Rhodium chemzymes: Michaelis-Menten kinetics in dirhodium(II) carboxylate-catalyzed carbenoid reactions

Article abstract of DOI:10.1021/ja011599l

Rhodium carboxylate-mediated reactions of diazoketones involving cyclopropanation, C-H insertion, and aromatic C-C double bond addition/electrocyclic ring opening obey saturation (Michaelis-Menten) kinetics. Axial ligands for rhodium, including aromatic hydrocarbons and Lewis bases such as nitriles, ethers, and ketones, inhibit these reactions by a mixed kinetic inhibition mechanism, meaning that they can bind both to the free catalyst and to the catalyst - substrate complex. Substrate inhibition can also be exhibited by diazocompounds bearing these groupings in addition to the diazo group. The analysis of inhibition shows that the active catalyst uses only one of its two coordination sites at a time for catalysis. Some ketones exhibit the interesting property that they selectively bind to the catalyst - substrate complex. The similarity of the kinetic constants from different types of reactions with similar diazoketones, regardless of the linking unit or the environment of the reacting alkene, suggests that the rate-determining step is the generation of the rhodium carbenoid. A very useful rhodium carboxylate catalyst for asymmetric synthesis, Rh₂(DOSP)₄, shows slightly slower kinetic parameters than the achiral catalysts, implying that enantiose-lectivity of this catalyst is based on slowing reactions from one of the enantiotopic faces of the reactant, rather than any type of ligand-accelerated catalysis. A series of rhodium catalysts derived from acids with pK_as spanning 4 orders of magnitude give very similar kinetic constants.

Full text of DOI:10.1021/ja011599l

Published on Web 01/19/2002
Rhodium Chemzymes: Michaelis-Menten Kinetics in
Dirhodium(II) Carboxylate-Catalyzed Carbenoid Reactions
Michael C. Pirrung,* Hao Liu, and Andrew T. Morehead, Jr.†
Contribution from the Department of Chemistry, LeVine Science Research Center,
Duke UniVersity, Durham, North Carolina 27708-0317
Received June 28, 2001. Revised Manuscript Received September 17, 2001
Abstract: Rhodium carboxylate-mediated reactions of diazoketones involving cyclopropanation, C-H
insertion, and aromatic C-C double bond addition/electrocyclic ring opening obey saturation (Michaelis-
Menten) kinetics. Axial ligands for rhodium, including aromatic hydrocarbons and Lewis bases such as
nitriles, ethers, and ketones, inhibit these reactions by a mixed kinetic inhibition mechanism, meaning that
they can bind both to the free catalyst and to the catalyst-substrate complex. Substrate inhibition can also
be exhibited by diazocompounds bearing these groupings in addition to the diazo group. The analysis of
inhibition shows that the active catalyst uses only one of its two coordination sites at a time for catalysis.
Some ketones exhibit the interesting property that they selectively bind to the catalyst-substrate complex.
The similarity of the kinetic constants from different types of reactions with similar diazoketones, regardless
of the linking unit or the environment of the reacting alkene, suggests that the rate-determining step is the
generation of the rhodium carbenoid. A very useful rhodium carboxylate catalyst for asymmetric synthesis,
Rh2(DOSP)4, shows slightly slower kinetic parameters than the achiral catalysts, implying that enantiose-
lectivity of this catalyst is based on slowing reactions from one of the enantiotopic faces of the reactant,
rather than any type of ligand-accelerated catalysis. A series of rhodium catalysts derived from acids with
pKas spanning 4 orders of magnitude give very similar kinetic constants.
The concept of a “chemzyme” was introduced by Corey1 to
describe oxazaborolidine catalysts that exhibit high enantiose-
lectivity and serve as catalysts for their own enantioselective
synthesis, and it received much attention.2 A chemzyme has
been subsequently defined as a specific molecule or complex
that can catalyze a single chemical reaction for a particular
chemical substrate with very high enantioselectivity and enan-
tiospecificity at rates that approach “catalytic perfection”.3 The
term has been applied to hetero-bimetallic complexes that
enhance the reactivity of both reactants in the asymmetric
Michael addition,4 Lewis acid catalysts for hetero-Diels-Alder
reactions,5 and even to achiral aluminum phenoxide catalysts
for conjugate allylation.6 Chemzyme membrane reactors have
been created from the oxazaborolidine chemzymes.7 However,
the kinetics of none of these catalytic systems have been
examined to support their catalytic perfection. Reactions are
generally regarded as catalytically perfected when they occur
at the diffusion-controlled limit, which may be ∼108 M-1 s-1
for macromolecular diffusion involving enzymes in water. Small
molecule organic catalysts might offer a faster diffusion limit,
∼1010 M-1 s-1. While enzymes often do exhibit exquisite
enantioselectivity, their most characteristic behavior is Michae-
lis-Menten kinetics. Surprisingly, few purely chemical catalytic
reactions have been examined for Michaelis-Menten or satura-
tion behavior, despite the fact that many might be expected to
exhibit saturation kinetics.
Conventional catalytic organic reaction processes that have
been analyzed using saturation kinetics are listed in Table 1
along with their kinetic parameters. The range of selectivity
constants, the apparent second-order rate constant for the
reaction of the substrate with the catalyst to give the product,
or kcat/Km, is 6 orders of magnitude, but they do not even
approach the diffusion-controlled limit. The reactions studied
include catalytic hydrogenation, redox reactions, phosphate
hydrolysis, and the Sharpless asymmetric dihydroxylation. The
effects of several potential inhibitors of this latter reaction were
also studied; for example, 2-naphthyl N-methylamine has a Ki
) 1.6 mM. Since virtually any catalytic reaction involving an
associative/dissociative step could obey saturation kinetics, it
is surprising that more systems have not been studied in this
manner. We have studied the kinetics of catalytic chemical
processes that have received wide attention in organic synthesis,
the rhodium-mediated reactions of diazocompounds via car-
benoid intermediates.8
† Current address: Department of Chemistry and Biochemistry, Univer-
sity of Maryland, College Park, MD 20742-2021.
(1) Corey, E. J.; Chen, C. P.; Reichard, G. A. Tetrahedron Lett. 1989, 30,
5547-50.
(2) Waldrop, M. M. Science 1989, 245, 354-5.
(3) Bugg, T. An Introduction to Enzyme and Coenzyme Chemistry; Blackwell
Science: Oxford, U.K., 1997.
(4) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem.
Soc. 1995, 117, 6194-8.
(5) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jorgensen, K. A. J.
Am. Chem. Soc. 1998, 120, 8599-605.
(6) Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 1997, 36,
1183-5.
(7) Woeltinger, J.; Bommarius, A. S.; Drauz, K.; Wandrey, C. Org. Process
Res. DeV. 2001, 5, 241-8.
(8) Pirrung, M. C.; Morehead, A. T. J. Am. Chem. Soc. 1996, 118, 8162-3.
9
1014 VOL. 124, NO. 6, 2002 J. AM. CHEM. SOC.
10.1021/ja011599l CCC: $22.00 © 2002 American Chemical Society

Rhodium Chemzymes
A R T I C L E S
Table 1. Kinetic Parameters for Selected Catalytic Reactions
Exhibiting Saturation Kinetics
understanding of these reactions is complicated by the highly
reactive nature of the intermediates, their low concentrations,
and the multitude of potential reaction pathways. In some cases,
these reaction pathways have been analyzed using theoretical
methods.24 Initial mechanistic study of the catalytic reactions
of diazo compounds by rhodium carboxylates was performed
by Hubert and Noels.25 The kinetic parameters of the cyclo-
propanation of styrene with ethyl diazoacetate (EDA) catalyzed
by rhodium acetate were determined to be ∆Hq ) 15.0 ( 0.6
kcal/mol and ∆Sq ) -3.1 ( 2 eu (0 °C). They also determined
that this reaction is first order in catalyst. Subsequently, Alonso
and Garc´ıa examined the rhodium acetate-catalyzed C-H
insertion reaction of ethyl diazoacetate into dioxane and
determined that the reaction is first order in EDA.26 The kinetic
parameters were determined to be ∆H q ) 16.4 ( 1.4 kcal/mol
and ∆S q ) -25 ( 4 eu. The large negative entropy of activation
for this reaction was attributed to a rate-determining step that
does not involve nitrogen loss. These workers postulated a
mechanism in which the rhodium acetate dimer is split to give
a catalytically active monomeric catalyst. However, splitting
of the dimer is not now widely believed to be involved in the
mechanism.
Km
(mM)
k
cat /Km
reaction
kcat (s-1
)
(M-1 s-1
)
ref
acrylamide/HRuCl(diop)2
acrylamide/[HRuCl(PPh3)2]2
flavin mimic/NADH analogue
thiol/cobalt-phthalocyanine
thiol/iron-phthalocyanine
0.32 8.60 × 10-3 2.7 × 10
9
9
0.67 1.10 × 10-3 1.6
101
3.65 × 10-5 3.61 × 10-4 10
44.4 3.13 × 10-3 7.05 × 10-2 11
9.64 6.75 × 10-4 7.00 × 102
11
12
13
14
15
styrene/asymmetric dihydroxylation 17
2.60 × 10-1 1.5 × 10
copper polymer/phosphate hydrolysis 8.77 4 × 10-2
5
Cu-catalyzed Diels-Aldera
0.86 2.56 × 10-3 2.97
Mo-catalyzed olefin epoxidation
48
53.3
1.1 × 103
a The kobs for this bimolecular reaction was scaled by 1 mM cyclopen-
tadiene.
Scheme 1
Yates’ model for diazo compound transformation can be
applied to the catalytic cycle for rhodium(II) catalysts. If the
first step is a reversible equilibrium complexation of the
negatively polarized carbon of the diazocompound with the
rhodium(II) catalyst and the second is a rate-determining loss
of dinitrogen (Scheme 1), these processes should obey saturation
kinetics. This study first aimed to evaluate this possibility; if
Michaelis-Menten behavior could be shown, determination of
the influence of catalyst and reactant structure on kinetic
properties would be undertaken. These could contribute to
understanding of the process of diazo loss, elucidate the role of
the metal in facilitating the process, and identify the presence
of any intermediates. Other concepts from Michaelis-Menten
Several reviews of transition metal catalysis in carbenoid
chemistry, particularly rhodium catalysis, are available.16-18 The
currently accepted mechanism of these reactions was first
proposed by Yates (Scheme 1)19 and invokes nucleophilic attack
by the diazo compound on the electrophilic metal. After loss
of nitrogen, the carbenoid reacts with an electron-rich substrate
X and regenerates the catalyst. The dirhodium(II) carboxylates
possess a “lantern” structure, with the two rhodium atoms
surrounded by four carboxylates in a nominal D4 symmetry and
bearing two open axial coordination sites. Two extensive reviews
of rhodium(II) complexes are available.20
(19) Yates, P. J. Am. Chem. Soc. 1952, 74, 5376-81.
(20) (a) Felthouse, T. R. Prog. Inorg. Chem. 1982, 29, 74-166. (b) Jardine, F.
H.; Sheridan, P. S. In Comput. Coord. Chem.; Wilkinson, G., Ed.; Pergamon
Press: New York, 1987; Vol. IV, pp 934-1083.
The current understanding of the mechanisms of reactions
of diazo compounds catalyzed by dirhodium(II) carboxylates
is certainly incomplete, with the primary studies based on
relative reactivity comparisons between potential substrates and
inferences about the reactive species. Studies of regioselectiv-
ity,21 enantioselectivity,22 and chemoselectivity23 in rhodium-
mediated reactions have shown that an impressive degree of
control can be exerted by the ligands. True mechanistic
(21) (a) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone,
W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958-
64. (b) Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org. Chem. 1992,
57, 436-41. (c) Taber, D. F.; Hoerner, R. S. J. Org. Chem. 1992, 57, 441.
(d) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedran Lett. 1992, 33,
2709-12. (e) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O.
Tetrahedran 1991 47, 7403-8. (f) Doyle, M. P.; Pieters, R. J.; Taunton,
J.; Pho, H. Q.; Padwa, A.; Hertzog, D. L.; Precedo, L. J. Org. Chem. 1991,
56, 820. (g) Demonceau, A.; Noels, A. F.; Hubert, A. J. Tetrahedron 1990,
46, 3889-96. (h) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.;
Brinker, D. A.; Eagle, C. T.; Loh, K. J. Am. Chem. Soc. 1990, 112, 1906-
12. (i) Doyle, M. P.; Bagheri, V.; Pearson, M. M.; Edwards, J. D.
Tetrahedron Lett. 1989, 30, 7001-4. (j) Demonceau, A.; Noels, A. F.;
Hubert, A. J.; Teyssie´, P. Bull. Chem. Soc. Belg. 1984, 93, 945-8.
(22) For reviews see: Doyle, M. P. Recl. TraV. Chim. Pays-Bas 1991, 110,
305-16. Brunner, H. Angew. Chem., Int. Ed. Engl. 1992, 31, 1183-5.
(23) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993,
115, 8669-80. (b) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones,
M. A.; Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114,
1874-6. (c) Reference 21b. (d) Hashimoto, S.; Watanabe, N.; Ikegami, S.
J. Chem. Soc., Chem. Commun. 1992, 1508-10. (e) Doyle, M. P.; Taunton,
J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397-400. (f) Cox, G. G.;
Moody, C. J.; Austin, D. J.; Padwa, A. Tetrahedron 1993, 49, 5109-26.
(g) Doyle, M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q.; Padwa, A.; Hertzog,
D. L.; Precedo, L. J. Org. Chem. 1991, 56, 820-9. (h) Doyle, M. P.;
Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker, D. A.; Eagle, C. T.;
Loh, K. L. J. Am. Chem. Soc. 1990, 112, 1906-12.
(9) (a) Hui, B. C.; James, B. R. Can. J. Chem. 1974, 52, 3760-8. (b) James,
B. R.; Wang, D. K. W. Can. J. Chem. 1980, 58, 245-50. (c) James, B. R.;
Wang, D. K. W. J. Chem. Soc., Chem. Commun. 1977, 550-1. (d) Joshi,
A. M.; MacFarlane, K. S. James, B. R. J. Organomet. Chem. 1995, 488,
161-7.
(10) Shinkai, S.; Ishikawa, Y.; Shinkai, H.; Tsuno, T.; Makishima, H.; Ueda,
K.; Manabe, O. J. Am. Chem. Soc. 1984, 106, 1801-8.
(11) Hanabusa, K.; Ye, X.; Koyama, T.; Kurose, A.; Shirai, H.; Hojo, N. J.
Mol. Catal. 1990, 60, 127-34.
(12) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319-29.
(13) Menger, F. M.; Tsuno, T. J. Am. Chem. Soc. 1989, 111, 4903-7.
(14) Otto, S.; Bertoncin, F.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1996, 118,
7702-7.
(15) (a) Su, C.-C.; Reed, J. W.; Gould, E. S. Inorg. Chem. 1973, 12, 337-42.
(b) Arakawa, H.; Moro-oka, Y.; Ozaki, A. Bull. Chem. Soc. Jpn. 1974, 47,
2958-2961.
(16) Doyle, M. P. Chem. ReV. 1986, 86, 919-39.
(17) (a) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765-808. (b) Padwa,
A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385-453.
(18) (a) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348. (b) Padwa, A.; Hornbuckle,
S. F. Chem. ReV. 1991, 91, 263-309. (c) Maas, G. Top. Curr. Chem. 1987,
137, 75.
(24) Padwa, A.; Snyder, J. P.; Curtis, E. A.; Sheehan, S. M.; Worsencroft, K.
J.; Kappe, C. O. J. Am. Chem. Soc. 2000, 122, 8155-67.
(25) Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie´, P. J.
Org. Chem. 1980, 45, 695-702.
(26) Alonso, M. E.; Garc´ıa, M. del C. Tetrahedron 1989, 45, 69-76.
9
J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002 1015

A R T I C L E S
Pirrung et al.
Table 2. Saturation Kinetic Parameters for Intramolecular Bu¨chner
and Cyclopropanation Reactionsa
reactant/catalyst
Km (mM)
kcat (s-1
)
kcat /Km (M-1 s-1
)
Ki(S) (mM)
1/Rh2Piv4
3/Rh2Piv4
5/Rh2Piv4
7/Rh2Piv4
1/Rh2TCA4
15
15
13
14
1
1100
1090
1170
1120
625
7.3 × 104
7.3 × 104
9.0 × 104
8.0 × 104
6.25 × 105
265
96
10
a CH2Cl2 solvent, room temperature.
(V vs [S]) shows a hyperbolic form, supporting the hypothesis
that rhodium-catalyzed diazoketone reactions exhibit saturation
kinetics. An Eadie-Hofstee plot (Figure 1) was used to
determine the kinetic parameters (Table 2).28 The saturation
kinetic model was further supported by study of the intramo-
lecular Bu¨chner reaction of compounds 3 and 5, which produce
the hydroazulene derivatives 4 and 6 in high yield. Both show
kinetic parameters essentially identical to 1.
Figure 1. Eadie-Hofstee plot of the rate of reaction of diazoketone 1
catalyzed by rhodium pivalate at low substrate concentration [5-25 mM].
Scheme 2
The rhodium-catalyzed reactions of 3 and 5 would be
expected to show different rate constants than that of 1 if
carbon-carbon bond formation were rate limiting. The electron-
donating methoxy group would be expected to increase the rate
of electrophilic attack on the aryl ring in 3, and the gem-dimethyl
effect29 would be expected to increase the rate of attack on the
phenyl ring in 5. With the exception of the substrate inhibition
parameters (vide infra), both 3 and 5 have kinetic parameters
virtually identical to 1, indicating that the rate-determining step
occurs before the attack on the aromatic ring. One caution should
be added concerning this intermediate conclusion, however. The
Bu¨chner reaction involves an initial formation of the norcara-
diene by cyclopropanation,30 followed by electrocyclic ring
opening to the cycloheptatriene. If the cyclopropanation step
were fast and the ring opening rate determining, similar
saturation kinetic behavior could be observed. It therefore
seemed prudent to examine a second reaction that could obey
saturation kinetics and was not subject to an alternative reaction
pathway.
The rhodium-catalyzed reaction of 7 to give 8 was examined
under conditions (0.2 µM rhodium pivalate, methylene chloride)
identical to those of the earlier reactions. In this case, the loss
of the diazo compound was followed spectrophotometrically at
370 nm. The kinetic parameters for this reaction are in excellent
agreement (<3% standard deviation in kcat) with those for the
Bu¨chner reactions.
The dirhodium(II)-catalyzed intramolecular Bu¨chner reaction
and cyclopropanation obey saturation kinetics. The kinetic
constants are insensitive to aromatic substitution in the Bu¨chner
reaction and are nearly identical for both the Bu¨chner reaction
and cyclopropanation. The simplest model that fits these results
is equilibrium complexation of the diazo compound with the
metal followed by dissociation of molecular nitrogen to generate
the rhodium carbenoid, as previously postulated by Yates; the
latter step must be the rate-determining step. However, it is
conceivable that other dissociative processes are rate limiting
in these rhodium-catalyzed reactions. For example, it is known
kinetics, including the study of Lewis basic inhibitors, could
also be applied, and the factors affecting the kinetic “perfection”
of these catalysts could be evaluated.
Results
The intramolecular Bu¨chner reaction of diazoketone 1 to
produce 2 (Scheme 2), introduced by McKervey,27 was well
suited to begin this study. It proceeds in high yields (>95%) at
room temperature, and product appearance is easily followed
at 340 nm, at which the wavelength of product 2 has a much
greater absorbance (ꢀ ) 187 M-1 cm-1) than the reactant (ꢀ )
37 M-1 cm-1). Reactions were performed at substrate concen-
trations from 5 to 25 mM in methylene chloride, catalyzed by
rhodium pivalate (0.2 µM). This rhodium carboxylate and all
those studied here fully dissolve in noncoordinating and
nonpolar solvents, in this case dichloromethane, so that catalyst
concentrations can be precisely calculated. Product formation
was followed by UV to <10% conversion, ensuring the rates
measured are initial rates. A direct kinetic plot of this reaction
(28) Abbreviations used in tables: Piv: pivalate; TCA: trichloroacetate; Oct:
octanoate; OBz: benzoate; OBz-F: p-fluorobenzoate; TFA: trifluoroacetate;
Ac: acetate; DOSP: tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate).
(29) Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224-32.
(30) For the first isolation of a norcaradiene intermediate in this reaction and
further citations to it, see: Manitto, P.; Monti, D.; Speranza, G. J. Org.
Chem. 1995, 60, 484-5.
(27) (a) McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Chem.
Commun. 1984, 129-30. (b) Kennedy, M.; McKervey, M. A. Maguire, A.
R.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc., Perkin Trans. 1 1990,
1047-54.
9
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Rhodium Chemzymes
A R T I C L E S
Scheme 3
Scheme 4
Figure 2. Eadie-Hofstee plot of the reaction of diazoketone 3 catalyzed
by rhodium pivalate at low substrate concentration [5-25 mM].
(substrate inhibition). The potential nonproductive binding sites
on these substrate molecules include the carbonyl, the terminal
nitrogen of the diazo group, and the aromatic ring. That the
substrate inhibition of rhodium pivalate catalysis appears at
lower substrate concentrations for the 4-methoxy substituted
compound 3 than for the simple phenyl substituted compound
1 suggests the nonproductive binding site is the aromatic ring.
Kinetic determination of the Kis for the substrate inhibition of
rhodium pivalate catalysis was accomplished by extrapolating
the linear portions of 1/V vs [S] plots to their x-axis intercept.32
Compound 3 (96 mM) has a lower substrate Ki than 1 (265
mM), supporting the postulated mechanism of inhibition by
binding of the aromatic ring to the catalyst. If inhibition were
occurring through binding of the carbonyl or diazo group to
the catalyst, 1 and 3 should exhibit substrate inhibition to the
same extent. Compound 5 demonstrates no substrate inhibition
with rhodium pivalate catalysis, which may be due to increased
steric demand of the quaternary carbon-substituted aromatic ring,
preventing binding to the catalyst.
Figure 3. Direct plots of the velocity of the reaction of diazoketones 1
and 3 catalyzed by rhodium pivalate at high substrate concentration [5-100
mM].
that the rate of formation of phosphine and nitrogenous base
adducts of dirhodium carboxylates in water and acetonitrile is
controlled by dissociation of the solvent from the axial
coordination sites.31 In an alternative kinetic scheme (Scheme
3), the initial dissociation of the solvent would be followed by
kinetically significant product formation. However, methylene
chloride is a very poorly coordinating solvent, and it is unlikely
that Km ) 15 mM could be attributed to the desolvation of the
catalyst. The rhodium pivalate had been freed of the axial waters
before use by heating under vacuum, so the dissociation of water
is not the source of the saturation kinetics observed. The lack
of a dependence of the kinetic constants on the particular
aromatic group in the diazoketone suggests that kinetic constants
characteristic of each diazo compound-catalyst combination
but independent of the type of chemical reaction (C-H insertion
or cyclopropanation) will be obtained because the rate-determin-
ing step is the formation of the carbenoid.
In initial studies of 3, a lower than expected rate was observed
at the higher concentrations of substrate. An Eadie-Hofstee
plot (Figure 2) shows this nonlinear dependence at the two
highest concentrations. Data were therefore collected at even
higher substrate concentrations, producing the direct plots for
1 and 3 shown in Figure 3. The effect is particularly pronounced
with 3. One possible mechanism that could result in such an
effect is nonproductive binding of the substrate to the catalyst
A general inhibition scheme that fits these data is shown in
Scheme 4, in which the substrate bound in a nonproductive
manner is indicated by S′. Nonproductive binding of a single
substrate molecule to the catalyst would result in simple mixed
inhibition kinetics (vide infra). Binding of a second substrate
nonproductively would prevent formation of the possibly
productive C‚S‚S′ complex, which could also lose S′ to give
the catalytically competent C‚S. The inhibition observed for
rhodium pivalate catalysis at the high concentrations of substrate
results in linear 1/V vs [S] plots, indicating the second
nonproductive binding event does not occur to a significant
extent.
To further probe this substrate inhibition process, rhodium
trichloroacetate was examined as a catalyst in the reaction of
1. Owing to its greater Lewis acidity than rhodium pivalate, it
would be predicted to bind the aromatic ring more strongly.
The parabolic V vs [S] direct plot shows strong substrate
inhibition (Figure S1, Supporting Material). Use of the linear
portion of the Eadie-Hofstee plot (at low [S], Figure S2)
allowed the kinetic constants to be determined. This more
electron-deficient catalyst gives a lower Km and kcat (Table 2),
but the selectivity constant is about 10-fold greater than that of
rhodium pivalate. The method of Dixon and Webb32 was used
to calculate Ki(S) for rhodium trichloroacetate catalysis, which
is 30-fold lower than with the pivalate (determined at substrate
(31) (a) Das, K.; Simmons, E. L.; Bear, J. L. Inorg. Chem. 1977, 16, 1268-71.
(b) Aquino, M. A. S.; Macartney, D. H. Inorg. Chem. 1987, 26, 2696-9.
(c) Aquino, M. A. S.; Macartney, D. H. Inorg. Chem. 1988, 27, 2868-72.
(32) Dixon, M.; Webb, E. C. Enzymes; Academic Press: New York, 1979; pp
126-36.
9
J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002 1017

A R T I C L E S
Pirrung et al.
Scheme 5
Scheme 6
Table 4. Saturation Kinetic Parameters for Reactions of Methyl
Phenyldiazoacetate with an Asymmetric Catalyst and Achiral
Catalysts
reactant/catalyst
Km (mM)
kcat (s-1
)
kcat /Km (M-1 s-1
)
15/Rh2(DOSP)4
15/Rh2Piv4
15/Rh2Oct4
24.7
9.07
9.08
1.58
1.29
1.27
6.40 × 10
1.42 × 102
1.39 × 102
Table 3. Dependence of Saturation Kinetic Parameters on
Diazocarbonyl Structure
Table 5. Dependence of Saturation Kinetic Parameters on
Dirhodium Carboxylate Catalysts in Reactions of 1
reactant/catalyst
Km (mM)
kcat (s-1
)
kcat /Km (M-1 s-1
)
catalyst
Km (mM)
kcat (s-1
)
kcat /Km (M-1 s-1
)
RCO HpK
2
a
1/Rh2Oct4
9/Rh2Oct4
11/Rh2Oct4
9.5
124
71
151
15
5.9
1.6 × 104
1.2 × 102
8.3 × 10
Rh2Piv4
Rh2Oct4
Rh2(OBz)4
Rh2(OBz-p-F)4
Rh2TFA4
7.53
9.53
6.34
6.08
3.51
101
151
92.2
121
70.9
1.33 × 104
1.58 × 104
1.45 × 104
2.00 × 104
2.02 × 104
5.03
4.89
4.19
2.90
0.67
concentrations > 50 mM). Since the plot of 1/V vs [S] used to
determine Ki(S) is linear at higher concentrations (Figure S3),
Kii(S) must be higher than 25 mM and is not a significant
contributor to inhibition in this case. It is well-established that
binding of one Lewis basic axial ligand to rhodium disfavors
the second axial binding by 10-100 times, and presumably the
second binding could occur only at high substrate concentra-
tions.33
Further evidence regarding substrate inhibition was gained
by a second, intermolecular inhibition study. If substrate
inhibition arises via nonproductive binding of the aromatic ring
to the catalyst, then another aromatic compound should also be
able to act as an inhibitor. The reaction of 5 catalyzed by
rhodium pivalate was examined in the presence of anisole. The
method of Dixon32 was used to determine the anisole Ki, which
is 107 mM, in reasonable agreement with the Ki for substrate
inhibition by 3 of 96 mM. Further studies of inhibition by Lewis
bases are given later.
Other types of diazo compounds were examined to determine
the influence of structure on saturation kinetic properties. Diazo-
â-ketoester 9 was prepared by dianion alkylation of ethyl
acetoacetate and diazo transfer, as was the diazo-â-diketone 11.
Their intramolecular C-H insertion reactions (Scheme 5) were
examined by following the loss of the diazocarbonyl absorption
in the UV with Rh2Oct4 as catalyst and compared with the
Bu¨chner reaction of 1. Results are summarized in Table 3. Weak
substrate inhibition (too weak to be accurately determined) was
observed with 9 and 11, but not with 1, as contrasted with its
reaction catalyzed by rhodium pivalate. The C-H insertion
reaction of 13 was also examined but proved too rapid to be
studied with the methods used here.
One of the most powerful new synthetic technologies based
upon rhodium-catalyzed reactions of diazo compounds exploits
chiral catalysis. The rhodium prolinate family of catalysts
developed by Davies show good enantioselectivity in reactions
of vinyl or aryl diazocarbonyls such as cyclopropanation and
C-H insertion.34 Methyl phenyldiazoacetate (15, Scheme 6)
insertion into C-H bonds is catalyzed by rhodium prolinates
with good to excellent enantioselectivity.35 Mu¨ller carried out
the reaction of 1,4-cyclohexadiene (20 equiv) with 15 promoted
by the chiral rhodium prolinate catalyst Rh2(DOSP)4 (in 65%
ee and 98% yield) by adding the diazo compound to a solution
of cyclohexadiene and catalyst via a syringe pump. Since it is
known that vinyl and aryl diazocarbonyls are not prone to
carbene dimerization,36 saturation kinetics studies of this reaction
could be performed by addition of the catalyst to a mixture of
the two reactants. Under these conditions with rhodium pivalate,
the C-H insertion product 16 is obtained in 88% isolated yield.
The kinetics of the reaction promoted by a chiral and two achiral
catalysts were examined using methods similar to those applied
to 1. The kinetic parameters are summarized in Table 4.
The foregoing was our first study of the effect of significant
catalyst variations on the kinetics of a dirhodium carboxylate-
catalyzed reaction. It seemed worthwhile to examine a wider
range of catalyst variants in the reaction of 1 for comparison.
These experiments were performed under slightly different
conditions but similar to those previously used. The results are
summarized in Table 5. Substrate inhibition occurs at concentra-
tions > 50 mM, and Ki(S) was determined in the case of Rh2-
TFA4 to be 48 mM.
The discovery that rhodium-catalyzed reactions of diazo
compounds could be inhibited by Lewis bases as weak as anisole
suggested examination of the inhibition by other weak Lewis
bases, with the further attraction of potentially providing insight
into the mechanism of rhodium carboxylate catalysis. Because
dirhodium complexes have two open axial coordination sites,
they could conceivably catalyze diazo compound reactions at
both sites. Strong ligands such as imidazoles, sulfides, and
phosphines completely abolish catalytic activity, presumably
through coordination at both axial sites. It has also been shown
that binding of a Lewis basic ligand (which might be extended
(35) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000,
122, 3063-70. Mu¨ller, P.; Tohill, S. Tetrahedron 2000, 56, 1725-31.
(36) Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.; Stafford, D. G.
Tetrahedron Lett. 1998, 39, 4417.
(33) Drago, R. S.; Long, L. R.; Cosmano, R. Inorg. Chem. 1981, 20, 2920-7
(34) Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001, 617-8,
47-55. Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459-69.
9
1018 J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002

Rhodium Chemzymes
A R T I C L E S
Table 6. Analysis of Inhibition of the Reaction of 1 Catalyzed by
Rhodium Octanoate Using Scheme 7
Lewis base
K (mM)
i1
K (mM)
i2
R
tetrahydrofuran
1,4-dioxane
acetone
5.29
27.9
5.00
134
14.85
55.4
196
74.8
114
81.8
12.9
4.1
0.52
∞
∞
1.27
0.0062
0.35
1.27
cyclobutanonea
cyclopentanonea
cyclohexanone
methyl cyclopropyl ketone
1-indanone
70.3
1.21
26.9
328
76.2
258
1,1,1-trifluoroacetone
a Competitive inhibitor.
Table 7. Saturation Kinetic Parameters for Rhodium
Acetate-Catalyzed Reactions of Varied Diazocarbonylsa
reactant/catalyst
Km( app) (mM)
kcat (s-1
)
kcat /Km (M-1 s-1
)
Figure 4. Lineweaver-Burk plot of the inhibition by acetonitrile of the
reaction catalyzed by rhodium pivalate of diazoketone 5.
1/Rh2Ac4
9/Rh2Ac4
11/Rh2Ac4
1.14 × 103
2.92 × 102
3.01 × 10
3.3 × 10
2.9 × 101
3.6 × 10-1
3.0
1.1 × 10-1
8.9 × 10-2
Scheme 7
a Dioxane solvent, 60.0 °C.
the rhodium octanoate-catalyzed reaction of the more readily
accessible 1, with the results summarized in Table 6. In all cases,
â ) 0.
In simple competitive inhibition, the Ki for a particular
inhibitor/catalyst combination should be the same no matter
which reaction is being catalyzed. With mixed inhibition, matters
are not so simple, since another species to which the inhibitor
may bind, C‚S, is different when S is different. An inhibition
study was therefore conducted with the same catalyst/inhibitor
combination, but with three different substrates (1, 9, and 11).
In this case the catalyst was Rh2(OAc)4 and 1,4-dioxane was
used as the solvent (inhibitor). To make the rates measurable,
the reactions were carried out at elevated temperature (60.0 °C).
This experiment also addresses the issue raised earlier concern-
ing catalyst desolvation being rate determining. The concentra-
tion of neat dioxane is 11.7 M, so far above the Ki2 measured
above that the catalyst must be doubly solvated in the resting
state, and at least one dioxane must dissociate for any catalysis
to occur. The data are summarized in Table 7. When the kinetic
constants were measured in a noncoordinating solvent, such as
CH2Cl2 (Table 3), the observed sequence of Kms is Km(9) >
Km(11) > Km(1). In the coordinating solvent 1,4-dioxane, the
measured parameter is Km(app) because the reaction is inhibited
(and must be run at higher temperature). The observed sequence
of Km(app) is Km(1) > Km(9) > Km(11), which is neither a
simple repeat nor the reverse of the sequence in CH2Cl2.
to include the carbenoid) at one site weakens binding at the
other site (via the trans effect), suggesting that only one site
might be catalytically active at any given time. Since this
influence would be analogous to competitive inhibition (weak-
ening binding ) raising Km), the study of the effect of a Lewis
base on the kinetics could lend insight into the mechanism.
With two possible inhibitor binding sites, the kinetics of these
reactions can be complex. A general analysis for this system is
given in Scheme 7, and its detailed analysis is presented in the
Supporting Information. Besides the conventional Michaelis-
Menten constants, two key parameters of the kinetics of this
system are R and â. The former classifies inhibition based on
the position of the intersection of double reciprocal lines at
multiple inhibitor concentrations. For mixed inhibition, the point
of intersection is in the second quadrant if R > 1, and it is in
the third quadrant if R < 1. If the point of intersection is on the
-x axis, R ) 1, and this is noncompetitive inhibition. If R )
∞, the point of intersection is on the +y axis and the situation
simplifies greatly to competitive inhibition. The value of â
exemplifies the catalytic power of a ternary complex with
substrate and inhibitor.
The weak ligand acetonitrile was examined in the rhodium
pivalate-catalyzed reaction of 5 (chosen because it is not
complicated by substrate inhibition). The reaction was performed
in the presence of 3.00, 5.00, 7.00, and 10.0 mM of acetonitrile
in dichloromethane, under conditions otherwise identical to those
employed previously. The resultant V vs [S] plots are shown in
Figure S4 (Supporting Information), and double reciprocal plots
of these data are shown in Figure 4. Graphic analysis indicates
mixed inhibition. Replots of the slope and intercepts are linear,
indicating that â ) 0 and giving kinetic constants of Ki ) 5.0
mM and R ) 3. That is, there is no catalysis from the C‚I‚S
intermediate.
Discussion
This work establishes that dirhodium carboxylate-catalyzed
reactions exhibit saturation kinetics and can be studied in detail
using this formalism. The agreement of the kinetic parameters
between the Bu¨chner and cyclopropanation reactions eliminates
rapid bimolecular formation of the norcaradiene intermediate
followed by slow ring opening to the observed product as an
alternative explanation for saturation, since no following reaction
is involved in the cyclopropanation reaction. The data of Table
7 provide further evidence that the saturation kinetics cannot
be attributed to dissociation of solvent from the catalyst, since
if this were so, all three reactants should exhibit the same Km-
(app). The electron-deficient catalyst rhodium trichloroacetate
These data suggested evaluation of other common Lewis basic
ligands as inhibitors. Ethers and ketones were used to inhibit
9
J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002 1019

A R T I C L E S
Pirrung et al.
Chart 1
is better at binding diazocompound 1 than rhodium pivalate (Km
) 1.0 mM vs 15 mM), due to increased Lewis acidity, but is
slightly slower in the catalytic step of nitrogen loss (kcat ) 625
s-1 vs 1100 s-1 for rhodium pivalate). This observation provides
further support for our previous linear free energy relationship
study that shows significant back-bonding from the metal to
the carbene.37 This back-bonding would tend to stabilize the
carbene and facilitate its formation. Recent theoretical study
has supported the ability of the dirhodium core to participate
in back-bonding with good π-acid ligands,38 though earlier
studies had not found back-bonding.39 The more electron
deficient catalyst has a nearly 10-fold increase in overall rate
due to its 15-fold stronger substrate binding, as is apparent in
the second-order rate constants given in Table 2. The substrate
inhibition of these reactions was surprising and sounds a
cautionary note concerning preparative rhodium-catalyzed reac-
tions conducted at high substrate concentrations or with electron-
deficient catalysts. The divergence of the effects of catalyst on
kcat/Km and on Ki(S) for 1 support the idea that they address two
different processes, one being binding of the diazo carbon to
the catalyst and the other binding of the aromatic ring.
The diazo compounds studied in Table 3 demonstrate an
interesting trend. As the pKa of the carbon acid from which the
diazo compound was derived decreases (ketone pKa > â-ke-
toester pKa > â-diketone pKa), kcat/Km decreases. The rate of
the reaction of 13 was too fast to be measurable, but is clearly
faster than 1. Since an ester R-C-H bond is less acidic than a
ketone R-C-H bond, this observation reinforces the trend. Our
interpretation of this overall phenomenon is that the diazo carbon
is more basic when adjacent to poorer anion-stabilizing groups
and therefore a better donor to rhodium in the initial association
step (neglecting steric effects).
A great deal can be learned about the electronic influence of
ligands on selectivity in rhodium-catalyzed reactions through
extensive catalyst variation and linear free energy relationship
analysis.37,40 An important result of such studies was demonstra-
tion of the significance of rhodium-to-carbenoid back-bonding.
A much smaller study of the effect of ligands on kinetic
parameters is reflected in Table 5. Given the 4 orders of
magnitude in variation of the ligand’s conjugate acid pKa, the
almost identical selectivity constants for these reactions are
startling. These data suggest that changing the rhodium ligands
to affect reaction selectivity should not strongly affect the ability
of the catalyst to catalyze reactions of diazo compounds. The
large literature on synthetic reactions exhibiting just this behavior
is reassuring regarding the results of the kinetic study, which
reiterate these observations.
Figure 5. Plot of 1/V vs [I] at constant [S] for rhodium pivalate-catalyzed
reaction of 5 in the presence of acetonitrile.
catalysts may be a statistical effect related to the D2 catalyst
symmetry, which sterically permits only four approach vectors
to the rhodium, whereas the achiral catalysts permit eight (Chart
1). Our other study shows that there is little effect of the catalyst
carboxylate ligand pKa on the kinetics.
The mixed inhibition demonstrated in these rhodium-
catalyzed reactions is consistent with their kinetic complexity
due to the dual binding sites. Inhibition by even weak Lewis
acids serves as a caution to experimenters conducting rhodium-
catalyzed reactions preparativelysfunctional groups often present
in substrates (aromatic rings!) or minor amounts of common
solvents can clearly affect reaction rates. The kinetically
determined inhibition constant for acetonitrile binding to
rhodium pivalate (5 mM) compares to a spectroscopically
determined value of 0.9 mM for the first acetonitrile binding to
rhodium butyrate33 and is significantly below the second binding
constant (90 mM). The magnitude of R suggests that the top
line of Scheme 7 carries most of the flux at reasonable substrate
concentrations since RKi1 ) 15 mM and RKm ) 36 mM. The
concentration of C‚I‚S is not significant at these substrate and
inhibitor concentrations (by assuming that Ki2 . Ki1 and that â
) 0, [C‚I‚S] can be calculated to be 6% of the total catalyst).
Because of this, â need not be truly zero, since the second line
is not highly populated at these inhibitor concentrations, and it
would have a small effect on the rate. Further evidence that the
second binding of the inhibitor is not kinetically significant at
these inhibitor concentrations comes from plotting 1/V vs [I] at
a constant [S], as shown in Figure 5. A deviation from linearity
would indicate that the second binding step was occurring, and
these plots are linear at the concentrations studied.
Because these dirhodium complexes have two open coordina-
tion sites, they might be thought to catalyze reactions at both
sites simultaneously. That the second catalytic site becomes less
efficient when even a weak ligand (inhibitor) is bound at the
other site suggests that the presence of a carbenoid at one site
would significantly inhibit binding and thereby retard catalysis
at the other site. It is not possible to use kinetics to measure
the strength of the binding once the carbenoid is formed, but it
is expected to be quite strong. Strong binding of the carbenoid
would disfavor the binding of a second diazo compound through
the trans effect. If only one site functions at a time as described,
these complexes could be considered to exhibit “half-of-the-
sites” activity like many enzymes, an extreme example of
The slower rate of the reaction of 15 catalyzed by the chiral
Rh2(DOSP)4 catalyst as compared to the two achiral catalysts
is consistent with the reactivity/selectivity principle. That the
chiral catalyst is approximately half the rate of the achiral
(37) Pirrung, M. C.; Morehead, A. T. J. Am. Chem. Soc. 1994, 116, 8991-8.
(38) Sargent, A. L.; Rollog, M. E.; Eagle, C. T. Theor. Chem. Acc. 1997, 97,
283-8.
(39) Bursten, B. E.; Cotton, F. A. Inorg. Chem. 1981, 20, 3042.
(40) Wang, J.; Chen, B.; Bao, J. J. Org. Chem. 1998, 63, 1853-62.
9
1020 J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002

Rhodium Chemzymes
A R T I C L E S
Chart 2
bind only as acceptors for the significantly enhanced electron
density at the free rhodium when a ligand is bound to the distal
rhodium. This explanation predicts that other electron-deficient
π-bonds should exhibit similar behavior. Finally, it may be
possible that certain ketones inhibit the reaction by binding
directly to the carbenoid carbon. The intramolecular coordina-
tion/binding of an ester/lactone carbonyl to a carbenoid carbon
has been used to explain the high enantioselectivity in rhodium-
mediated reactions of lactate/pantolactone diazoesters.42 If this
were the case, the donor ability of the ketone as reflected in its
HOMO energy should be key. The DFT-calculated HOMO
energies of this group of ketones also provided in Table 8 do
not support this model, however. Indanone also has another
potential binding site for rhodium, the aromatic ring. Based on
our earlier results showing that unhindered and electron-rich
aromatic rings have greater affinity for dirhodium carboxylates,
it seems unlikely that the electron-deficient aromatic ring of
indanone would be a good ligand for rhodium octanoate.
The proposal of Alonso and Garc´ıa,25 who postulated that
nitrogen is not lost in the rate-determining step because of the
large negative entropy of activation found in their kinetic study
is in direct opposition to our proposal for the mechanism of
dirhodium carboxylate-catalyzed reactions. However, it should
be noted that a bimolecular C-H insertion reaction could quite
possibly have a different rate-determining step. The C-H
insertion reaction would likely have a high entropy of activation
due to the constrained approach of the C-H bond to the
carbenoid, which would cost both translational and vibrational
entropy in the transition state. However, we did observe valid
saturation kinetics in the bimolecular C-H insertion reaction
of 15. The demonstration of the first-order dependence on
rhodium acetate of the cyclopropanation of styrene by ethyl
diazoacetate by Hubert and Noels is consistent with our
proposal, since the study was performed at saturating concentra-
tions of ethyl diazoacetate.24
Applying the Yates model and our kinetics to these reactions,
the relative energies of certain intermediates and transition states
in the rhodium pivalate-catalyzed reaction of 1 can be estimated
(Figure 6). If Km is assumed to be equal to Ks, the relation ∆G
) -RT ln Km may be used to show that the catalyst/
diazocarbonyl complex (C‚S) is 2.5 kcal/mol lower in energy
than the starting materials (using Km ) 15 mM). The use of Km
≈ Ks assumes that kcat , k-1, a presumption supported by the
known off rates of water and acetonitrile,33 which must be
greater than 105-106 M-1 s-1, the rate at which phosphine and
nitrogen adducts are formed in water and acetonitrile solution
by a dissociative process. These rates are several orders of
magnitude higher than kcat (≈1100). Since Km will always be
larger than Ks (Supporting Information), 2.5 kcal/mol is the
lower limit on the binding energy. Application of the Eyring
equation to kcat allows calculation of the ∆Gq for loss for
nitrogen from the bound intermediate to be 13.3 kcal/mol (for
kcat ) 1100 s-1). The loss of nitrogen in this step effectively
makes it irreversible. No inference can be made about the
relative energy of the metal-carbene complex or the transition
state for formation of the initial catalyst/diazocarbonyl complex
from these data.
Table 8. DFT-Calculated Frontier Molecular Orbital Energies and
R Values for Carbonyl Inhibitors of Dirhodium
Carboxylate-Catalyzed Reactions
ketone
E
LUMO (eV)
EHOMO (eV)
R
methyl cyclopropyl ketone
acetone
1-indanone
cyclohexanone
1,1,1-trifluoroacetone
-1.7
-1.9
-2.8
-1.9
-3.2
-5.82
-5.82
-5.77
-5.55
-6.97
0.0062
0.52
0.35
1.27
1.27
negative cooperativity in the binding step.41 Our data suggest
that the kinetically most efficient pathway involves only one
carbenoid ligand per dirhodium catalyst.
A more subtle mechanistic point is that dissociation of a
carboxylate to open another coordination site is not likely, since
these data indicate only one binding site for inhibition, rather
than multiple sites, as would be expected if another coordination
site is opened. The dissociative mechanism of Alonso and Garc´ıa
is also strongly disfavored by these findings, since the Ki and
kcat for a monomer would be expected to react differently to
the inhibitor than the dimer, leading to a nonlinearity of the
replots of V vs [I] (analogous to a catalytically active and
significant concentration of a C‚I‚S complex).
A notable feature of the data in Table 6 is that acetone has
an R value less than 1. This indicates that acetone prefers to
bind to the substrate-bound form of the catalyst (or the
carbenoid) rather than the free catalyst. However, it should be
emphasized that â is still 0, so that the C‚I‚S complex formed
must lose acetone to catalyze the reaction. Efforts to further
understand this phenomenon through variation of the carbonyl
basicity and π-bond strength were frustrated by the fact that
cyclobutanone and cyclopentanone do not show mixed inhibition
(R ) ∞). Rather, they are pure competitive inhibitors. Two other
ketones, indanone and methyl cyclopropyl ketone, were also
found to exhibit an R value less than 1. This phenomenon might
be explained as shown in Chart 2. The carbonyl is bound to the
rhodium through an unshared pair, but unlike most other
inhibitors is capable of back-bonding. This may reduce its trans
effect, which may permit binding of a ligand at the other axial
coordination site of the dirhodium core or, conversely, that its
trans effect is reduced by back-bonding may permit its binding
when another strong trans effect ligand is already bound. This
explanation suggests a correlation of the back-bonding ability
of the carbonyl to the R value. To examine this idea, the LUMO
energies of the five carbonyl compounds exhibiting mixed
inhibition were obtained by DFT methods, as summarized in
Table 8. These data are confusing at best. To be sure, calculated
LUMO energies are approximate at best, and the correlation
between LUMO energies and R is clearly not direct. Steric
factors and HOMO energies (correlating to the strength of the
carbonyl-rhodium association) may also be important to this
model. Back-bonding may be the basis for the unusual inhibition
behavior of some ketones, but inhibition by others may have a
different basis. Carbonyls, as electron-deficient π-bonds, may
(42) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L. J. Am.
Chem. Soc. 1993, 115, 9468-79.
(43) Guthikonda, G. N.; Cama, L. D.; Christensen, B. G. J. Am. Chem. Soc.
1974, 96, 7584-5.
(41) Seydoux, F.; Malhotra, O. P.; Bernhard, S. A. Crit. ReV. Biochem. 1974,
2, 227.
9
J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002 1021

A R T I C L E S
Pirrung et al.
126.0, 128.2, 128.3, 147.8, 193.3. IR (thin film): 2936, 2103, 1635
cm-1. HRMS for C12H15N2O (FAB+, MH+). Calcd: 203.1186. Found:
203.1184.
3,8a-Dihydro-2,2-dimethyl-1(2H)-azulenone (6). 1-Diazo 4-methyl
4-phenylpentan-2-one (100.2 mg, 0.495 mmol) was dissolved in 50
mL of CH2Cl2 and treated with 1.5 mg (0.0025 mmol) of rhodium
pivalate. After stirring for 30 min, the solvent was removed under
vacuum and the residue was filtered through a short plug of silica gel
1
to give 82.7 mg (0.474 mmol, 96%) of a clear oil. H NMR (CDCl3):
δ 1.14 (s, 3H), 1.40 (s, 3H), 2.35 (d, J ) 16.8 Hz, 1H), 2.59 (dd, J )
16.9 Hz, 0.7 Hz, 1H), 2.89 (m, 1H), 5.19 (dd, J ) 9.4, 4.1 Hz, 1H),
6.14 (ddd, J ) 9.3, 5.7, 1.8 Hz, 1H), 6.20 (dd, J ) 5.7, 1.5 Hz, 1H),
6.43 (dd, J ) 11.1, 5.7 Hz, 1H), 6.53 (dd, J ) 11.1, 5.7 Hz, 1H). 13C
NMR (CDCl3): δ 27.3, 32.9, 40.1, 51.4, 54.1, 117.0, 119.8, 126.7,
129.7, 130.3, 148.5, 216.1. IR (thin film): 2960, 2867, 1747 cm-1
.
HRMS for C12H14O (EI, 70 eV). Calcd: 174.1045. Found: 174.1049.
2-Diazo-3-oxododecanoic Acid Methyl Ester (9). NaH (1.22 g, 60%
in mineral oil, 30.6 mmol) was placed in a 100 mL round-bottom flask
and suspended in 50 mL of dry tetrahydrfuran (THF) under nitrogen.
Methyl acetoacetate (3.00 mL, 27.8 mmol) was added slowly to the
suspension at 0 °C. The mixture turned from cloudy suspension to a
clear solution upon completion of addition. Then n-BuLi (19.1 mL,
1.6 M in hexane, 30.6 mmol) was added at 0 °C over 15 min, and the
solution turned orange. The solution was stirred for an additional 10
min before 1-bromooctane was added, and the mixture was stirred
overnight. The reaction was quenched with 4 mL of concentrated HCl
in 10 mL of water and 25 mL of ether. The aqueous layer was extracted
with ether (25 mL × 2). The combined organic phase was washed
with brine until neutral, and the solvent was removed under vacuum.
The crude product was purified by flash chromatography (Rf ) 0.25,
1:9 ethyl acetate:hexane) to obtain the alkylated product as a clear oil
Figure 6. Free energy profile for the rhodium pivalate-catalyzed reaction
of 1.
The second-order rate constants measured for the rhodium-
catalyzed reactions reported in this paper are as high as 105
M-1 s-1. While far superior to the other catalytic chemical
reactions whose saturation kinetic parameters have been deter-
mined, and certainly fast enough to qualify rhodium carboxylates
as chemzymes, clearly they also require significant enhancement
to reach the “catalytic perfection” of diffusion-controlled
reactions. Furthermore, the introduction of chirality into this
catalyst framework has the effect of slowing the catalytic process
(by about half). A reasonable suggestion is that this is due to
blockage of enantiotopic catalytic sites in an achiral catalyst
framework. While the concept of asymmetric ligand-accelerated
catalysis has certainly been powerful in developing catalytic
asymmetric reactions, asymmetric catalysis may also involve
ligand-decelerated catalysis by steric blockage of one of the
two enantiotopic pathways. Detailed kinetic analyses of chiral
and comparable achiral catalysts, such as we have performed
here for Rh2(DOSP)4, will be required to assess this factor in
other catalytic systems.
1
(4.12 g, 82%). H NMR (CDCl3): δ 0.85 (t, J ) 6.30 Hz, 3H), 1.24
(br s, 12H), 1.56 (m, 2H), 2.50 (t, J ) 7.2 Hz, 2H), 3.42 (s, 2H), 3.71
(s, 3H).
The alkylated product, 3-oxododecanoic acid methyl ester, was
subjected to a diazo transfer procedure. The ester (4.12 g, 18.0 mmol)
and mesyl azide (1.72 mL, 19.8 mmol) were dissolved in 20 mL of
dry acetonitrile under nitrogen, to which solution Et3N (2.76 mL, 19.8
mmol) was added at room temperature. The solution was stirred for 6
h. The solvent was removed under vacuum. The residue was redissolved
in 20 mL of ether and washed sequentially with NaOH (10% aq, 20
mL × 2), brine twice, dried over Na2SO4, filtered, and evaporated.
The product was purified by chromatography (Rf ) 0.52, 1:4 ethyl
1
acetate:hexane) and obtained as a yellow oil (3.70 g, 81%). H NMR
Experimental Section
(CDCl3): δ 0.85 (t, J ) 6.9 Hz, 3H), 1.24 (m, 12H), 1.60 (m, 2H),
2.81 (t, J ) 7.2 Hz, 2H), 3.81 (s, 3H). 13C NMR (CDCl3): δ 14.19,
22.74, 24.46, 29.33, 29.46, 29.51, 31.93, 40.27, 52.14, 76.80, 77.21,
161.64, 192.75. IR (thin film): 2135, 1718, 1653 cm-1. HRMS for
C13H22N2O3 (EI, 30 eV, M+). Calcd: 254.1630. Found: 254.1640.
Known compounds are as follows: 1-diazo-4-phenyl-2-butanone (1),
3,8a-dihydro-1(2H)-azulenone (2), 1-diazo-4-(4-methoxyphenyl)-2-bu-
tanone (3), and 3,8a-dihydro-6-methoxy-1(2H)-azulenone (4).36 Also
known are 1-diazo-5-hexen-2-one (7)43 and bicyclo[3.1.0]hexan-2-one
(8).44
2-Hexyl-5-oxocyclopentanecarboxylic Acid Methyl Ester (10).
Compound 9 (222.3 mg, 0.87 mmol) was dissolved in 25 mL of dry
CH2Cl2. To this solution at room temperature rhodium acetate (4.5 mg,
0.01 mmol) was added. The solution was stirred at room temperature
for 2 h, and the solvent was removed under vacuum. The crude product
was flash chromatographed (Rf ) 0.20 1:9 ethyl acetate:hexane) to
obtain 10 as a clear oil (162.2 mg, 82%). 1H NMR (CDCl3): δ 0.86 (t,
J ) 6.9 Hz, 3H), 1.25-1.52 (m, 12H), 2.15-2.60 (m, 3H), 2.81 (d, J
) 11.4 Hz, 1H), 3.74 (s, 3H). 13C NMR (CDCl3): δ 13.97, 22.50,
27.05, 27.28, 29.21, 31.63, 34.91, 38.40, 41.37, 52.28, 61.83, 169.97,
211.91. IR (thin film): 1750, 1725 cm-1. HRMS for C13H22O3 (EI, 30
eV, M+). Calcd: 226.1569. Found: 226.1561.
1-Diazo-4-methyl-4-phenylpentan-2-one (5). Oxalyl chloride (3.05
g, 2.10 mL, 24.0 mmol) was added to 3.56 g (20.0 mmol) of 3-methyl-
3-phenylbutanoic acid in 50 mL of Et2O under Ar, followed by one
drop of dimethylformamide (DMF; gas evolution). After stirring for 1
h, the solvent was removed under vacuum to leave a clear oil. The oil
was dissolved in 50 mL of Et2O and transferred to a 250 mL Erlenmeyer
flask and immediately treated with approximately 50 mmol of CH2N2
in Et2O. After 1 h, the solvent was removed under vacuum and the
residual yellow oil was chromatographed on silica gel using 2:1 hexane:
ethyl acetate. The solvent was removed under vacuum to give 3.60 g
(17.8 mmol, 89%) of a clear yellow oil. 1H NMR (CDCl3): δ 1.45 (s,
6H), 2.60 (s, 2H), 4.66 (s, 1H), 7.24 (dd, J ) 8.7, 7.2 Hz, 1H), 7.35
(m, 4H). 13C NMR (CDCl3): δ 28.7, 37.8, 54.9, 55.4, 125.2, 125.4,
1
3-Diazotridecane-2,4-dione (11). H NMR (CDCl3): δ 0.88 (t, J
) 6.6 Hz, 3H), 1.27 (m, 12H), 1.65 (quintet, J ) 7.5 Hz, 2H), 2.45 (s,
3H), 2.70 (t, J ) 7.5 Hz, 2H). 13C NMR (CDCl3): δ 14.15, 22.70,
24.16, 28.68, 29.18, 29.20, 29.40, 29.44, 31.88, 40.61, 83.83, 188.38,
(44) Newman-Evans, R. H.; Simon, R. J.; Carpenter, B. K. J. Org. Chem. 1990,
55, 695-711.
9
1022 J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002

Rhodium Chemzymes
A R T I C L E S
Table 9. Absorption Properties of Reactants and Products in
190.79. IR (thin film): 2217, 1650 cm-1. HRMS for C13H22N2O2 (EI,
30 eV, M+). Calcd: 238.1681. Found: 238.1675.
Kinetic Studies
compds
λ (nm)
ꢀp (M-1 cm-1
)
ꢀr (M-1 cm-1
)
2-Acetyl-3-hexylcyclopentanone (12). 1H NMR (CDCl3; 2:1 diketo
and enolic forms): δ 0.86 (t, J ) 6.3 Hz, 1H), 0.87 (t, J ) 6.9 Hz,
2H), 1.25-1.50 (m, 11H), 1.67-1.75 (m, 0.33H), 1.89-2.04 (m,
1.66H), 2.11-2.35 (M, 3.66 H), 2.42-2.56 (m, 0.33H), 2.61-2.70 (m,
0.33H), 2.75-2.84 (m, 0.33H), 3.01 (d, J ) 10.5 Hz, 0.33H), 5.28 (s,
0.33H). 13C NMR (CDCl3): δ 14.14, 20.44, 22.65, 23.16, 25,91, 26.85,
27,17, 27.46, 27.83, 29.39, 29.48, 29.98, 30.63, 31.09, 31.77, 31.92,
32.84, 35.17, 35.52, 38.39, 38.96, 39.03, 48.75, 69.44, 114.85, 175.59,
202.84, 205.86, 212.46. IR (thin film): 3100, 1739, 1708 cm-1. HRMS
for C13H22O2 (EI, 30 eV, M+). Calcd: 210.1620. Found: 210.1628.
1 and 2
340
360
340
370
340
360
330
186.8
175.0
106.8
11.0
9.40
2.39
39.7
37.2
91.6
23.0
30.0
31.8
36.8
3 and 4
5 and 6
7 and 8
9 and 10
11 and 12
15 and 16
260
that the reaction proceeds in quantitative yield.
d[S]/dt ) (dA/dt)/{(ꢀp - ꢀr)l}
(1)
General Procedures for Saturation Kinetics. All UV measure-
ments were conducted on a Shimadzu UV160U instrument. For
reactions with stable reactants and products, pure compounds were used
for the measurement of their UV spectra from 200 to 400 nm. The
single wavelength for following the reaction was chosen by two criteria,
where their absorbance has the biggest difference and where both UV
spectra are as flat as possible, so that the effect of instrumental
fluctuations would be minimal. The extinction coefficients of both
reactant and product at this wavelength were measured and used in the
calculation of reaction rate. For reactions conducted at high substrate
concentration, for example to determine substrate Kis, it was necessary
to use longer wavelengths at which the total absorbance was lower.
where ꢀp and ꢀr are the extinction coefficients of the product and
reactant, dA/dt is the rate of change of the absorbance, and l is the
path length in centimeters.
For inhibition studies, normal rectangular hyperbolae were converted
to Lineweaver-Burk plots. All straight lines for different inhibitor
concentrations were plotted on the same plot. The type of inhibition
can be determined according to the position of their intersection point.
Most of our inhibition studies showed mixed inhibition (intersection
to the left of the y-axis, not on the x-axis), which can be described by
V ) {V/(1 + [I]/Ki2)}/
{1 + [Km(1 + [I]/Ki1)]/[[S](1 + [I]/Ki2)]} (2)
A stock solution of each diazo compound and catalyst was prepared
in a volumetric flask using CH2Cl2. Addition of the appropriate volume
of the stock solution of diazo compound and dilution with CH2Cl2 to
a volume of 3.000 mL by using Hamilton syringes in a quartz cell (10
mm path length) was performed for each rate determination. The capped
cells were equilibrated to 25.0 °C (28.0 °C for rates in Table 2 and
otherwise noted) before the catalyst was introduced. Addition of an
aliquot of catalyst solution (concentration of catalyst in the reaction
after addition was 2.00 × 10-7 M) and mixing using a disposable pipet
or the tip of the Hamilton syringe was followed by determination of
the rate by monitoring the change in absorbance at the appropriate
wavelength (see Table 9 for measured UV absorbances) at 1 s intervals.
Linear least squares line fit (using the Shimadzu UV160 software line
fitting function) to at least 20 points were used to determine initial
velocities. For the inhibition analysis, the appropriate volume of a stock
solution of inhibitor in CH2Cl2 was added to the diazo compound
solution before diluting to 3.000 mL in an analogous manner.
In this case, secondary plots are required to determine the inhibition
constants. The intercept of the secondary plot of the slopes vs [I] is
Ki1. The intercept of the secondary plot of the intercept on the vertical
axis in the V vs [S] plots is Ki2.
Acknowledgment. This work was supported by the donors
of the Petroleum Research Fund, administered by the American
Chemical Society (ACS). A.T.M. was a C. R. Hauser Fellow
and an ACS Division of Organic Chemistry Upjohn Graduate
Fellow.
Note Added after ASAP: There was an incorrect R value
in the version posted ASAP January 19, 2002; the corrected
version was posted February 6, 2002.
Supporting Information Available: Saturation kinetic analy-
sis, additional kinetic plots, NMR spectra for 5, 6, and 9-12
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
The slope of the straight line fitting the raw data was used to calculate
the rates. The velocities were scaled to the appropriate units (M s-1
)
by applying eq 1, easily derived from Beer’s Law with the assumption
JA011599L
9
J. AM. CHEM. SOC. VOL. 124, NO. 6, 2002 1023