Hydrophobic effects in a simple Diels-Alder reaction in water

Article abstract of DOI:10.1016/j.tetlet.2006.03.093

The endo/exo ratio for a simple Diels-Alder reaction carried out in water has been used to argue that hydrophobic effects can dominate the geometries of the transition states.

Full text of DOI:10.1016/j.tetlet.2006.03.093

Tetrahedron Letters 47 (2006) 3957–3958
Hydrophobic effects in a simple Diels–Alder reaction in water
Diganta Sarma, Sanjay S. Pawar, Suvarna S. Deshpande and Anil Kumar*
Physical Chemistry Division, National Chemical Laboratory, Pune 411 008, India
Received 19 September 2005; revised 22 February 2006; accepted 10 March 2006
Available online 27 April 2006
Abstract—The endo/exo ratio for a simple Diels–Alder reaction carried out in water has been used to argue that hydrophobic effects
can dominate the geometries of the transition states.
Ó 2006 Elsevier Ltd. All rights reserved.
In this letter, we report the stereoselectivities of a simple
Diels–Alder (DA) reaction in water to demonstrate that
hydrophobic packing effects can dominate the geome-
tries of transition states. The simple explanation of stereo-
selectivities in DA reactions on the basis of secondary
been reported in organic solvents to show endo/exo
ratios of 1:1.6,7 For this reaction, the convention
endo/exo refers to endocarboxy/exocarboxy
.
The endocarboxy/exocarboxy ratios8 for the reaction of 1
with 2a (Table 1) show that the endocarboxy/exocarboxy
ratio obtained in water is lower than those obtained in
other solvents. The reaction of 1 with 2a in water was
expected to give a higher endocarboxy/exocarboxy ratio,
similar to that of the reaction of 1 with 2c or other
DA reactions discussed elsewhere.5 In general, DA reac-
tions in water offer higher endo/exo ratios as compared
to those in conventional organic solvents, but this was
not the case for the reaction of 1 with 2a. This reaction,
orbital interactions (SOI)1,2 has been questioned.3
A
combination of solvent effects, steric interactions,
hydrogen bonds, electrostatic interactions, etc. can be
used in their place. The pioneering work of Rideout
and Breslow4 on the special role of water in DA reac-
tions suggested that both diene and dienophile dislike
water and tend to come closer (the hydrophobic effect)
in order to realize the reaction at a faster rate than in
the absence of water. Because of the hydrophobic pack-
ing of diene and dienophile, the endo stereoisomer is
preferred over the exo one.5 In order to demonstrate
the role of hydrophobic effects we measured the endo/
exo ratios for the DA reaction of cyclopentadiene 1
and methyl trans-crotonate 2a (Scheme 1) in water and
in other organic solvents. In the past, this reaction has
in n-heptane (a nonpolar solvent) gave an endocarboxy
/
exocarboxy ratio lower than that in water. The highest
endocarboxy/exocarboxy ratio of 2.57, a twofold increase
as compared to that in water was obtained when
the reaction was carried out in the highly polar solvent,
N-methylformamide. The endocarboxy/exocarboxy value
R2
R2
+
COOCH3
R2
R1
+
R1
R1
COOCH3
COOCH3
3b
R1 = H, R2 = CH3
R1 = CH3, R2 = H
3a
4a
5a
1
2a
4b
5b
2b
2c
= R2
R1
= H
Scheme 1. Diels–Alder reactions.
*
Corresponding author. Fax: +91 20 2589 3044; e-mail: a.kumar@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.093

3958
D. Sarma et al. / Tetrahedron Letters 47 (2006) 3957–3958
Table 1. endocarboxy/exocarboxy Ratiosa,b for the reaction of 1 with 2a in different solvents and for the reactions of 1 with 2b and 2c in water alone
Solvent
endocarboxy/exocarboxy Isolated yield % Solvent
endocarboxy/exocarboxy Isolated yield (%)
Water
Methanol
Ethanol
Propan-1-ol
Butan-1-ol
Ethylene carbonate
Reaction 1 + 2b in water 0.40c
1.28
2.09
1.85
1.78
1.84
1.95
78
60
58
55
50
50
60
DMSO
Nitrobenzene
Formamide
N-Methylformamide
Ethylene glycol
n-Heptane
Reaction 1 + 2c in water 1.97d
2.29
1.73
2.09
2.57
2.14
0.97
62
49
69
65
68
35
85
a Also implies the same as exomt/endomt
.
b An average of triplicate data with a standard deviation of 0.03.
c From Ref. 9.
d From Ref. 10.
in propan-1-ol, butan-1-ol, ethanol, ethylene carbonate,
methanol, formamide, ethylene glycol and DMSO
increases by 35%, 39%, 44%, 44%, 52%, 63%, 67% and
68%, respectively, as compared to that in water alone.
References and notes
1. (a) Hoffman, R.; Woodward, R. B. J. Am. Chem. Soc.
1965, 87, 4388–4389; (b) Hoffman, R.; Woodward, R. B.
J. Am. Chem. Soc. 1965, 87, 4389–4390.
2. Saur, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980,
19, 779–807.
3. Garcia, J. I.; Mayoral, J. A.; Salvetella, L. Acc. Chem. Res.
2000, 33, 658–664, and references cited therein.
4. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816–7817.
5. For example see: Breslow, R. Acc. Chem. Res. 1991, 24,
159–164.
6. Berson, J. A.; Hamlet, Z.; Mueller, W. A. J. Am. Chem.
Soc. 1962, 84, 297–304.
The methyl group is more hydrophobic than the carboxyl-
ate group, so the hydrophobic packing of the methyl
group in the transition state would lead to more endomt
,
corresponding to more exocarboxy. This is exactly what
one finds in this water-mediated reaction of 1 with 2a.
This suggests that hydrophobic effects influence the
stabilization of the geometry of the transition states. A
similar change in the endocarboxy/exocarboxy selectivity
was observed for the exo-selective reaction of 1 with
methyl methacrylate 2b (Scheme 1) in water9 (Table 1)
and organic solvents.6,7 In the absence of methyl group
substitution, as in the reaction of 1 with methyl acrylate,
2c (Scheme 1), hydrophobic interactions become less
important and SOIs direct the reaction to be endocarboxy
selective leading to a higher endocarboxy/exocarboxy ratio
in water (Table 1).6,10
7. Kobuke, Y.; Fueno, T.; Furukawa, J. J. Am. Chem. Soc.
1970, 92, 6548–6553.
8. Compound 1 was freshly cracked from its dimer just
before its use. Compound 2a was prepared by heating
freshly crystallized trans-crotonic acid with methanol and
sulfuric acid for 18 h using the procedure given elsewhere.7
Deionized water was used for carrying out the reactions.
The organic solvents (purity > 99+%, spectrophotometric
grade) were used in the investigation. In a typical run,
0.6 mL (7.24 mmol) of freshly cracked 1 was transferred
into 5 mL of solvent. Then 0.6 mL (6.44 mmol) of 2a was
dissolved in 5 mL of the solvent. The solution containing 1
was added to the solution containing 2a. The reaction
mixture was magnetically stirred at 27 °C for about 12 h.
The stereochemical assignments were made by condensing
crotonic acid with 1 and the resultant endo and exo bicylic
acids separated by iodolactonization as described by
Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1988, 110, 1238–1256; The 1H NMR spectrum of the
endo ester is also reported by Ikota, N. Chem. Pharm. Bull.
1989, 37, 2219–2221, The products were analyzed by gas
chromatography using a CP SIL 5CB column. The
retention times for the endo and exo products were 8.411
and 8.278 min, respectively. GC analyses of the individual
isomers were found to be 8.633 min for the endo and
8.249 min for the exo ester. GC and NMR were also used
to check the dimerization of 1, which was found to be
negligible.
The endocarboxy/exocarboxy values in water were checked
after every 30 min before the completion of the reaction
to yield the ratio as 1.28 0.08 (an average of six read-
ings) indicating that selective decomposition of either
endo or exo-product did not take place. Also the sepa-
rated endo and exo products were kept in water for
the same time without any change suggesting that the
endo product (56%) did not convert into the exo isomer
(44%) and vice versa.
In summary, it is possible to invoke the role of hydro-
phobic packing to explain the stereoselectivity of a
Diels–Alder reaction in water.
Acknowledgements
The authors thank Professor R. Breslow and an anony-
mous reviewer for making useful suggestions on this
work. D.S. and S.S.D. thank CSIR, New Delhi, for
awarding them Research Fellowships.
9. Deshpande, S. S.; Kumar, A. Tetrahedron 2002, 58, 8759–
8762.
10. Pawar, S. S.; Phalgune, U.; Kumar, A. J. Org. Chem.
1999, 64, 7055–7060.