the
mechanism, the crude reaction mixture from the hydrogenative
coupling of N-benzenesulfonyl aldimine 13a and gaseous
acetylene was subjected to ESI-MS analysis. As noted above
for the corresponding carbonyl couplings, ions matching the
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A R T I C L E S
Williams et al.
Figure 5. Hydrogen-mediated of 1,6-diyne 12a to R-ketoester 2a (Ar ) p-NO2Ph) using triphenylacetic acid as cocatalyst. (A) ESI mass spectrum with
proposed structural assignment of observed ions. (B) CAD mass spectrum of the ion of m/z 1132 with proposed structural assignment of observed ions.
Scheme 3. Rhodium-Catalyzed Coupling of Acetylene to Aldehyde
Scheme 4. Rhodium-Catalyzed Hydrogenation of Acetylene in
14a in the Absence of Hydrogen and Brønsted Acid Cocatalyst
the Presence of Dehydroalanine 15a Delivers the Product of
Delivers Ketone 14b, Corroborating Intervention of the Proposed
Reductive [2 + 2 + 2] Cycloaddition 15b, Corroborating
Oxarhodacycloheptadiene Intermediate
Intervention of the Proposed Rhodacyclopentadiene
Intermediate
Further support for the intervention of rhodacyclopentadiene
intermediates in the hydrogen-mediated couplings of acetylene
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Studies on the H2-Mediated Coupling of Acetylene
A R T I C L E S
Figure 6. Hydrogen-mediated coupling of gaseous acetylene to N-benzenesulfonyl aldimine 13a (Ar ) p-NO2Ph, Bs ) Benzenesulfonyl) using triphenylacetic
acid as cocatalyst. (A) ESI mass spectrum with proposed structural assignment of observed ions. (B) CAD mass spectrum of the ion of m/z 1255 with
proposed structural assignment of observed ions.
is found in the reductive cycloaddition of N-p-toluenesulfonyl-
dehydroalanine ethyl ester 15a.19 Specifically, hydrogenation
of acetylene in the presence of 15a results in the formation of
the reductive [2 + 2 + 2] cycloaddition products 15b and iso-
15b in a combined 75% isolated yield (Scheme 4).20 The
structural assignment of 15b was confirmed by single crystal
X-ray diffraction analysis. If the reaction is performed under
identical conditions, but in the absence of triphenylacetic acid,
15b and iso-15b are formed in only 8% isolated yield, again
underscoring the key role of Brønsted acids as cocatalysts for
the hydrogenolysis of organorhodium intermediates.14 Consistent
with intervention of an allyl rhodium intermediate, isomeric
alkenes 15b and iso-15b are generated. Hydrogenation of 15b
and iso-15b results in convergence to a common cyclohexane
derivative, as described in the experimental section. Under an
atmosphere of deuterium, 15a provides deuterio-15b as the
major reaction product, which incorporates two deuterium atoms,
as is consistent with the proposed mechanism (eq 3).
Conclusion
In summary, the catalytic mechanism of the hydrogen-
mediated coupling of acetylene to carbonyl compounds and
imines has been illuminated using three powerful techniques:
(a) ESI-MS and ESI-CAD-MS analyses, (b) computational
modeling, and (c) experiments wherein putative reactive
intermediates are diverted to alternate reaction products. The
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A R T I C L E S
Williams et al.
M.J.K. and F1155 to J.S.B.), and the NSF (J.S.B., CHE-0718320;
M.H.B., CHE-0645381) for partial support of this research. Oliver
Briel of Umicore is thanked for a generous donation of Rh(cod)2OTf
and Rh(cod)2BF4. Fernando Pedraza is acknowledged for initial
experiments on the conversion of 14a to 14b.
collective data provide strong evidence for Cycle A (Scheme
1), which involves oxidative coupling of acetylene to furnish
a rhodacyclopentadiene that engages in carbonyl and imine
insertion.13 Additionally, all three methods of analysis point
to the key role of Brønsted acid additives as cocatalysts in
the hydrogenolysis of organorhodium intermediates.4,14 These
studies provide further insight into the structural and
interactional features of catalytic systems for hydrogen-
mediated C-C bond formation and should facilitate the
design of related processes.
Supporting Information Available: Spectral data for all new
compounds. computational details, Cartesian coordinates of all
computed structures, discussion of additional mechanistic
pathways considered computationally and single crystal X-ray
diffraction data for 15b. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Acknowledgment is made to the Research
Corporation Cottrell Scholar Program, the Sloan Foundation, the
Dreyfus Foundation, Johnson & Johnson, Merck, the NIH-NIGMS
(RO1-GM69445), the Robert A. Welch Foundation (F1466 to
JA906225N
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16062 J. AM. CHEM. SOC. VOL. 131, NO. 44, 2009