University of Groningen
On the mechanism of the copper-catalyzed enantioselective 1,4-addition of grignard reagents
to alpha,beta-unsaturated carbonyl compounds
Harutyunyan, Syuzanna R.; Lopez, Fernando; Browne, Wesley R.; Correa, Arkaitz; Pena,
Diego; Badorrey, Ramon; Meetsma, Auke; Minnaard, Adriaan J.; Feringa, Ben L.; Lo´pez, F.
Published in:
Journal of the American Chemical Society
DOI:
10.1021/ja0585634
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Harutyunyan, S. R., Lopez, F., Browne, W. R., Correa, A., Pena, D., Badorrey, R., Meetsma, A., Minnaard,
A. J., Feringa, B. L., Lo´pez, F., & Pen~a, D. (2006). On the mechanism of the copper-catalyzed
enantioselective 1,4-addition of grignard reagents to alpha,beta-unsaturated carbonyl compounds.
Journal
of the American Chemical Society
,
128
(28), 9103-9118. https://doi.org/10.1021/ja0585634
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On the Mechanism of the Copper-Catalyzed Enantioselective
1,4-Addition of Grignard Reagents to r,β-Unsaturated
Carbonyl Compounds
Syuzanna R. Harutyunyan, Fernando Lo´pez,
†
Wesley R. Browne, Arkaitz Correa,
Diego Pen˜a,
†
Ramon Badorrey,
‡
Auke Meetsma, Adriaan J. Minnaard,* and
Ben L. Feringa*
Contribution from the Department of Organic Chemistry and Molecular Inorganic Chemistry,
Stratingh Institute, UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen,
The Netherlands
Received December 18, 2005; E-mail: B.L.Feringa@rug.nl
Abstract:
The mechanism of the enantioselective 1,4-addition of Grignard reagents to R,β-unsaturated
carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines is explored through
kinetic, spectroscopic, and electrochemical analysis. On the basis of these studies, a structure of the active
catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined.
Kinetic studies support a reductive elimination as the rate-limiting step in which the chiral catalyst, the
substrate, and the Grignard reagent are involved. The thermodynamic activation parameters were
determined from the temperature dependence of the reaction rate. The putative active species and the
catalytic cycle of the reaction are discussed.
Introduction
The copper-catalyzed conjugate addition (CA) of organo-
metallic reagents to R,β-unsaturated carbonyl compounds is one
of the most versatile synthetic methods for the construction of
C-C bonds.
1
Catalytic enantioselective versions of this trans-
formation employing chiral copper complexes
2-5
have been
achieved primarily with organozinc reagents,
2-4a,b
although
organoaluminum compounds have proven to be successful
also.
4c-e
The inherently low reactivity of organozinc reagents
toward unsaturated carbonyl compounds has facilitated the
development of a plethora of chiral phosphorus-based ligands
(i.e. phosphoramidites, phosphines, phosphonites) capable of
providing highly efficient ligand-accelerated catalysis with
excellent enantioselectivities over a broad range of substrates.
2,3
In contrast, the application of Grignard reagents, which are
among the most widely used of organometallic compounds, in
the CA to R,β-unsaturated carbonyl systems has received much
less attention.
6
Despite intensive research over the last two
decades, only modest selectivity in the CA of Grignard reagents
was observed in comparison to dialkyzinc reagents.
6
This is most
probably due to the higher reactivity of Grignard reagents, which
†
Present address: Departamento de Quı´mica Orga´nica, Facultad de
Quı´mica, Universidad de Santiago de Compostela, 15706 Santiago de
Compostela, Spain.
‡
Present address: Departamento de Quı´mica Orga´nica, Facultad de
Ciencias, Instituto de Ciencia de Materiales de Arago´n, Universidad de
Zaragoza, Consejo Superior de Investigaciones Cientı´ficas, 50009 Zaragoza,
Spain.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry, Series 9; Pergamon: Oxford, 1992. (b)
Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806..
(2) (a) Feringa, B. L.; de Vries, A. H. M. In Asymmetric Chemical Transforma-
tions; Doyle, M. D., Ed.; Advances in Catalytic Processes; JAI Press Inc.:
Greenwich, 1995; Vol. 1, pp 151-192. (b) Krause, N. Angew. Chem., Int.
Ed. 1998, 37, 283-285. (c) Tomioka, K.; Nagaoka, Y. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: New York, 1999; Vol. 3, pp 1105-1120. (d) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (e) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(3) (a) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 224-258. (b) de Vries, A. H. M.; Meetsma, A.; Feringa,
B. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374-2376. (c) Feringa, B.
L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2620-2623.
(4) (a) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 779-781. (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002,
3221-3236 and references therein. (c) For an addition of AlMe
3
to linear
aliphatic enones, see: Frase, P. K.; Woodward, S. Chem.sEur. J. 2003, 9,
776-783. (d) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508-11509. (e) Alexakis, A.; Albrow, V.; Biswas,
K.; d’Augustin, M.; Prieto, O.; Woodward, S. Chem. Commun. 2005, 22,
2843-2845.
(5) For recent advances in the catalytic enantioselective conjugate reduction
of R,β-unsaturated carbonyl compounds, which provides an alternative route
to the optically active β-substituted carbonyl compounds see: (a) Lipshutz,
B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789-4792. (b)
Lipshutz B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126,
8352-8353. (c) Lipshutz, B. H.; Frieman, B. A. Angew. Chem., Int. Ed.
2005, 44, 6345-6348.
(6) (a) Villacorta, G. M.; Rao, C. P.; Lippard, S. J. J. Am. Chem. Soc. 1988,
110, 3175-3182. (b) Ahn, K.-H.; Klassen, R. B.; Lippard, S. J. Organo-
metallics 1990, 9, 3178-3181. (c) Lambert, F.; Knotter, D. M.; Janssen,
M. D.; van Klaveren, M.; Boersma, J.; van Koten, G. Tetrahedron:
Asymmetry 1991, 2, 1097-1100. (d) Knotter, D. M.; Grove, D. M.; Smeets,
W. J. J.; Spek, A. L.; van Koten, G. J. Am. Chem. Soc. 1992, 114, 3400-
3410. (e) Spescha, D.; Rihs, G. HelV. Chim. Acta 1993, 76, 1219-1230.
(f) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467-4478. (g) Braga,
A. L.; Silva, S. J. N.; Lu¨dtke, D. S.; Drekener, R. L.; Silveira, C. C.; Rocha,
J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002, 43, 7329-7331. (h)
Seebach, D.; Jaeschke, G.; Pichota, A.; Audergon, L. HelV. Chim. Acta
1997, 80, 2515-2519. (i) Pichota, A.; Pregosin, P. S.; Valentini, M.; Wo¨rle,
M.; Seebach, D. Angew. Chem., Int. Ed. 2000, 39, 153-156. (j) Kanai,
M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275-4278. (k) Nakagawa,
Y.; Kanai, M.; Nagaoka, Y.; Tomioka, K. Tetrahedron 1998, 54, 10295-
10307. (l) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron 1999, 55,
3843-3854. (m) Stangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53,
16503-16510.
Published on Web 06/23/2006
10.1021/ja0585634 CCC: $33.50 © 2006 American Chemical Society J. AM. CHEM. SOC. 2006,
128
, 9103-9118
9
9103
leads to uncatalyzed 1,2- and 1,4-additions. Moreover, the
presence of several competing organometallic complexes in
solution (typical of cuprate chemistry) further complicates access
to effective enantioselective catalysis.
Recently, we demonstrated that high enantioselectivities (up
to 99% ee) can be achieved in the CA of Grignard reagents to
R,β-unsaturated carbonyl compounds using catalytic amounts
of chiral ferrocenyl diphosphine ligands and Cu(I) salts (Figure
1, Scheme 1).
7
Most notably, the Josiphos- and Taniaphos-type
ligands (Figure 1) allow for a broad substrate scope to be used
successfully in these reactions, including cyclic and acyclic
enones, enoates, and thioenoates (Scheme 1). Despite these
breakthroughs, the nature of the complexes involved and a
rationalization of the electronic factors, which govern the
substrate specificity of the various Cu(I)-ferrocenyl-diphosphine
complexes is highly desirable. A detailed understanding of the
reaction mechanism, including the generation of the active
species, insight into key steps in the catalytic cycle, and kinetic
information is essential for the elucidation of the mechanism
and future rational improvement of this important transforma-
tion.
The mechanism of the copper-catalyzed enantioselective CA
of organometallic compounds may follow similar principles as
proposed for the noncatalytic organocuprate addition.
8,9
A
widely accepted mechanism (Scheme 2) for noncatalytic organo-
cuprate addition is supported by kinetic studies,
9a,b
in particular
kinetic isotope effect measurements
9c,d
and NMR spectroscopy
9e,f
of intermediates observed during the reaction. The current
mechanistic view is that the CA of organometallic compounds
proceeds through reversible formation of a copper-olefin
π-complex, involving d,π* back-donation,
9e-h
followed by a
formal oxidative addition to the β-carbon leading to a d
8
copper(III) intermediate
9h-k
and, finally, reductive elimination
to form the enolate (Scheme 2).
Although π-complexes for R, β-unsaturated esters, ketones,
and nitriles have been observed by low-temperature NMR
spectroscopy,
10
direct observation of copper(III) intermediates
has not been achieved in organocuprate CA, and their involve-
ment is supported primarily through quantum-chemical calcula-
tions.
11
Experimental and theoretical studies made by Snyder
et al.
9c
and Krause et al.
9d
on organocuprate CAs indicate that
the rate-determining step is the C-C bond formation via
reductive elimination of the copper(III) intermediate (Scheme
2).
On the basis of the cumulative mechanistic data obtained for
the stoichiometric organocuprate CA, a similar mechanism for
the copper-catalyzed enantioselective CA of dialkylzinc re-
agents, involving an oxidative addition-reductive elimination
pathway, has been postulated.
12
However, relatively few mecha-
nistic studies have been reported to date for the enantioselective
copper-catalyzed CA of any class of organometallic reagent.
13
Moreover, these studies are related, exclusively, to the catalytic
CA of dialkylzinc reagents and have not, as yet, led to a general
(7) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.; Minnaard,
A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b) Lo´pez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2004, 126, 12784-12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756. (d)
Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967. (e) Woodward,
S. Angew. Chem., Int. Ed. 2005, 44, 5560-5562.
(8) For reviews on reaction mechanisms of organocuprates, see: (a) Woodward,
S. Chem. Soc. ReV. 2000, 29, 393-401 and references therein. (b) Nakamura
E.; Mori S. Angew. Chem., Int. Ed. 2000, 39, 3750-3771. (c) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186-204. (d) Mori, S.;
Nakamura, E. In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 315-346.
(9) For mechanistic studies in organocuprates chemistry, see: (a) Krauss, S.
R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141-148. (b) Canisius, J.;
Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644-1645. (c)
Frantz, D. E.; Singleton, D. A.; Snyder, J. P. J. Am. Chem. Soc. 1997, 116,
3383-3384. (d) Mori, S.; Uerdingen, M.; Krause, N.; Morokuma, K.
Angew. Chem., Int. Ed. 2005, 44, 4715-4719. (e) Bertz, S. H.; Miao, G.;
Eriksson, M. Chem. Commun. 1996, 815-816. (f) Murphy, M. D.; Ogle,
G.; Bertz, S. H. Chem. Commun. 2005, 854-856. (g) Nilson, K.; Anderson,
C.; Ullenius, A.; Gerold, A.; Krause, N. Chem.sEur. J. 1998, 4, 2051-
2058 and references therein. (h) Mori, S.; Nakamura, E. Teterahedron Lett.
1999, 40, 5319-5322. (i) Kingsbury, C. L.; Smith, R. A. J. Am. Chem.
Soc. 1997, 62, 4629-4634. (j) Casey, C. P.; Cesa, M. J. Am. Chem. Soc.
1979, 101, 4236-4244. (k) Corey, E. J.; Boaz, N. Tetrahedron Lett. 1985,
26, 6015-6018. (l) Lipshutz, B. H.; Aue, D. H.; James, B. Teterahedron
Lett. 1996, 37, 8471-8474.
(10) For low-temperature NMR studies in CAs of cuprates, see: (a) Christenson,
B.; Olsson, T.; Ullenius, C. Tetrahedron 1989, 45, 523-534. (b) Bertz, S.
H.; Smith, R. A. J. Am. Chem. Soc. 1989, 111, 8276-8277. (c) Bertz, S.
H.; Carlin, M. K.; Deadwyler, D. A.; Murphy, M.; Ogle, C. A.; Seagle, P.
H. A. J. Am. Chem. Soc. 2002, 124, 13650-13651. (d) Krause, N.; Wagner,
R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381-382 (e) Nilsson, K.;
Ullenius, C.; Krause, N. J. Am. Chem. Soc. 1996, 118, 4194-4195. (f)
Krause, N.; Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381-
382. (g) See also refs 8 b, e-g.
(11) For the calculations that support the participation of Cu(III) intermediates
in the CA of cuprates, see: (a) Nakamura, E.; Mori, S.; Morokuma, K. J.
Am. Chem. Soc. 1997, 119, 4900-4910. (b) Yamanaka, M.; Nakamura, E.
J. Am. Chem. Soc. 2004, 126, 6287-6293. (c) Nakanishi, W.; Yamanaka,
M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 1446-1453. (d) Nakamura,
E.; Yamanaka, M.; Mori, S. J. Am. Chem. Soc. 2000, 122, 1826-1827. (e)
Yamanaka, M.; Nakamura, E. J. Am. Chem. Soc. 2005, 127, 4697-4706.
(f) Yamanaka, M.; Nakamura, E. Organometallics 2001, 20, 5675-5681.
(12) (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.;
Feringa, B. L. Tetrahedron 2000, 56, 2865-2878. (b) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-
5263.
Figure 1.
Chiral ligands used in the CA of Grignard reagents.
Scheme 1.
Enantioselective CA of Grignard Reagents to
R,β-Unsaturated Compounds
Scheme 2.
Proposed Mechanistic Pathway for the Stoichiometric
1,4-Addition of Organocuprates
ARTICLES
Harutyunyan et al.
9104 J. AM. CHEM. SOC.
9
VOL. 128, NO. 28, 2006
agreement regarding the rate-determining step. Noyori,
13a
Kitamura,
13b
and co-workers have proposed a catalytic cycle
for the Cu/sulfonamide-catalyzed 1,4-addition of diethylzinc to
cyclohexenone based on kinetic data and
12
C/
13
C isotope effect
studies. Their results point toward a concerted mechanism. In
another report, the CA of dialkylzincs involving copper
complexes of Schiff base ligands was studied by Gennari et
al.
13c
The oxidative addition of a Cu-complex to cyclohexenone
was proposed as the rate-limiting step in this reaction. Alter-
natively, Schrader and co-workers
13d
proposed, on the basis of
kinetic studies in a related copper-catalyzed CA using phos-
phorus ligands, a different mechanism involving a reductive
elimination as the rate-limiting step.
Thus far, a detailed mechanistic study of the copper-catalyzed
CA of Grignard reagents is lacking. A single, general mechanism
for the catalytic CA of different organometallic reagents may
not be possible due to the sensitivity of the CA reaction to almost
any variation in the reaction parameters (i.e. ligand, copper
source, solvent, temperature). The difficulties in mechanistic
interpretations are complicated further by the absence of
structural information regarding the intermediate species under
catalytic conditions.
14
The majority of the studies related to the mechanism of the
copper-catalyzed 1,4-addition postulates the transmetalation
between the organometallic compounds and the copper species
as the first step in the catalytic cycle. However, in the enantio-
selective catalytic CA, transmetalated copper intermediates
derived from organometallic compounds have not been charac-
terized to date.
15
In only one case a dramatic (107 ppm) upfield
shift in the
31
P NMR spectra of the copper complex with a chiral
diphosphite ligand was reported upon addition of Et
2
Zn.
16
This
shift was assigned to the presence of an Et-Cu species.
In the present report, we explore the mechanism of the
copper-catalyzed enantioselective CA of Grignard reagents,
through spectroscopic, structural, and kinetic methods. On the
basis of these mechanistic studies we identify catalytically active
species and propose a possible catalytic cycle that is consistent
with the results observed in enantioselective CA.
Results and Discussion
In our earlier communication
7c
we demonstrated that equally
high enantioselectivity can be obtained by using either pre-
formed, air-stable Cu-complexes 1a and 2a or the same
complexes prepared in situ from the chiral diphosphine ligands
(L1 and L2) and CuBr‚SMe
2
(Scheme 3). Furthermore, we have
shown that these copper complexes could be recovered easily
and reused without loss in catalytic activity.
Thus, prior to discussing the species which are present during
catalysis, it is pertinent to consider first the formation and
properties of the copper(I) phosphine complexes employed and
their dynamic behavior in solution. An interesting aspect of this
class of complex is the rapid equilibration to form either a
mononuclear (1′ and 2′) or a binuclear complex (1 and 2),
depending on the solvent employed (Scheme 3).
Structures of the Cu-Halide complexes. The air-stable
copper complexes are prepared by addition of equimolar
amounts of a copper(I) salt and the chiral ligands L1 or L2,
respectively, in the appropriate solvent (Scheme 3). Interestingly,
a solvent-dependent equilibrium between dinuclear (1) and a
mononuclear (1′) species is established in solution.
7c
For
example, the preparation of the bromide complex from CuBr‚
SMe
2
and L1 using ethereal (Et
2
O,
t
BuOMe) or halogenated
(CH
2
Cl
2
, CHCl
3
) solvents led to the dinuclear structure 1a,as
deduced by ESI-MS and IR spectroscopy.
17a
Attempts to obtain
crystals suitable for X-ray analysis of 1a from these solvents
(Et
2
O,
t
BuOMe, CH
2
Cl
2
), commonly used in the CA of Grignard
reagents,
7a-d
were unsuccessful thus far.
In a similar manner, the dinuclear complex 2a was prepared
from CuBr‚SMe
2
and L2 in
t
BuOMe. Suitable crystals for X-ray
analysis of this complex were obtained from an Et
2
O solution.
The asymmetric unit consists of one moiety of a dinuclear
copper complex, which is bridged by two Br atoms resulting in
a C2-symmetric unit. A molecule of the water is also present
in the cell (Figure 2). The dimeric structure of 2a in
t
BuOMe,
(13) To date only four mechanistic studies on copper-catalyzed CA of organozinc
reagents have been reported: (a) Kitamura, M.; Miki, T.; Nakano, K.;
Noyori, R. Bull. Chem. Soc. Jpn. 2000, 73, 999-1014. (b) Nakano, K.;
Bessho, Y.; Kitamura, M. Chem. Lett. 2003, 32, 224-225. (c) Gallo, E.;
Ragaini F.; Bilello, L.; Cenini, S.; Gennari, C.; Piarulli, U. J. Organomet.
Chem. 2004, 689, 2169-2176. (d) Pfretzschner, T.; Kleemann, L.; Janza,
B.; Harms, K.; Schrader, T. Chem.sEur. J. 2004, 10, 6049-6057.
(14) Two structural types of organocuprates formed by the addition of Grignard
reagents to a Cu(I) source, in a 1:1 ratio, have been proposed; e.g. a “RCu‚
MgX
2
”
14a
species and an ate complex “R(X)CuMgX”.
14b
The latter is
considered more relevant and has been proposed in the related 1,4-additions
of allylic copper species prepared from Grignard reagents. (a) Alexakis,
A.; Commercon, A.; Coulentianos, C.; Normant, J. F. Pure Appl. Chem.
1983, 55, 1759-1766. (b) Lipshutz, B. H.; Hackmann, C. J. Org. Chem.
1994, 59, 7437-7444.
(15) Hypothetical structures of the species formed by transmetalation (with
organomagnesium, organolithium, or organoaluminum compounds) of
copper complexes bearing chiral ligands only have been proposed for
enantioselective CA.
12
In contrast, a number of studies have been reported
towards elucidation of the structures of nonchiral transmetalated copper
salts (organocuprates).
8a,10,14
(16) Yan, M.; Yang, L.; Wong, K.; Chan, A. S. C. Chem. Commun. 1999,11-
12.
Scheme 3.
Formation of the Copper (I) Diphosphine Complexes
Figure 2.
X-ray structure of (S,R)-2a (hydrogen atoms are omitted for
clarity).
Cu-Catalyzed Enantioselective CA of Grignard Reagents
ARTICLES
J. AM. CHEM. SOC.
9
VOL. 128, NO. 28, 2006 9105
CH
2
Cl
2
and Et
2
O solutions was also confirmed by ESI-MS.
17b
In a similar manner the preparation of copper chloride and
copper iodide complexes from L1 (Scheme 3) in halogenated
solvents led to the formation of dinuclear complexes 1b and
1c. The dimeric structure of 1b and 1c in CH
2
Cl
2
was confirmed
by ESI-MS.
A different behavior, however, was observed when these
complexes were prepared in more polar solvents, such as
CH
3
CN (or MeOH). Thus, the mixture of CuBr and L1 in
CH
3
CN led to the formation and precipitation of the mono-
nuclear complex 1a′. This mononuclear Cu-complex 1a′ can
be prepared by dissolving the dinuclear complex 1a in CH
3
CN
also (by ESI-MS and IR).
7c
In contrast to the dinuclear complex
1a, the mononuclear complex 1a′ is insoluble in Et
2
O and
t
BuOMe. However, in halogenated solvents, such as CH
2
Cl
2
or
CHCl
3,
1a′ dissolves readily yielding the dinuclear complex 1a
(Scheme 3). Interestingly, both 1a′ and 1a in CD
3
CN and
CD
2
Cl
2
, respectively, showed nearly identical
1
H and
31
P NMR
spectra, thus, precluding the use of NMR spectroscopy to
distinguish mono- or dinuclear structures. Further evidence of
the monomeric structure of 1a′ was obtained by X-ray diffraction
of crystals obtained by slow evaporation of a CH
3
CN solution.
The crystal structure shows a trigonal planar mononuclear
Cu-complex 1a′ (Figure 3). No solvent molecules are coordi-
nated to the copper center. The asymmetric unit consists of two
molecules of the monomeric complex 1a′. The difference
between the two molecules in the unit cell is due to a
conformational change in the dicyclohexyl moieties. In the
crystal structure copper exhibits distorted trigonal coordination
geometry with the copper ion bound to two phosphorus and
one bromide atoms. The metal forms a six-member chelate ring
with the ligand, in a boatlike conformation.
The propensity of the Cu complexes of L1 and L2 to form
dinuclear structures in solvents used in the CA reaction (Et
2
O,
CH
2
Cl
2
,
t
BuOMe) is demonstrated also by the formation of the
stable heterocomplex 3 (Figure 4).
Complex 3 was prepared by mixing, (R,S)-L1,(S,R)-L2, and
CuBr‚SMe
2
in ratio 1:1:2 in CH
2
Cl
2
. Complete formation of
the heterocomplex 3 was monitored by TLC.
17c
The dinuclear
structure of heterocomplex 3 was confirmed by X-ray analysis
(Figure 4). The asymmetric unit consists of one molecule of
dinuclear Cu-complex 3 and two highly disordered hexane
solvent molecules.
In conclusion, in solution the copper complexes exhibit a
mononuclear structure in CH
3
CN and MeOH, while in ethereal
and halogenated solvents the dinuclear structure is dominant.
Importantly, the mononuclear complex is insoluble in ethereal
solvents and dissolves in the halogenated solvent due to its rapid
conversion to the dinuclear form.
Redox Properties of Cu-Halide Complexes. It is apparent
from our earlier reports
7a-c
that there is a considerable sensitivity
of the outcome of the copper(I)-catalyzed, enantioselective CA
of Grignard reagents to the nature of the ligand and substrate
class employed. This sensitivity is expected to arise from both
steric and electronic differences between the various Cu(I)
diphosphine complexes. Electrochemistry represents a powerful
tool in probing the electronic properties of redox active systems,
and in the present study, it enables a direct measurement of the
(17) (a) For full spectroscopic details, see ref 7c. (b) See Supporting Information.
(c) The R
f
value for the heterocomplex 3 is different from the R
f
value of
the dinuclear complexes 1a and 2a.
Figure 3.
X-ray structure of 1a′ (hydrogen atoms are omitted for clarity).
Figure 4.
X-ray structure of (R,S,S,R)-3 (hydrogen atoms are omitted for clarity).
ARTICLES
Harutyunyan et al.
9106 J. AM. CHEM. SOC.
9
VOL. 128, NO. 28, 2006
