Acidity effect in the regiochemical control of the alkylation of phenol with alkenes

Article abstract of DOI:10.1039/a604598g

Treatment of 1:1 mixtures of phenol and linear alkenes in the presence of an acidic promoter in CHCl₃ at room temperature results in ortho-regioselective monoalkylation producing sec-alkylphenols in 48-60% yield. In similar reactions, branched alkenes lead exclusively to the corresponding para-tert-alkylphenols in 80-85% yield. Addition of increasing amounts of potassium phenolate to the reacting system reduces the protic acidity and promotes ortho-regioselective tert-alkylation. These results are tentatively explained in terms of competition of 'H-bond-template' and 'charge-controlled' mechanisms.

Full text of DOI:10.1039/a604598g

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Acidity effect in the regiochemical control of the alkylation of phenol
with alkenes
Giovanni Sartori,* Franca Bigi, Raimondo Maggi and Attilio Arienti
Dipartimento di Chimica Organica e Industriale dell’Università, Viale delle Scienze,
I-43100 Parma, Italy
Treatment of 1 :1 mixtures of phenol and linear alkenes in the presence of an acidic promoter in CH Cl3 at
room temperature results in ortho-regioselective monoalkylation producing sec-alkylphenols in 48–60%
yield. In similar reactions, branched alkenes lead exclusively to the corresponding para-tert-alkylphenols
in 80–85% yield. Addition of increasing amounts of potassium phenolate to the reacting system reduces
the protic acidity and promotes ortho-regioselective tert-alkylation. These results are tentatively explained
in terms of competition of ‘H -bond-template’ and ‘charge-controlled’ mechanisms.
The regiochemical control of the electrophilic alkylation of
aromatic substrates has been the subject of intensive synthetic
and theoretical investigations.1 Traditionally, alkyl halides,
alcohols, ethers, esters and alkenes have been utilized as alkyl-
ating agents and protic or Lewis acids have been utilized to
promote the reaction.2 In the particular case of the protic
acid-promoted alkylation of phenol with alkenes, it is well
established that the reaction leads initially to predominantly
4-substituted products when the para position is available for
reaction, ortho derivatives being formed only when the para
position is already occupied or by further substitution to give
2,4- and 2,4,6-trialkylphenols. However the ortho-directing
effect of the OH group has been utilized in the aluminium
phenolate catalyzed tert-alkylation of phenol affording ortho-
tert-butylphenol in preference to the para isomer.3
moter of the process in agreement with previous reports from
the literature concerning the alkylation of arenes with alkenes.3
In all cases 2-sec-hexylphenol 7 was obtained accompanied
by minor amounts of 2,6-di-sec-hexylphenol 9.† The
exceptional activation effect toward ortho-regioselective alkyl-
ation of the present system was further showed by some add-
itional experiments. Thus, compound 9 was obtained in 82%
yield by carrying out the reaction with an excess of hex-1-ene.
In addition to mono- and di-alkylation products, variable quan-
tities of 2-chlorohexane 10, were detected in all experiments.
Compound 10 was recovered as the major product (65% yield)
when HCl (molar ratio PhOH :HCl = 1:1) was utilized as the
protic acid promoter (entry c). 2-Chlorohexane is not an alkyl-
ating agent, since its reaction with phenol and AlCl3 under the
same conditions resulted in complete recovery of unchanged
starting materials. Moreover, the use of CF3SO3H as the catalyst
resulted in the production of a mixture of ortho- and para-sec-
hexylphenols.
In previous studies we have reported a series of metal-driven
ortho-regioselective electrophilic substitutions on metal pheno-
lates with different electrophilic reagents such as aldehydes,4
ketones,5 acyl chlorides6 and nitriles.7
As expected, by allowing dichloroaluminium phenolate
(which is not a potential proton source) to react with hex-1-ene
all the starting phenol was recovered unchanged (entry e). By
contrast, addition of phenol to the unreactive dichloroalu-
minium phenolate (molar ratio 1:1) resulted in promotion of
the exclusive ortho-alkylation in moderate yield (16%) (entry b).
In a series of further experiments, different alkenes were
treated with phenol under the same experimental conditions.
Results are listed in Table 2. It clearly appears that all linear
alkenes react exclusively at the ortho-position of the phenol ring
in good yield (entries a–e). In contrast, the reaction with
branched alkenes resulted in the exclusive production of para-
alkylphenols in higher yield (entries f–h). The essential mechan-
isms of the reactions with both linear and branched alkenes are
depicted in Scheme 2.
Scheme 1
The results showed that the oriented complex 3, formed
between the phenolate 1 and the electrophilic reagent 2, acti-
vates both reagents and promotes complete ortho-regioselective
control.
We undertook the present study to obtain information about
the role played by the acidity of the reacting system on the
regiochemical control of the alkylation of phenol with alkenes.
As earlier reported in the literature, the phenol reacts with
AlCl3 in non-polar solvents giving the donor–acceptor complex
15 which is a strong Brönsted acid.‡ Compound 15 can equi-
librate with dichloroaluminium phenolate 16 by loss of HCl; it
is reasonable to suppose that hydrogen bonding between 15 and
Results and discussion
First we examined the influence of different acid promoters in
the model reaction between phenol and hex-1-ene in dry chloro-
form purged from ethanol (see Experimental section) at 25 ЊC
for 10 h. The experimental conditions for carrying out the reac-
tion were quite simple. The chloroform solution of phenol was
added to a stirred mixture of the selected acid in chloroform in
a closed reaction flask and this was followed by slow addition
of 6 in the same solvent. Results are reported in Table 1.
† Isomerization of the double bond of the alkene would be expected
to occur under acidic conditions producing all possible 2-hydroxy-
phenylhexanes; however, due to the mild experimental conditions, only
products 7 and 9 were recovered.
‡ It was demonstrated that aluminium alkoxides and phenoxides can
coordinate a molecule of alcohol or phenol to form acid solutions.
Although the acid HAl(OR)4 could not be isolated, a similar complex
has been isolated and characterized with titanium phenoxide: G. W.
Svetich and A. A. Voge, Acta Crystallogr., Sect. B, 1972, 28, 1760.
It is apparent from Table 1 that the reactivity of the system is
quite sensitive to the acid utilized, AlCl3 being the best pro-
J. Chem. Soc., Perkin Trans. 1, 1997
257

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Table 1 Reaction of phenol with hex-1-ene in the presence of different acidic promotersa
Entry
M
Acidic promoter
Recovered 5 (%)
7 Yield (%)
8 Yield (%)
9 Yield (%)
10 Yield (%)
a
b
c
d
e
H
H
H
H
AlCl3
33
82
90
40
99
62
16
5
20
—
—
—
—
18
—
4
1
—
5
—
Neb
Ne
65
Ne
Ne
PhOAlCl2
HClc
CF3SO3H d
—
AlCl2
a
All reactions were carried out in a closed vessel and the reagent 6 was added dropwise during 2 h; the molar ratio PhOH :MXn :6 was 1:1:1. b Not
estimated. c Molar ratio PhOH :HCl:6 = 1:1:1. d 15% of a mixture of isomerized hexylphenols was detected by gas-mass analysis.
Table 2 Reaction of phenol with different alkenes in the presence of AlCl3
Entry
R
RЈ
RЉ
Recovered 11 (%)
13 Yield (%)
14 Yield (%)
a
b
c
d
e
f
H
H
H
H
Et
Bu
C6H13
C10H21
H
H
H
H
59
36
36
44
49
13
16
17
45
60
59
52
48
—
—
—
—
—
—
—
—
85
82
80
H
᎐C4H8᎐
Me
Me
Me
Me
Me
H
Me
g
h
᎐C4H8᎐
the alkene gives rise to the complex 17.§ This interaction has
two effects: the simultaneous activation of both the alkene (by
H-bonding) and the phenol (by loosening the O᎐H bond) and
the association of the partners in a complex with a favourable
geometry for concerted ortho-specific alkylation (Route A).3
The observation that para-alkylation mainly occurs when
alkylating agents such as isobutene, 2-methylbut-2-ene and 1-
methylcyclohexene were used, leads us to the suggestion that
para-alkylation is diagnostic of the intermediacy of carbonium
ions¶ which reacts with phenol by a process involving reversible
O- and C-attack followed by the predominant formation of the
thermodynamically more stable 4-tert-alkylphenol at equi-
librium (Route B).8 In connection with this study we have
recently demonstrated that under controlled conditions 2,4-di-
tert-butylphenol undergoes selective and exclusive AlCl3-
promoted ortho-de-tert-butylation.9
If such are the mechanisms of the activation of both
reagents, one may expect a different regiochemical behaviour in
§ Previous IR spectroscopy studies suggested that π electrons of double
and triple bonds are comparable acceptors of hydrogen bonds:
S. A. McDonald, G. L. Johnson, B. W. Keelan and L. Andrews, J. Am.
Chem. Soc., 1980, 102, 2892; L. W. Buxton, P. D. Aldrich, J. A. Shea,
A. L. Legon and W. H. Flygare, J. Chem. Phys., 1981, 75, 2651.
¶ tert-Butyl cations were recognized in both the solid state and the gas
phase: (a) S. Hollestein and T. Laube, J. Am. Chem. Soc., 1993, 115,
7240; (b) M. E. Crestoni and S. Fornarini, J. Am. Chem. Soc., 1994,
116, 7240.
Scheme 2
the tert-alkylation process, by reducing the Brönsted acidity of
the complex 15 and disfavouring the charge-controlled
mechanism.
258
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 3 Reaction of phenol with isobutene in the presence of AlCl3* and different amounts of potassium phenolate
Entry 19/11
Recovered phenol (%)
14f Yield (%)
21 Yield (%)
(21–14f)/(21 + 14f) × 100
Ϫ100
Ϫ97
Ϫ76
Ϫ27
3
33
72
95
100
100
100
a
b
c
d
e
f
0.000
0.100
0.200
0.225
0.250
0.275
0.300
0.400
0.500
0.750
1.000
19
23
28
31
36
39
45
52
57
60
61
78
71
60
42
29
19
7
—
1
8
24
31
38
43
43
40
38
36
g
h
i
j
k
1
—
—
—
* Molar ratio 11/AlCl3 = 1.
‘H-bond template’11 or ‘charged-controlled’ mechanisms,||
respectively. Our results also indicate that it is possible to
promote such processes selectively by varying the basicity of
the alkene or the protic acidity of the complex involving the
phenolic substrate and the Lewis acid.
Experimental
Bps and mps were obtained on a Gallenkamp melting-point
apparatus. IR spectra were recorded on a Perkin-Elmer 298
spectrophotometer. 1H NMR spectra were recorded on a
Bruker AC 300 spectrometer at 300 MHz and on a Varian
EM 360 spectrometer at 60 MHz.
Fig. 1 Diagram of the ortho/para isomeric excess (%) in the reaction
of phenol with isobutene in the presence of increasing amounts of
potassium phenolate
Chemical shifts are expressed in ppm relative to tetramethyl-
silane as internal standard and J values are expressed in Hz.
Mass spectra were recorded on a Varian MAT CH 5 spectro-
meter in EI mode at 70 eV. Microanalyses were carried out
by Dipartimento di Chimica Generale ed Inorganica, Chimica
Analitica, Chimica Fisica dell’Università di Parma. TLC analy-
ses and chromatography were performed on Merck PF254 silica
gel using hexane–ethyl acetate (90:10) as eluent. Quantitative
analyses were performed on a Dani 3900 gaschromatograph
equipped with SE 52 capillary column. All reagents were of
commercial quality from freshly opened containers. Chloro-
form was washed 15 times with water, dried (Na2SO4), distilled
twice and kept over molecular sieves before use.
Thus phenol, AlCl3 and isobutene (molar ratio 1:1:1) were
allowed to react under the same conditions as those described
for the preceding experiments but in the presence of increasing
amounts of potassium phenolate (PhOK) which could react
replacing HCl with phenol. Results of these experiments are
reported in Table 3 and Fig. 1
In the absence of PhOK the reaction proceeds with 81% con-
version and a 78% yield of para-tert-butylphenol 14f, while
in the presence of PhOK, mixtures of para- and ortho-tert-
butylphenols 14f and 21 were produced. The composition of
these mixtures depends on the PhOK/PhOH ratio. Two interest-
ing trends are apparent from the experimental data reported.
First, the reactivity of the present system seems to be governed
by the protic acidity effect: as the PhOK/PhOH molar ratio
becomes higher, the phenol conversion decreases. Second, an
increase in the ortho/para tert-butylation ratio resulted upon
addition of increasing amounts of PhOK to the reaction mix-
ture. ortho-tert-Butylphenol 21 was obtained as the sole product
in 40% yield by using a 0.5 PhOK/PhOH ratio. The regio-
selectivity variation as a function of the PhOK/PhOH ratio is
shown in Fig. 1. The S-shaped curve obtained shows an
inflection point when the PhOK/PhOH ratio is 0.25. This is in
contrast with a typical salt effect; in fact, addition of a salt to the
reaction mixture increases the dielectric constant. This effect
would be predicted to increase the rate of para- relative to ortho-
alkylation.10
Synthesis of the alkylphenols 13 and 14: general procedure
A solution of phenol (0.94 g, 10 mmol) in dry CHCl3 (30 ml)
was added dropwise, under nitrogen, to a stirred suspension of
AlCl3 (1.33 g, 10 mmol) in dry CHCl3 (30 ml). After 30 min a
solution of the selected alkene (10 mmol) in dry CHCl3 (30 ml)
was added to the mixture over 30 min. The stirring was con-
tinued at room temperature for 10 h after which the reaction
was quenched by addition of 10% aqueous HCl (100 ml) to the
mixture which was then extracted with diethyl ether (3 × 100
ml). The combined extracts were dried (Na2SO4) and evapor-
ated and the residue was subjected to preparative TLC with
hexane–ethyl acetate (90:10) to give the products.
Reaction of isobutene with phenol in the presence of potassium
phenolate: general procedure
A solution of phenol (0.94 g, 10 mmol) in dry CHCl3 (30 ml)
and potassium phenolate were successively added, under nitro-
Finally, attempted alkylation by isobutene of a 1:1 mixture
of PhOK and AlCl3 resulted in complete recovery of the start-
ing reagents.
These results indicate that the different positional selectivities
observed can be explained in terms of the different mechanisms
involved: thus, ortho- and para-alkylation are obtained through
|| Control in the relative electrophilicity of alkylating agents by vari-
ation of the Lewis acid concentration has been previously reported:
H. Mayr, C. Schade, M. Rulbow and R. Schneider, Angew. Chem., Int.
Ed. Engl., 1987, 26, 1029.
J. Chem. Soc., Perkin Trans. 1, 1997
259

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gen, to a stirred suspension of AlCl3 (1.33 g, 10 mmol) in dry
CHCl3 (30 ml). After 30 min a titred solution of isobutene (10
mmol) in dry CHCl3 (30 ml) was added to the mixture over 30
min. The stirring was continued for 10 h at room temperature
after which the reaction was quenched by the addition of satur-
ated aqueous NH4Cl (100 ml) to the mixture which was then
extracted with diethyl ether (3 × 100 ml). The combined
extracts were dried (Na2SO4) and evaporated and the residue
was subjected to preparative TLC with hexane–ethyl acetate
(90:10) to give the products.
The authors are grateful to the Centro Interdipartimentale
Misure (CIM) for the use of NMR and mass spectrometry
instruments.
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2-(1-Methylpentyl)phenol 7. Pale yellow oil, bp 82–84 ЊC/0.1
mmHg (lit.,12 bp 60 ЊC/0.01 mmHg).
2,6-Bis(1-Methylpentyl)phenol 9. Pale yellow oil (Found: C,
82.3; H, 11.3. C18H30O requires C, 82.4; H, 11.5%); νmax(NaCl)/
cmϪ1 3420; δH (60 MHz; CDCl3) 0.7–1.0 (6 H, m, 2 CH2CH3),
1.0–1.8 (18 H, m, 2 CH3 and 6 CH2), 2.85 (2 H, m, J 7.0, 2 CH),
4.62 (1 H, s, OH) and 6.7–7.1 (3 H, m, H-arom); m/z 262 (M+,
10%), 205 (100) and 191 (14).
4-(1-Methylpentyl)phenol 8. Pale yellow oil, bp 92–94 ЊC/0.1
mmHg (lit.,12 bp 80 ЊC/0.05 mmHg).
2-(1-Methylpropyl)phenol 13a. Pale yellow oil, bp 224–226 ЊC
(bp of an authentic sample 226–228 ЊC).
2-(1-Methylheptyl)phenol 13c. Pale yellow oil, bp 72–75 ЊC/
0.05 mmHg (lit.,13 bp 129–132 ЊC/2 mmHg).
2-(1-Methylundecyl)phenol 13d. Pale yellow oil, bp 150–
153 ЊC/0.05 mmHg (Found: C, 82.6; H, 11.7. C18H30O requires
C, 82.4; H, 11.5%); νmax(NaCl)/cmϪ1 3420; δH (300 MHz;
CDCl3) 0.83 (3 H, t, J 7.1, CH2CH3), 1.1–1.7 (21 H, m, CH3CH
and 9 CH2), 3.00 (1 H, m, J 7.0, CH), 4.69 (1 H, s, OH), 6.67 (1
H, d, J 7.5, H-arom), 6.84 (1 H, t, J 7.5, H-arom), 6.99 (1 H, t,
J 7.5, H-arom), 7.10 (1 H, d, J 7.5, H-arom); m/z 262 (M+,
31%), 135 (29), 121 (100) and 107 (70).
7 F. Bigi, R. Maggi, G. Sartori, G. Casnati and G. Bocelli, Gazz. Chim.
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2-Cyclohexylphenol 13e. Pale yellow solid, mp 55–57 ЊC
(lit.,14 mp 56–57 ЊC).
4-tert-Butylphenol 14f. White solid, mp 96–98 ЊC (mp of an
authentic sample 98–99 ЊC).
11 (a) D. V. Banthorpe, Chem. Rev., 1970, 70, 295; (b) K. Norrman and
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4-(1-Methylcyclohexyl)phenol 14h. White solid, mp 111–
113 ЊC (lit.,15 mp 112.5 ЊC).
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14 S. Skraup and W. Beifuss, Chem. Ber., 1927, 60, 1070.
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Acknowledgements
The authors acknowledge the support of the Ministero dell’
Università e della Ricerca Scientifica e Tecnologica (MURST),
Italy and the Consiglio Nazionale delle Ricerche (CNR), Italy.
Paper 6/04598G
Received 2nd July 1996
Accepted 26th September 1996
260
J. Chem. Soc., Perkin Trans. 1, 1997