Linear Free Energy Correlation Analysis on the Electronic Effects of Rh(II) Carbene O-H Insertion

Article abstract of DOI:10.1021/jo0350312

The relative rate constants for the Rh(II)-catalyzed insertion of diazoacetone into the O-H bond have been measured through intermolecular competitions. The kinetic data were subjected to Hammett correlation analysis, and mechanistic implication of the results with respect to a stepwise vs a concerted O-H insertion pathway is discussed.

Full text of DOI:10.1021/jo0350312

SCHEME 1
Lin ea r F r ee En er gy Cor r ela tion An a lysis
on th e Electr on ic Effects of Rh (II) Ca r ben e
O-H In ser tion
Zhaohui Qu,† Weifeng Shi,† and J ianbo Wang*
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, Department of
Chemical Biology, College of Chemistry, Peking University,
Beijing 100871, China
wangjb@pku.edu.cn
Received J uly 17, 2003
be stepwise (Scheme 1).1,2b,d Nevertheless, there exists
little experimental evidence to support a stepwise mech-
anism, and a concerted pathway cannot be ruled out.
It is conceivable that the electronic effect imposed by
the R group on the stepwise reaction mechanism should
be significantly different from the concerted one due to
the formation of the oxonium ylide intermediate in the
stepwise pathway. Experimental study of such electronic
effects may provide useful insights into the operating
mechanism of O-H insertion.
To evaluate the electronic effects of O-H insertion, we
studied a series of substituted phenol derivatives (6a -
h , Scheme 2).4 Diazoacetone 7 was used to generate the
Rh(II) carbene instead of the traditional ethyl diazoac-
etate (EDA), because of the relatively low reactivity of
EDA toward phenol O-H bond.5
Abstr a ct: The relative rate constants for the Rh(II)-
catalyzed insertion of diazoacetone into the O-H bond have
been measured through intermolecular competitions. The
kinetic data were subjected to Hammett correlation analysis,
and mechanistic implication of the results with respect to a
stepwise vs a concerted O-H insertion pathway is discussed.
The Rh(II) complex catalyzed reaction of R-diazocar-
bonyl compounds generates Rh(II) carbene intermediates,
which can subsequently undergo diverse synthetically
useful transformations such as cyclopropanation, ylide
formation, and insertion into C-H and X-H (X ) O, S,
N, Si, etc.) bonds. The Rh(II) carbene insertion into a
polar X-H (X ) O, S, N, etc.) bond, along with the
insertion into C-H and Si-H bond, has attracted much
attention in recent years. In the case of O-H insertion,
the reaction provides an efficient and powerful method
for generating new C-O bond.1,2 Despite the practical
value of O-H insertion in organic synthesis, its detailed
reaction mechanism is not fully understood. In contrast
to the generally accepted mechanism of concerted inser-
tion of Rh(II) carbene into nonpolar C-H or Si-H bonds,3
the insertion into the polar O-H bond is speculated to
SCHEME 2
* Corresponding author.
† Z.Q. and W.S. contributed equally to this work.
The relative reactivity of the O-H bond in 6a -h can
be measured by the product distribution during the
intermolecular competition when a mixture of 6a -h is
allowed to react with 7. This requires that the O-H
insertion be clean and efficient. To establish a suitable
protocol for this reaction, we examined four of the most
common Rh(II) catalysts, namely rhodium(II) acetate
[Rh2(OAc)4], rhodium(II) octanoate [Rh2(OOct)4], rhod-
ium(II) acetamide [Rh2(acam)4], and rhodium(II) trifluo-
roacetate [Rh2(tfa)4]. The reaction of 7 with 6a -h in
CH2Cl2 at room temperature, catalyzed by Rh2(OAc)4,
gave O-H insertion products 8a -h with isolated yields
ranging from 65 to 88%. Similar results were obtained
with Rh2(OOct)4 as the catalyst. The same reactions with
Rh2(tfa)4 as the catalyst yielded clean O-H insertion
products, but its rate is markedly slower than that with
Rh2(OAc)4.6 Unfortunately, the reactions with Rh2(acam)4
(1) For comprehensive reviews, see: (a) Doyle, M. P.; McKervey, M.
A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley-Interscience: New York, 1998. (b) Ye, T.; McKervey,
M. A. Chem. Rev. 1994, 44, 1091.
(2) For reviews on carbene and carbenoids O-H insertions, see: (a)
Kirmse, W. In Advances in Carbene Chemistry; Brinker, U., Ed.; J AI
Press: Greenwich, CT, 1994; Vol. 1; pp 1-57. (b) Miller, D. J .; Moody,
C. J . Tetrahedron 1995, 51, 10811. For recent examples of carbenoid
O-H insertions, see: (c) Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D.
J .; Moody, C. J . J . Org. Chem. 1995, 60, 4449. (d) Doyle, M. P.; Yan,
M. Tetrahedron Lett. 2002, 43, 5929. (e) Davies, H. M. L.; Yokota, Y.
Tetrahedron Lett. 2000, 41, 4851. (f) Bulugahapitiya, P.; Landais, Y.;
Parra-Rapado, L.; Planchenault, D.; Weber, V. J . Org. Chem. 1997,
62, 1630. (g) Schils, R.; Simal, F.; Demonceau, A.; Noels, A. F.;
Eremenko, I. L.; Sidorov, A. A.; Nefedov, S. E. Tetrahedron Lett. 1998,
39, 7849. (h) Kettle, J . G.; Faull, A. W.; Fillery, S. M.; Flynn, A. P.;
Hoyle, M. A.; Hudson, J . A. Tetrahedron Lett. 2000, 41, 6905.
(3) For mechanistic investigations on Rh(II) carbene C-H insertion
and Si-H insertion, see: (a) Taber, D. F.; Ruckle, R. E., J r. J . Am.
Chem. Soc. 1986, 108, 7686. (b) 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. (c) Wang, P.; Adams, J . J . Am. Chem.
Soc. 1994, 116, 3296. (d) Pirrung, M. C.; Morehead, A. T., J r. J . Am.
Chem. Soc. 1994, 116, 8991. (e) Wang, J .; Chen, B.; Bao, J . J . Org.
Chem. 1998, 63, 1853. (f) Nakamura, E.; Yoshikai, N.; Yamanaka, M.
J . Am. Chem. Soc. 2002, 124, 7181. (g) Landais, Y.; Parra-Rapado, L.;
Planchenault, D.; Weber, V. Tetrahedron Lett. 1997, 38, 229. (h) Davies,
H. M. L.; J in, Q.; Ren, P.; Kovalevsky, A. Y. J . Org. Chem. 2002, 67,
4165.
(4) For an earlier report on the Rh(II) carbene O-H insertion with
phenols, see: Haigh, D. Tetrahedron 1994, 50, 3177.
(5) Ethyl diazoacetate failed to react when it was treated with
catalytic Rh2(OAc)4 in CH2Cl2 in the presence of phenol at room
temperature.
10.1021/jo0350312 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003
J . Org. Chem. 2004, 69, 217-219
217

TABLE 1. Rela tive Ra te Con sta n ts of th e Rh (II) Ca r ben e In ser tion in to P h en ol O-H Bon d
Rh2(OAc)4 Rh2(OOct)4
Rh2(tfa)4
b
b
b
entry
6 (X ) )
GC yield (%)
ratioa
krel
GC yield (%)
ratioa
krel
GC yield (%)
ratioa
krel
1
2
3
4
5
6
7
8
p-OMe
p-Me
p-Ph
H
p-Cl
m-Br
m-NO2
p-NO2
71.6
67.3
60.5
-
61.6
66.9
50.8
70.9
1.26
0.82
0.93
-
0.86
0.67
0.66
0.54
1.33
0.78
0.92
1.00
0.83
0.61
0.62
0.46
79.2
47.4
71.4
-
70.5
52.0
54.5
61.2
1.51
0.86
0.91
-
0.90
0.66
0.64
0.60
1.70
0.84
0.89
1.00
0.88
0.62
0.59
0.54
18.0
16.1
24.0
-
19.2
19.3
21.0
18.1
0.96
0.85
0.99
-
0.92
0.78
1.18
0.63
0.96
0.84
0.99
1.00
0.92
0.77
1.19
0.62
a
b
The product ratio of 8a -c and 8e-h to 8d in each competition experiment. Relative rate constant krel is calculated from the yields;
see the Supporting Information.
TABLE 2. Ha m m ett Cor r ela tion Da ta of Rela tive
reaction mechanism. First, the relatively small magni-
tude of the reaction constants, F, in all three catalytic
systems indicates that the O-H insertion is only slightly
sensitive to the change in the electronic nature of the
substituents on the phenyl ring. This finding contradicts
the stepwise mechanism in which a much greater elec-
tronic effect would have been expected due to the fully
developing positive charge in the oxonium ylide inter-
mediate (Scheme 1). Second, our observed small negative
reaction constants indicate that the Rh(II) carbene inser-
tion into the O-H bond is slightly accelerated by electron-
donating groups on the phenyl ring. This result is
consistent with the model of a concerted insertion1a in
which the p orbital of the electrophilic carbene overlaps
more efficiently with the more electron-rich O-H bond.
If the O-H insertion follows a concerted mechanism
as C-H and Si-H insertions, then the small reaction
constants are also in agreement with a relatively early
three-center two-electron transition state 3 (Scheme 1),3b
where little positive charge is being developed. The
stronger electron-withdrawing ligand in Rh2(tfa)4, as
compared to that in Rh2(OAc)4 and Rh2(OOct)4, increases
the electrophilicity of the carbene and results in an even
earlier transition state. As a result, there would be less
positive charge developing on the oxygen due to the
greater distance between the carbene and the O-H bond
in this transition state. This is in good agreement with
our observed trend of reaction constant magnitude (-0.13
for Rh2(tfa)4 vs -0.32 for Rh2(OAc)4 and -0.35 for Rh2-
(OOct)4). We notice that for Rh(II) carbene insertion into
C-H bonds, Rh2(tfa)4-catalyzed reaction also gives a
smaller reaction constant compared to the corresponding
C-H insertion catalyzed by Rh2(OAc)4.3e
Ra te kr el
F(r)b
substituent
constanta
Rh2(OAc)4
Rh2(OOct)4
Rh2(tfa)4
σ+
σ
-0.25 (-0.91)
-0.32 (-0.88)
-0.25 (-0.89)
-0.28 (-0.93)
-0.35 (-0.86)
-0.26 (-0.82)
-0.09 (-0.70)
-0.13 (-0.74)
-0.11 (-0.83)
σ-
a
b
Substituent constants were taken from ref. 7. F ) reaction
constants. r ) correlation coefficient.
gave a complex mixture of products and no effort was
made to identify them. Based on these results, we limited
our study of the electronic effect to three Rh(II) cata-
lysts: Rh2(OAc)4, Rh2(OOct)4, and Rh2(tfa)4.
The intermolecular competition was carried out with
a solution of equimolar phenol 6d , substituted phenols
6a -c,e-h , and diazoacetone 7 in CH2Cl2 containing 0.1
mol % Rh(II) catalyst. After the reaction was stirred for
12 h at room temperature, biphenyl was added as the
internal standard and the reaction mixture was directly
analyzed by GC. To ensure the reproducibility, at least
two GC runs were performed for each experiment. The
relative rate constants for each phenol can then be
derived from the yield of each insertion product (for
detailed kinetic treatment, see the Supporting Informa-
tion). The experimental results and the derived rate
constants (relative to the unsubstituted phenol, 6d ) are
displayed in Table 1. It is worth noting that no products
other than 8a -h could be detected and all unreacted
phenols were recovered quantitatively. Control experi-
ments indicated that without Rh(II) catalysts, no reaction
occurred. Therefore, the O-H insertion is Rh(II) complex
catalyzed and presumably occurs through the Rh(II)
carbene intermediate.
Next, we proceeded to correlate the relative rate
constants with Hammett substituent constants (σ, σ+,
and σ-). The Hammett plots are included in the Sup-
porting Information, and the linear fit results are sum-
marized in Table 2 along with the correlation coefficients.
Clearly, the rate constants correlate better with σ+ for
the Rh2(OAc)4- and Rh2(OOct)4-catalyzed reactions than
with σ+ and σ-. For the Rh2(tfa)4-catalyzed reaction,
however, the rates correlate better with σ-. Even though
the linearity is not excellent in general, the Hammett
reaction constants do provide useful insights into the
The concerted insertion mechanism is also consistent
with the observation that the O-H bond of aliphatic
alcohols has a higher reactivity than that of phenols.8
Because of the small positive charge being developed on
the oxygen in the concerted mechanism, the electron
density of the O-H bond becomes crucial. The inductive
effect of alkyl groups is electron-donating, while that of
a phenyl group is weakly electron-withdrawing. Conse-
quently, an alkyl group enhances the O-H bond electron
density, thus accelerating the O-H insertion. Previous
reports also suggest that the O-H insertion is insensitive
to steric effects,8 which is in accordance with an early
transition state of a concerted mechanism.
(6) Moody et al. have observed the same phenomena that electron-
withdrawing ligands on Rh(II) retard the O-H insertions. It is
rationalized that the alcohol coordinates more strongly to the more
electron-demanding catalysts. See ref 8.
(7) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(8) Cox, G. G.; Miller, D. J .; Moody, C. J .; Sie, E.-R. H. B.;
Kulagowski, J . J . Tetrahedron 1994, 50, 3195.
218 J . Org. Chem., Vol. 69, No. 1, 2004

h under N2. The solution was washed with 10% aqueous NaOH
to remove unreacted phenol, washed with water and brine, and
finally dried over MgSO4. Solvent was removed by rotavap, and
the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc ) 5:1) to give O-H insertion products
8a -h : 8a , 83%; 8b, 78%; 8c, 76%; 8d , 88%; 8e, 67%; 8f, 65%;
8g, 78%; 8h , 72%. The products were characterized or confirmed
by spectra data.
1-(p-P h en yl)p h en oxyp r op a n -2-on e (8c): IR 3080, 3035,
1723, 1686, 1606, 1524, 1489 cm-1; 1H NMR (200 MHz, CDCl3)
δ 2.31 (s, 3H), 4.58 (s, 2H), 6.93-6.98 (m, 2H), 7.38-7.57 (m,
7H); 13C NMR (50 MHz, CDCl3) δ 26.65, 73.14, 114.79, 116.00,
126.77, 126.88, 128.38, 128.75, 134.89, 157.24, 205.75; MS (m/
z, relative intensity) 226 (M+, 100), 183 (62), 153 (71), 115 (18),
43 (58). Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found: C,
79.63; H, 6.24.
Gen er a l P r oced u r e for Kin etic Com p etition Exp er i-
m en ts. Each insertion product is mixed with the reference
compound biphenyl in different molar ratios (10:1, 5:1, 2:1, and
1:1). The samples were then analyzed on GC to obtain the
detector responding factors [a standard working line of lg(molar
ratio) versus lg(GC peak area ratio) of insertion product to
biphenyl].
Phenol 6d (94 mg, 1 mmol) and a substituted phenol (1 mmol)
were dissolved in CH2Cl2 (10 mL), followed by the addition of
Rh(II) catalyst (0.1 mmol %). Under N2 atmosphere and with
stirring was added a solution of diazoacetone 7 (84 mg, 1 mmol)
in CH2Cl2 (5 mL) dropwise. The reaction mixture was stirred
overnight. Biphenyl (31 mg, 0.2 mmol) was added as the internal
standard, and the reaction mixture was directly subjected to GC
analysis. The product ratio and the yields were obtained from
the responding factors. The relative rate constants were then
calculated from the product yields and ratios (see the Supporting
Information for details).
For Rh2(OAc)4-catalyzed C-H and Si-H insertion,
reaction constants of -1.26 and -0.31 (both against σ)3e,g
have been reported, respectively. It is well-known that
O-H bonds and Si-H bonds are much more reactive
toward Rh(II) carbene insertion than C-H bonds. The
insertion of Rh(II) carbene into a C-H bond is also known
to be sensitive to steric hindrance.3a If all insertions follow
a similar concerted mechanism, then the Hammett
reaction constants clearly reflect this trend of reactivity.
The more reactive O-H and Si-H bonds cause an early
transition state while the less reactive C-H bond results
in a relatively late transition state (thus more sensitive
to electronic and steric effect). An early transition state
may also be responsible for the fact that the asymmetric
O-H insertion is much less successful than the corre-
sponding C-H insertion.1
It is interesting to note the comparable reaction
constants [-0.32 (σ) vs -0.31 (σ)] for Rh2(OAc)4-catalyzed
O-H and Si-H insertion, respectively. Further compari-
son of these two types of insertion discloses other
similarities.3g For Si-H insertion, the rate of arylsilanes
is slower than that of alkylsilanes [k(iPr3Si-H):k(Ph3Si-
H))1.17:1], while phenols are less reactive than alcohols
in O-H insertion. Moreover, the effect of steric hindrance
on Si-H insertion is quite small [k(ClMe2Si-H):k(CltBu2-
Si-H) ) 1:2], just as in O-H insertion. These similarities
further support the idea that O-H and Si-H insertions
follow similar concerted reaction mechanisms with early
transition states, in which the Rh(II) carbene and O-H
or Si-H bond are relatively far away from each other.
Although our study of electronic effect does not provide
conclusive evidence on the mechanism of Rh(II) carbene
insertion into the O-H bond, the Hammett correlation
data are in favor of a concerted insertion process, as in
the case of corresponding C-H or Si-H bond insertion.
Further experimental evidence is needed to eventually
solve this mechanistic puzzle.
GC Con d ition s. The reaction mixture was analyzed by a
flame ionization detector (FID) and a HP-5 analytical column
(30-m fused silica column with an internal diameter of 0.32 mm
and a film thickness of 0.25 µm). The initial oven temperature
was 70 °C, which was ramped by 10 °C/min to the final
temperature of 270 °C. At least two GC runs were performed
for each sample to ensure reproducibility.
Ack n ow led gm en t. The project is generously sup-
ported by the National Natural Science Foundation of
China (Grant Nos. 20225205, 20172002, and 20390050).
We thank Prof. Linfeng Xie of the University of
WisconsinsOshkosh for the extensive editing of this
manuscript.
Exp er im en ta l Section
Ca u tion : Diazoketone 7 is presumed to be toxic and poten-
tially explosive. It should be handled with care in a well-
ventilated fumehood.
Gen er a l P r oced u r e for Rh 2(OAc)4-Ca ta lyzed Rea ction
of Dia zok eton e 7 w ith P h en ols 6a -h . To a solution of phenol
6a -h (1 mmol) and Rh2(OAc)4 (0.4 mg, 0.1 mmol %) in CH2Cl2
(10 mL) was added dropwise a solution of diazoketone 7 (92 mg,
1.1 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 10-12
Su p p or tin g In for m a tion Ava ila ble: Kinetic treatments
and the Hammett plots with σ, σ+, and σ-. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0350312
J . Org. Chem, Vol. 69, No. 1, 2004 219