C O M M U N I C A T I O N S
Table 2. Scope of Alkyne Hydrationa
Under our standard reaction conditions (acetone, 70 °C, 5 equiv of
H2O), neither ketone nor aldehyde product was seen for 1-nonyne
after 28 days.15 Given that we could detect 2 ppm product if it
were present, we can infer that the rate of the uncatalyzed product
formation is <3 × 10-9 mol h-1, meaning a half-life of at least
20 000 years. Even more striking is our observation that when the
aldehyde yields
3 h later (time)
entry
alkyne
1 h
1
2b
3
4
5
6
7
8
9
CH3(CH2)6CtCH
CH3(CH2)6CtCH
C6H5CtCH
55.0
nd
99.9
30.2b
33.1
42.7
nd
nd
98.6 (48 h)
99.8 (20 h)
99.8 (24 h)
nd
11.8
14.0
0.31d
3.6
16
Brønsted-Lowry acid HNTf2 is used to catalyze hydration of
4-MeOC6H4CtCH
4-O2NC6H4CtCH
NtC(CH2)3CtCH
HCtC(CH2)4CtCH
THPOCH2CtCH
TsNHCH2CH2CtCH
CH3CtCSi(CH3)3
(CH3)2C(OH)CtCH
1-ethynylcyclohexene
1-nonyne, the ratio of ketone to aldehyde formed at low conversion
is 33 to 1.8 Thus, since under protic catalysis appearance of aldehyde
is 33 times slower than appearance of ketone, in the experiment
under neutral conditions, an upper bound for the rate of aldehyde
formation is 1 × 10-10 mol h-1, or a half-life of at least 600 000
years! Finally, since 6 gives initial TOF of 23.8 mol aldehyde mol
catalyst-1 h-1, we calculate a rate acceleration of >2.4 × 1011. As
for selectivity, there is no detectable ketone from the hydration of
1-nonyne by 6 under conditions where we could detect one part
ketone in the presence of 10,000 parts aldehyde. Thus, compared
with protic catalysis, 6 changes the selectivity of alkyne hydration
by a factor of over 300 000, all within the realm of enzymatic
performance.
In conclusion, bifunctional catalyst 6 is the most general to date
for anti-Markovnikov hydration of terminal alkynes and should be
practical for fine chemical synthesis applications. The catalyst also
exhibits enzyme-like rate acceleration and selectivity. We are
actively exploring the mechanism of this reaction, the synergy of
this and related metal-ligand systems, and applying enzyme-
inspired design principles to other reactions.
12.0
nd
76.2
97.0e
24.3f
nd
97.8 (96 h)
71.2c (8 h)
98.0 (9 h)
98.1e (6 h)
100f (66 h)
80.7g (168 h)
41.0g,h(168 h)
47.7c
26.1
nd
10
11
12
6.7f
nd
nd
nd
a Unless otherwise specified, using 6 (2 mol %), H2O (5 equiv), acetone,
70 °C, initial alkyne concentration 0.50 M. b Room-temperature reaction
with 5 mol % catalyst; 30.2% after 5.5 h. c Yields of dialdehyde and ynal
(double and single hydration products) at 1 and 8 h ) 27.9 + 19.8 and
51.6 + 19.6%, respectively. d In addition, 2.1% of corresponding alkane
and deactivated catalyst. No further reaction seen. e Product formed as 1:8
mixture of aldehyde and its cyclized form (N-tosyl-2-hydroxypyrrolidine).
f Product is propanal. g Room-temperature reaction. h 34.2 and 6.9% â,γ-
and isomerized R,â-unsaturated aldehydes, respectively.
extensively by Bianchini et al.11 is operative, giving a Ru-CO
complex and the alkane RCH3 from RCtCH. Our conclusion for
now is that the CpRu+ metal center is ideally suited for the anti-
Markovnikov hydration of terminal alkynes. A more electron-rich
or more sterically crowded metal center may favor phosphine loss
and alkyl migration, ultimately resulting in alkane and carbonyl
complex. In contrast, a more electron-deficient and less sterically
demanding metal center may not favor the isomerization of the
alkyne to a vinylidene ligand,12 thought to be a necessary step in
the anti-Markovnikov mechanism.11,13
With an optimized catalyst composition in hand, we determined
that either acetone or i-PrOH were the best cosolvents. Table S18
illustrates the use of catalyst 6 in a variety of solvents, both polar
and nonpolar, protic and aprotic. We note that the catalyst can
operate on water-immiscible liquid alkynes without any cosolVent
or surfactant, although the rate of hydration is slower.
Acknowledgment. We thank Yi Gong for several preliminary
experiments toward the goals of this manuscript. The NSF and
SDSU are thanked for financial support.
Supporting Information Available: Procedures for preparation of
catalysts and their evaluation, determination of uncatalyzed hydration
rates, and exemplary GC traces of hydration reactions. This material
References
(1) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705.
Focusing on a variety of alkyne substrates, Table 2 shows the
scope of successful hydration. Several important classes of func-
tional groups are tolerated and unaffected: a cyanide (entry 6), the
acid-sensitive protecting group THP (entry 8), a tertiary hydroxyl
group (entry 11), and a sulfonamido group (entry 9). The conversion
shown in entry 8 suggests an alternative route to aldol products
(acetylide addition to a ketone, followed by hydration). Although
the yield of aldehyde in entry 12 is relatively low, it is remarkable
that most of the product remains as the unconjugated isomer. The
conversion of CH3CtCSi(CH3)3 to propanal (entry 10) illustrates
a high-yielding in situ deprotection and hydration. Significantly,
both electron-rich and normal arylalkynes are effectively hydrated
at the same 2 mol % loading (entries 3 and 4), unlike results seen
before.2b,6 The hydration of cyanonitrile in entry 6 is slow for an
alkyl-substituted alkyne, an effect seen using 26 but not seen using
4,2b in which the resting state of the catalyst includes a coordinated
water molecule and excludes a nitrile. Finally, entry 2 of Table 2
shows for the first time that practical hydration may be carried
out at 25 °C.
(2) (a) See citations 3-9 of ref 2b. (b) Grotjahn, D. B.; Incarvito, C. D.;
Rheingold, A. L. Angew. Chem., Int. Ed. 2001, 40, 3884-3887.
(3) Borman, S. Chem. Eng. News 2004, 82, 42-43.
(4) Radzicka, A.; Wolfenden, R. J. Am. Chem. Soc. 1996, 118, 6105-6109.
(5) Bryant, R. A. R.; Hansen, D. E. J. Am. Chem. Soc. 1996, 118, 5498-
5499.
(6) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001, 3, 735-737.
(7) (a) Alvarez, P.; Bassetti, M.; Gimeno, J.; Mancini, G. Tetrahedron Lett.
2001, 42, 8467-8470. In this work, 5 mol % (indenyl)Ru(Cl)(PPh3)2 and
50 mol of surfactant per mole of catalyst were used. (b) Alvarez, P.;
Gimeno, J.; Lastra, E.; Garc´ıa-Granda, S.; Van der Maelen, J. F.; Bassetti,
M. Organometallics 2001, 20, 3762-3771.
(8) See Supporting Information for full details.
(9) Baur, J.; Jacobsen, H.; Burger, P.; Artus, G.; Berke, H.; Dahlenburg, L.
Eur. J. Inorg. Chem. 2000, 1411-1422.
(10) Fukumoto, Y.; Dohi, T.; Masaoka, H.; Chatani, N.; Murai, S. Organo-
metallics 2002, 21, 3845-3847.
(11) Bianchini, C.; Casares, J. A.; Peruzzini, M.; Romerosa, A.; Zanobini, F.
J. Am. Chem. Soc. 1996, 118, 4585-4594.
(12) (a) Lomprey, J. R.; Selegue, J. P. J. Am. Chem. Soc. 1992, 114, 5518-
5523. (b) Review of vinylidene chemistry: Bruneau, C.; Dixneuf, P. H.
Acc. Chem. Res. 1999, 32, 311-323.
(13) Tokunaga, M.; Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.;
Wakatsuki, Y. J. Am. Chem. Soc. 2001, 123, 11917-11924.
(14) (a) Though the effect of substituents on rate of acid-catalyzed hydration
has been studied,14b the uncatalyzed rate has not. (b) Allen, A. D.; Chiang,
Y.; Kresge, A. J.; Tidwell, T. T. J. Org. Chem. 1982, 47, 775-779.
Because these promising results prompted comparison of the rate
acceleration of our best bifunctional catalyst with those ac-
complished by enzymes in other reactions, we conducted the first
determination of the uncatalyzed rate of alkyne hydration.14 As
detailed in Supporting Information,8 a GC protocol was developed
such that the estimated lower limit of product detection was 2 ppm.
(15) In the case of phenylacetylene, after 28 days 0.4 and 2.0% yields of
aldehyde and ketone were seen.
(16) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Synlett 2000,
1777-1778.
JA046360U
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J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12233