A rational approach towards the nucleophilic substitutions of alcohols "on water"

Article abstract of DOI:10.1002/anie.200800622

(Chemical Equation Presented) Walking on water: Which alcohols react with nucleophiles on the surface of water? The correlations introduced by Mayr et al., in which electrophiles are characterized by the parameter E, gives practical indications about the reactivity of alcohols with nucleophiles in pure water. Stable carbocations generated from the alcohols and characterized by E <-2.5 readily react with nucleophiles in pure water at 80°C, without added Bronsted or Lewis acids.

Full text of DOI:10.1002/anie.200800622

Communications
DOI: 10.1002/anie.200800622
Heterogeneous Reactions
A Rational Approach towards the Nucleophilic Substitutions of
Alcohols “on Water”**
Pier Giorgio Cozzi* and Luca Zoli
When water, which is unquestionably cheap, safe, and
environmentally benign,[1] is used as a solvent,[2] the reactivity
and selectivity observed are different from those of the same
reactions conducted in standard organic solvents.[3] Although
coupling reactions between benzylic halides and nucleophiles
are possible in water,[4] in general, alcohols are not reactive
substrates under these conditions.[5] In fact, the reaction
between benzhydrol and the strong p nucleophile 1-methyl-
indole is not promoted in water, and common Brønsted acids
(AcOH, trifluoroacetic acid, trifluoromethanesulfonic acid)
are also ineffective catalysts for this reaction in water.[6]
Nevertheless, a number of methods for the promotion of
direct catalytic nucleophilic substitution of alcohols in organic
solvents have been reported.[7] Kobayashi and Shirakawa
have recently found that dodecylbenzenesulfonic acid
(DBSA), a Brønsted acidic surfactant, efficiently catalyzes
dehydrative nucleophilic substitution of benzylic alcohols
with various carbon nucleophiles in water.[6] We report herein
that the direct substitution of alcohols “on water”[2,8] without
added Brønsted or Lewis acid is possible; the reaction is
related to the stability of the corresponding carbocation.
Recently, we have demonstrated the direct substitution of
optically active ferrocenyl alcohols “on water”[9] with indole,
pyrrole, and thiophenols, which proceeds in good to moderate
yield.[10] Electrophilicity parameters were introduced by Mayr
et al., and they demonstrated that one parameter for the
electrophile (E) and two parameters for the nucleophiles are
sufficient for a quantitative description of the rates of a large
variety of electrophile–nucleophile combinations.[11] We real-
ized that in all attempts to react alcohols in water, alcohols
that can form carbocations at the top of Mayrꢀs list (see the
Supporting Information) were always selected. In aqueous
solution such carbocations tend to have very short lifetimes as
a result of their rapid reactions with water.[12] However, the
lifetimes of carbocations can be increased substantially by the
introduction of electron-donating substituents on the aryl
ring.[13] Ferrocenylcarbenium ions are characterized by an E
value of À2.57;[11b] therefore we decided to explore the
reactivity “on water” of alcohols that can generate carboca-
tions with a similar or lower E value. We examined the
reactions of the alcohols depicted in Figure 1 and the
nucleophiles shown in Figure 2.[14] All the reactions were
Figure 1. Alcohols selected for the reaction “on water”.
carried out in deionized water (pH 6.52) at 808C without inert
gas protection and with vigorous stirring. Under these
conditions the reactants float on the water emulsion surfaces
owing to their low solubility.[15]
[*] Prof. Dr. P. G. Cozzi, Dr. L. Zoli
ALMA MATER STUDIORUM Università di Bologna
Dipartimento di Chimica “G. Ciamician”
Via Selmi 2, 40126 Bologna (Italy)
Fax: (+39)051-209-9456
E-mail: piergiorgio.cozzi@unibo.it
[**] This work was supported by PRIN 2005 (Progetto Nazionale: Sintesi
e Stereocontrollo di Molecole Organiche per lo Sviluppo di
Metodologie Innovative di Interesse Applicativo) and ST Micro-
electronics. Dr. Armin Ofial and Prof. Herbert Mayr are fully
acknowledged for providing us the electrophilicity scale depicted in
the Supporting Information. Antonio Zanotti Gerosa and Johnson
Matthey Catalysis are acknowledged for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 2. Nucleophiles a–j employed in the direct nucleophilic substi-
tution of the alcohols 1–8 “on water”.
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Chemie
Electrophiles with E values close to 0 are simply too
reactive for the direct substitution of their alcohol precursors
“on water”. (In fact, alcohols 5 and 8 were isolated unchanged
after prolonged reaction time). For the other alcohols tested,
the generation of a more stabilized electrophile in water is
possible. The E values for the corresponding carbocations in
Mayrꢀs scale range from À8.5 (for the carbocation generated
from 6) to À2.5 (for the carbocation generated from 1). We
were pleased to see our prediction confirmed by the
experimental results (Table 1). It is worth noting that C, N,
and S nucleophiles could be employed in water and the
products were isolated in good to excellent yields. Various
ketoesters, diketones, and nitroacetates can react smoothly
with the selected alcohols in water without the requirement
for Lewis or Brønsted acids.
highlights the applicability of this methodology; the products
are readily obtained from a clean reaction in water.[17] To the
best of our knowledge, this is the first report of general and
direct substitution reactions of alcohols “on water”. The
unsatisfactory results obtained with alcohol 6 could be
explained by the higher stabilization of the generated
carbocation in water.[18]
To compare the reactivity of alcohols “on water” with that
under other conditions, we carried examined the reactions of
alcohols 1 and 4 with indole at room temperature and 808C
using a range of solvents (see Table 1 in the Supporting
Information). Alcohol 1 does not react in the absence of
solvent or in a range of solvents at either room temperature or
at 808C. The more reactive 4 gives the product in good yield,
in both the presence and absence of solvent. However, the
conversions were significantly lower than those of the
corresponding reaction “on water”. In practical terms,
The preparation of a series of substituted benzhydrols,
which are key intermediates for the preparation of drugs,[16]
Table 1: Reactions of ferrocenyl alcohols 1–10 with the nucleophiles a–j “on water”.
Entry[a] t [h] Alcohol[b] Nu
Product
Yield [%][c] Entry[a] t [h] Alcohol[b] Nu
Product
Yield [%][c]
1
24
72
24
24
1
1
1
1
a
b
c
85
68
65
90
16[e]
17[f]
18
72
72
24
16
3
3
3
3
b
b
c
e
65
2[d]
80
90
95
3
4
h
19
5
24
1
i
48
20
14
4
a
98
6
7
24
24
1
2
j
78
82
21
22
24
24
4
4
c
e
79
a
85[g]
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Communications
Table 1: (Continued)
Entry[a] t [h] Alcohol[b] Nu
Product
Yield [%][c] Entry[a] t [h] Alcohol[b] Nu
Product
Yield [%][c]
8
9
12
48
24
24
2
2
2
2
e
f
68
0
23
24
4
4
4
5
h
i
92
–
24
24
88
91
10
11
c
d
90
85
25
26
24
48
j
a
–
–
0
[h]
12
13
48
24
2
2
g
i
–
0
27
48
6
7
a
b
83
28
29
16
16
60
95
14
15
24
16
2
3
j
91
82
7
8
e
a
a
30
48
–
0
[a] All reactions were carried out in air. The alcohol (0.2–0.4 mmol) and the nucleophile (0.4–0.8 mmol) were suspended in of water (2.0–4.0 mL) at
808C and stirred for the time indicated. [b] The alcohols are commercially available or were prepared as described in the Supporting Information.
Alcohols 1 and 7 were used as racemic mixtures. [c] Yield of purified product. [d] The reaction was performed with 10 equiv of pyrrole. [e] The reaction
was performed with 4 equiv of pyrrole. [f] The reaction was performed with 8 equiv of pyrrole. [g] The product decomposed on attempted purification
on silica gel. The yield was determined based on the crude reaction mixture. [h] The desired compound was detected by HPLC MS in less than 10%
estimated yield.
reactions of 4 (a solid) with indole in aqueous suspensions are
more reproducible and convenient than in the absence of
solvent, as water provides for the efficient mixing of the
reactants.
The direct generation of carbocations in water from
alcohols is probably driven by the formation of hydrogen
bonds between water and the hydroxy group of the alcohol.
Marcus and Jung recently proposed that the formation of
hydrogen bonds on the interface between water and oil is
responsible for the acceleration of the reactions “on
water”.[19] On the other hand, a templated, water-promoted
epoxide-opening cascade was recently reported by Jamison
and Vilotijevic,[20] who suggested the concomitant activation
of the nucleophile (OH) and electrophile (epoxide) mediated
by a cooperative network of hydrogen bonds.
Although benzylic alcohol 5 and ferrocenyl alcohol 6 are
not reactive in water, we took into account the N parameter
for solvents studied by Mayr et al.[21] and used the less
nucleophilic 2,2,2-trifluoroethanol as the reaction solvent
(Scheme 1).[22] Remarkably, the reaction with indole provided
the desired product, showing that other possible combinations
of solvents able to form hydrogen bonds with alcohols are
suitable for direct alcohol substitutions, without the need of
Brønsted or Lewis acid.
In summary, we have described examples of the direct
nucleophilic substitution of alcohol “on water”, without the
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Chemie
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[8] For a discussion of reactions performed in water, see: Ref. [2].
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Scheme 1. Direct substitution of the alcohols 6 and 8 in 2,2,2-
[9] P. G. Cozzi, L. Zoli, Green Chem. 2007, 9, 1292 – 1295.
[10] For the reaction of a ferrocenyl alcohol promoted by an indium
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trifluoroethanol.
use of Lewis or Brønsted acids or surfactants. Mayrꢀs electro-
philicity parameters enabled us to predict that many different
alcohols bearing metal p complexes will react with nucleo-
philes “on water” and Nicholas-type reactions may also be
possible.[23]
[11] Mayr et al. introduced the following equation: logk = s(N+E)
The parameter E in the equation represents the electrophilicity
parameter, defined by comparison to a reference compound.
See: a) H. Mayr, A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807 –
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Received: February 7, 2008
Published online: April 25, 2008
Keywords: alcohols · electrophilicity scale ·
.
Friedel–Crafts reaction · heterogeneous reactions ·
nucleophilic substitution
[13] The 4,4’-bis(dimethylamino)diphenylmethane carbocation has a
half-life of 10–20 s; see: R. A. McCLelland, V. M. Kanagasaba-
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[14] Other nucleophiles—2,5-dimethylthiophene, 1,3-(MeO)C6H4,
tBuOCONH2, allyltin, allylsilane, 4-MeOC6H4NH2, Bu3SnCN,
4-butyn-1-ol, 3-acetylbutanol, 2,4-ditertbutylphenol, p-toluensu-
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Me3SiCN with ferrocenenylethanol 1, ether byproducts, derived
by the attack of the alcohol 1 with ferrocenylcarbenium, were
isolated; see Ref. [9] for further details.
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