Article
Organometallics, Vol. 29, No. 23, 2010 6557
proximity to Ru for β-elimination. The high temperature
would also help in surmounting this high energy barrier.
and placed under nitrogen. At the top of the condenser, a
septum cap was fitted with a nitrogen inlet needle and an outlet
needle leading to an oil bubbler. 5-Aminopentanol (1.0 mmol) and
dry, degassed toluene (1 mL) were then added via syringe. The
reaction was heated to a vigorous reflux in a 125 °C oil bath.
During the reaction, a nitrogen flow rate of approximately
Conclusions
This study highlights some of the factors that are impor-
tant in favoring formation of amide versus alkylated amine
in the Ru-catalyzed reaction of alcohol with amine. The rela-
tively high temperature of 110° that is needed for the reaction is
proposed to be required to access an empty coordination
site in the presence of such good coordinating agents as the
reactant amine. High temperatures are also needed for β-
hydrogen elimination, especially the one involved in the
formation of the amide. For amide to be formed, the amine
must add to a metal-bound aldehyde to form a zwitterionic
hemiaminal. This key intermediate must then eliminate H2
to provide a vacant site for β-elimination. The NMR observa-
tion of ruthenium monohydride species under conditions close
to those of the catalytic reaction is consistent with the suggestion
from calculation that ruthenium monohydrides are implicated
in catalysis; there is also good agreement between experi-
ment and theory concerning the geometry of these inter-
mediates. We have shown that in the calculated pathway a
redirection of the intermolecular hydrogen bond associated with
10 mL/min was maintained at the top of the reflux condenser.
At the end of the reaction the mixture of products was analyzed by
H NMR. NMR yields were calculated with respect to a known
1
quantity of internal standard (1,3,5-trimethoxybenzene) added at
the end of the reaction.
Computational Details. All calculations were performed with
2
7
28
Gaussian03 at the DFT(B3PW91) level. The basis set was
the ECP-adapted SDDALL with a set of polarization func-
2
9
3
0
31
32
tions for Ru and P and the all-electron 6-31G(d,p) for
N, O, C, and H. All structures were fully optimized without any
geometry or symmetry constraint. Each stationary point was
classified as minimum or transition state by analytical calcula-
tion of the frequencies. The connection between reactant and
product through a given transition state was checked by opti-
mization of slightly altered geometries of the transition state along
the two directions of the transition-state vector associated with the
imaginary frequency. Entropy effects calculated in the gas
phase from harmonic approximation of frequencies were included
in order to compare the inner- and outer-sphere mechanisms, since
the former is unimolecular whereas the latter is bimolecular.
The effect of toluene solvent, which is weakly coordinating and of
low polarity (ε = 2.379), was evaluated by using the continuum
the formation of the H ligand is of crucial importance in
2
lowering the energy barrier for dihydrogen release. For amine to
be formed, the neutral hemiaminal must be liberated and the
3
3
PCM model with single-point 6-311þG** calculations and
34
the methodology proposed by Maseras et al. for the Gibbs
-
þ
H must be retained on the metal, in the form of H þ H ,
2
energy in solution. It was verified that the solvent does
not modify significantly the results found in the gas phase.
Therefore, we present the results in the gas phase in the
article and report the results in solution in the Supporting
Information.
for reduction of the imine intermediate. If the hemiaminal
is liberated and the H is lost from the system, imine is
2
necessarily formed, but this is a significant pathway only in
the intermolecular amine/alcohol reactions. On this basis,
the rarity of amide formation in experimental systems is a
result of the rarity of catalysts that can retain the aldehyde
before the nucleophile addition of the amine but release H2
from the O-metalated hemiaminal.
Acknowledgment. O.E. thanks the CNRS and Minist ꢁe re
de l’Enseignement Sup ꢀe rieur et de la Recherche for
funding. A.N. thanks the Spanish MICINN for a MEC
postdoctoral fellowship. D.B. thanks Sanofi-Aventis
for a postdoctoral fellowship (2007-2009) and the
Spanish MICINN for his current Juan de la Cierva position.
R.H.C. thanks the ACS-GCI Pharmaceutical Round
Table for funding, and N.S and G.D. thank the U.S.
Department of Energy, Office of Basic Energy Sciences
catalysis grant DE-FG02-84ER13297 and the ACS GCI
Pharmaceutical Roundtable. We would also like to
thank Miriam Bowring for her early work on dehydro-
genative imine formation at Yale.
Experimental Section
2
1
Complex I was prepared according to the literature procedure.
NMR spectra were recorded at room temperature in CDCl3
or CD Cl on a 400 or 500 MHz Bruker spectrometer and
2
2
referenced to the residual protio solvent signal. The identities of
the δ-valerolactam and piperidine products were confirmed by
GC-MS and by comparison to the NMR spectra of commercially
available samples.
Representative Procedure for Catalytic Amidation/Alkylation.
The catalyst (0.025 mmol) and a catalytic amount of potassium
hydroxide (0.07 mmol) were loaded into a flame-dried 10 mL
round-bottom flask attached to a straight-walled reflux condenser
(
28) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5662. (b) Perdew,
J. P.; Wang, Y. Phys. Rev. B 1992, 45, 13244–13249.
(
27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
(29) (a) Andrae, D.; H €a ussermann, U.; Dolg, M.; Stoll, H.; Preuss, H.
Theor. Chim. Acta 1990, 77, 123–141. (b) Bergner, A.; Dolg, M.; K €u chle,
W.; Stoll, H.; Preuss, H. Mol. Phys. 1993, 80, 1431–1441.
(30) Ehlers, A. W.; B o€ hme, M.; Dapprich, S.; Gobbi, A.; H o€ llwarth,
A.; Jonas, V.; K o€ hler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G.
Chem. Phys. Lett. 1993, 208, 111–114.
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong,
M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03 (Revision E.01); Gaussian,
Inc.: Wallingford, CT, 2004.
(31) H o€ llwarth, A.; B o€ hme, H.; Dapprich, S.; Ehlers, A. W.; Gobbi,
A.; Jonas, V.; K o€ hler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G.
Chem. Phys. Lett. 1993, 203, 237–240.
(32) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
213–222.
(33) (a) Canc ꢁe s, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997,
107, 3032–3041. (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem.
Phys. Lett. 1998, 286, 253–260. (c) Mennucci, B.; Tomasi, J. J. Chem.
Phys. 1997, 106, 5151–5158.
(34) (a) Balcells, D.; Ujaque, G.; Fernandez, I.; Khiar, N.; Maseras,
F. J. Org. Chem. 2006, 71, 6388–6396. (b) Braga, A. A. C.; Ujaque, G.;
Maseras, F. Organometallics 2006, 25, 3647–3658.