B. Gacem, G. Jenner / Tetrahedron Letters 44 (2003) 1391–1393
1393
Table 4. Effect of the medium in DPAT-catalysed esterifications (80°C, 24 h, DPAT 2% mol)
Acid
Alcohol
Yield (%)
C F
FC-77®
DFPa
n-Hexane
6
14
Cyclohexanecarboxylic
d°
Isobutyric
2-Propanol
Neopentanol
d°
65
84
48
52
65
22
31
59
28
19
40
12
a
1
,1,1,2,3,4,4,5,5,5-Decafluoropentane
(
iv) In place of DPAT, we used iodine which was
catalyst, diphenylammonium triflate. The yield of ester,
however, is very variable. The advantage of using
fluorous hydrocarbons, in addition to enhancing reac-
tivity, materialises in their environmental innocuity, full
recovery by simply extracting the ester layer and re-use
in subsequent runs. Other fluorous compounds with
higher boiling points can also serve as media provided
that they have non-amphiphilic properties. In summary,
the present esterification process involving hindered
reagents is revealed as a cheap and the most performant
method to date. However, in order to acquire its full
potentiality, the yields must still be improved.
recommended as an efficient catalyst for esterifica-
tions (entry 2). The original method used the alco-
hol as the medium. In C F the yield of ester was
1
0
6
14
much lower than in the presence of DPAT.
v) In our temperature conditions, all reagents were
(
liquid except benzoic acid. In order to solubilise this
acid a small amount of either toluene or chloroform
(
(
3.5 mmol) was added, before dilution with C F
6 14
entry 8). The yield was lowered (16%). This may be
in relation with the paragraph below.
i) As the fluorous reactional system was heteroge-
(
neous, stirring was preferred (compare the yields of
ester obtained in C F in entries 2 and 3).
6
14
The results of Table 3 may be rationalised in the
following way. DPAT remains in the organic phase
containing the reagents since the blue-green colour
developed during reaction is only visible in this layer.
Reaction occurs, therefore, mainly at the interface
between the fluorous medium and the organic phase.
The results obtained with unhindered alcohols and
acids (comparable yields in toluene and fluorous media)
could be explained by a partial miscibility of water with
the acid and/or alcohol. Hindered reagents are less
miscible impeding hydrolysis to some extent. The role
of the fluorous phase is certainly determining in sepa-
rating the water produced. In runs carried out with
References
1. Otera, J. Angew. Chem., Int. Ed. 2001, 40, 2044–2045.
2. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
Tetrahedron Lett. 2000, 41, 5249–5252.
3. Ishihara, K.; Nakayama, M.; Ohara, S.; Yamamoto, H.
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4. Jenner, G. J. Chem. Soc., Faraday Trans. 1 1985, 2437–
2460.
5. For a most recent paper, see: Jenner, G. Tetrahedron
2002, 58, 4311–4317.
6. Typical experimental procedure: A mixture of DPAT (20
mg, 0.31 mmol), cyclohexane carboxylic acid (400 mg,
3.12 mmol), bibenzyl (standard) (about 50 mg), and
alcohol (3.43 mmol) were placed in a 6 mL flat-bottomed
stainless steel autoclave equipped with a magnet. The
volume was adjusted with the solvent. The cell was
closed, placed on a magnetic stirrer and heated to 80°C
for 24 h. After reaction, the autoclave was cooled down
before opening and the bilayered liquid system (when
hexane or fluorous media were used) was poured into a
separatory funnel. The blue upper organic layer was
separated from the fluorous compound which was kept
for re-use. After evaporation of the volatile compounds,
hindered structures
fluorous medium–water–reagents). Whether the
increase in reactivity under such conditions may be
a
three-phase system exists
(
11
ascribed to fluorophobic interactions should be taken
into account. To verify this possibility, esterifications
were performed in n-hexane which is also a non-polar
immiscible medium of similar dielectric constant and
cohesive energy density (Table 4). The yields were
decidedly lower in hexane compared to fluorous media.
This could be an indication of the operation of fluoro-
phobic activation. If this is true, solvophobic interac-
tions should be highest in perfluorohexane. The
partially fluorinated compound DFP is less efficient
probably owing to the two hydrogen atoms, reducing
solvophobicity.
1
the residue was analyzed by H NMR and the yields
determined from relative intensities of characteristic pro-
tons of the ester versus methylene groups of the internal
standard.
. Jenner, G. J. Phys. Org. Chem. 1999, 12, 619–625.
. Jenner, G.; Gacem, B. J. Phys. Org. Chem. 2003, 16, in
press.
7
8
Conclusion
9. Zhu, D. W. Synthesis 1993, 953–954.
0. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. Tetra-
1
In conclusion, esterification of bulky acids and alcohols
are best performed in fluorous media, particularly
perfluorohexane, in the presence of the mild and cheap
hedron Lett. 2002, 43, 5249–5252.
11. Myers, K. E.; Kumar, K. J. Am. Chem. Soc. 2000, 122,
879–882.