On the para-selective chlorination of ortho-cresol

Article abstract of DOI:10.1016/S0040-4020(02)00996-1

Merrifield-bound o-cresol undergoes electrophilic aromatic chlorination using SO₂Cl₂ leading to para/ortho ratios in excess of 50, the highest such ratio reported for this chlorinating agent. Model studies suggest that this significant para/ortho ratio results not just from steric effects but that considerable electronic influence can be detected.

Full text of DOI:10.1016/S0040-4020(02)00996-1

Tetrahedron 58 (2002) 8059–8065
On the para-selective chlorination of ortho-cresol
Emmanuelle A. Bugnet,a Adrian R. Brough,b Robert Greatrexa and Terence P. Keea
,
*
aSchool of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
bDepartments of Materials and Civil Engineering, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
Received 11 June 2001; revised 8 July 2002; accepted 8 August 2002
Abstract—Merrifield-bound o-cresol undergoes electrophilic aromatic chlorination using SO2Cl2 leading to para/ortho ratios in excess of
50, the highest such ratio reported for this chlorinating agent. Model studies suggest that this significant para/ortho ratio results not just from
steric effects but that considerable electronic influence can be detected. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(trifluoroacetic or aqueous sulfuric acids),6 returning high
Rp/o values ,65. However, for the commercially favoured
reagent SO2Cl2, Rp/o have generally been ,10 unless Lewis
basic8 (ethers, organonitrogen compounds, organosulfur
compounds) or Lewis acidic9 (metal halides) species are
added; raising Rp/o values for o-cresol to ca. 20.10
Commercial applications of isomerically pure ortho- and
para-chlorophenols1 include dyestuffs, preservatives, disin-
fectants, insecticides and herbicides. 4-Chloro-2-methyl-
phenol (para-chlorocresol; PCC), for example, is
commercially important in the manufacture of 4-chloro-2-
methyl-phenoxyacetic acid, a major phenoxy herbicide used
to control weeds in small grains2 and for post-emergence
control of many broad-leaved weeds in cereals, grassland,
and asparagus.3 In addition, PCC is used also to
make 4-chloro-2-methylphenoxybutyric acid for selective
post-emergence weed control in leguminous crops (e.g.
peas and clover) and in under-sown cereals where the
analogous phenoxyacetic acid derivatives would damage
the legumes.4
It has been reported that para-chlorination is favoured over
ortho-chlorination as the steric demand of the chlorinating
agent increases.10 Consequently, substituting a cresol ether
(ROC6H4-2-CH3) for o-cresol (HOC6H4-2-CH3) should
also provide increased steric protection ortho to the phenoxy
function. Revealingly, it has been found that anisole is
chlorinated with greater regioselectivity than parent
phenol by chloroamine salts.6 Moreover, we reasoned
that significant advantages might accrue from attachment
of the cresol substrate to a polymer resin via an ether
linkage including, (i) simplified synthetic chemistry,
(ii) potentially greater steric protection of the ortho site
by secondary or tertiary polymer structure and (iii) poten-
tial for parallel processing, for example, in the screening
of different chlorination agents and additives. Conse-
quently, we decided to work with o-cresol bound to
Merrifield resin.
Chloro-substitution in 2-, 4- or 2,4-positions greatly
enhances the herbicidal activity of phenols.4 Consequently,
considerable efforts have been directed towards controlling
para-(4-position) selectivity in the chlorination of o-cresol
over ortho-(6-position) and poly-chlorination [Rp/o¼para/
ortho ratio; Scheme 1(a)].
Phenol halogenation is usually so fast that it can be carried
out in dilute aqueous solutions at room temperature.5
However, since Cl2 is such a strong halogenating agent
that polychlorination occurs frequently, the search for
milder chlorinating agents has turned to main-group
derivatives such as chlorodimethylsulfonium chloride
(Me2SClþCl2),5 N-chloroamines and ammonium salts6
and sulfuryl chloride (SO2Cl2),7 among several others.8
Indeed, N-chloroamines have proved extremely selective
para-chlorinating agents for o-cresol in acid solvent
2. Results and discussion
2.1. Chlorination of 4-substituted benzyl-o-cresol ethers
However, we first wished to ascertain if our strategy had
potential. We therefore prepared benzylphenol ether
PhCH2OC6H4-2-CH3,11 performed chlorination and subse-
quent debenzylation as outlined in Scheme 1(b) to afford a
para/ortho ratio Rp/o of 40,12 considerably higher than
previously reported ratios using SO2Cl2 as a chlorinating
agent. Armed with this valuable model evidence we
Keywords: ortho-cresol; chlorination; para/ortho ratio; Merrifield resin.
*
Corresponding author. Tel.: þ44-113-233-6421; fax: þ44-113-233-6565;
e-mail: terryk@chemistry.leeds.ac.uk
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00996-1

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E. A. Bugnet et al. / Tetrahedron 58 (2002) 8059–8065
Scheme 1. (a) Chlorination of 2-methylphenol (o-cresol) resulting in 6-chloro-2-methylphenol, 4-chloro-2-methylphenol and 4,6-dichloro-2-methylphenol;
(b) (i) BzCl, NaOH, 1 h, reflux; (ii) SO2Cl2, CH2Cl2, 2 h, 358C; (iii) Me3SiI (2 equiv.), CH2Cl2, 2 h, 258C; (c) (i) Cs2CO3, NaI, DMF 48 h, 90%; (ii) SO2Cl2,
CH2Cl2, 258C, 2 h; (iii) TFA, CH2Cl2, 258C.
performed the same chemical transformations on o-cresol
bound to Merrifield resin (Scheme 1(c)).
Reproducibility of this result is an important issue since
several factors, such as the coupling efficiency, the resin
loading, the volume of swelling solvent (CH2Cl2) used and
the number of equivalents of SO2Cl2 employed during the
chlorination step, may influence the reaction, and hence
Rp/o. The coupling step was examined on resins of different
loading: (i) high loading 3.1 mmol Cl/g resin and (ii) low
loading 1.0–1.6 mmol Cl/g resin under conditions of dif-
ferent reaction times (48 and 72 h), in presence of sodium
iodide and caesium carbonate in DMF at room temperature.
Mass difference measurements revealed that the high
loading resin returned a coupling efficiency of 74–75%
bound o-cresol after 48 h and 80% after 72 h, somewhat
lower than those values for the low loading resin above.
The Rp/o ratio was measured following chlorination in the
presence of different amounts of swelling solvent (CH2Cl2),
at room temperature, over a reaction time of 2 h with
differing quantities of chlorinating agent (SO2Cl2). Results
revealed that Rp/o tended to increase with a larger quantity of
solvent (e.g. Rp/o ca. 25 with 1 cm3 CH2Cl2 and Rp/o ca. 55
with 4 cm3 CH2Cl2). A complete explanation has yet to be
2.2. Chlorination of Merrifield resin-linked o-cresol
The coupling step (i) proceeded smoothly following
literature precedent.13 Quantitative analysis of the coupling
efficiency is not easily achieved. Both FT-IR and solid state
13C NMR (see below) afford qualitative information but we
have found that mass difference measurements are the best
method for determining coupling efficiency, subsequently
allowing us to determine an effective reaction time of 48 h
whereupon ca. 85–87% of 1.0–1.6 mmol/g resin active
sites have been replaced by o-cresol. This figure reaches
89% coupling efficiency after 72 h. Chlorination [step (ii)]
proceeded smoothly also followed by decoupling [step (iii)]
for which, in contrast to the model benzyl ether, we found
trifluoroacetic acid in CH2Cl2 (1:1 v/v) to be very effective.
Upon decoupling from the polymer resin, both product
composition and Rp/o ratio was determined by 500 MHz
NMR to be consistently in excess of 50.12

E. A. Bugnet et al. / Tetrahedron 58 (2002) 8059–8065
8061
Figure 1. Percentage conversion (%) vs time (h) to chlorinated products in the reaction between o-cresol and SO2Cl2; CH2Cl2 solvent; 298 K.
provided but it seems clear that degree of dilution is an
important feature.
HOC6H4-2-CH3 suggest an Rp/o value of ca. 5 based on
sterics alone.†
Obviously, quantitative product analysis is most easily
achieved after cleavage from the polymer resin. Never-
theless, qualitative analysis via solid-state 13C{1H} NMR is
revealing. Cross polarisation magic angle spinning
(CPMAS) analysis of Merrifield resin clearly differentiates
aromatic from non-aromatic carbons.14 Upon loading the
resin with o-cresol 13C{1H} analysis clearly locates signals
associated with the bound o-cresol methyl and phenolic ipso
carbon. Similarly, loading Merrifield with pure 4-chloro-
and 6-chloro-2-cresol reveals significant shifts in key
aromatic resonances, mirroring similar shift changes in
solution-phase spectra. CPMAS NMR analysis of a sample
of o-cresol-bound Merrifield resin which has been
chlorinated using the protocol outlined in Supplementary
Information reveals only 4-chlorination.
Consequently, we have examined Rp/o values for a range of
substituted benzylphenol ethers (40-XC6H4CH2OC6H4-2-
CH3; X¼H, NO2, CF3, Cl, CH3), to investigate any
relationship between Rp/o and electronic parameters of the
substituents. In each case we have compared the results to
our standard, chlorination of o-cresol using SO2Cl2 in
CH2Cl2 solvent at the same temperature (298 K) and at the
same concentration (0.57 mmol). In Fig. 1 is reproduced the
percentage conversion (%) vs time (h) to chlorinated
products in the reaction between o-cresol and SO2Cl2.
Reaction has essentially reached completion after 20 h and
during this time, the Rp/o values vary between 4.0 and 5.9
but after 20 h start to level off at 3.5. There does not appear
to be any regular variation in Rp/o value during the reaction.
For each system (X¼H, NO2, CF3, Cl, CH3) results reveal
that reaction proceeds smoothly to afford only para-chloro,
2.3. Chlorination of 4-substituted benzyl-o-cresol ethers.
Electronic or steric control?
†
Chem3D calculations on putative transition states for the chlorination of
benzyl-o-cresol ether (C) and (D) and parent o-cresol itself (A and B) are
instructive. If we use the Hammond postulate to approximate the rate-
determining transition state to model intermediates (C) and (D) we find a
greater steric energy differential in the ether system over the parent
phenol analogues (A) and (B). Under kinetically controlled conditions,
the energy difference between (A) and (B) may be equated to the energy
difference between rate-determining transition states. If rate constants
leading to para and ortho products are kp and ko, respectively, one may
suppose that kp=ko ¼ expð2DDE=RTÞ where DDE is the energy difference
between (A or C) and (B or D) (10.1 kJ mol21). Under these conditions
kp=ko ca. 5 for A/B, very close to the values observed in practise; 3.5–6.
Moreover, kp=ko ca. 59 for C/D, considerably larger than for A/B but
comensurate with experimental values (vide supra).
To what extent are the Rp/o ratios observed influenced by
steric and/or electronic factors? Obviously, differential
steric effects at the ortho and para sites in phenolic systems,
ArOH, are likely to lead to favouring of the latter. Indeed,
simple MM2 calculations (Chem3D PRO) of putative
transition states for both para and ortho-chlorination in
Table 1. Reactions of SO2Cl2 with X–C6H4CH2OC6H4-2-CH3
(0.57 mmol) in CH2Cl2 solvent, 298 K
X
Conversion p-Chloro o-Chloro Dichloro
(%)
o-Cresol
(%)
(recovered)
Rp/o
H
Cl
94.5
90.6
92.3
88.8
91.2
88.8
96.6
1.3
0.9
1.0
0.6
0.8
0.9
0.9
2.2
1.0
0.4
5.5
9.4
5.6
9.6
2.2
71
98
91
148
120
NO2 94.4
CF3 90.4a
CH3 97.8
a
After 4 h.

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E. A. Bugnet et al. / Tetrahedron 58 (2002) 8059–8065
Table 2. Characterising data for benzyloxy-benzene derivatives
Compound name
Microanalysis (%)
Found (required)
MS(EI) m/z
1H; 13C{1H} NMR d(CDCl3)
1-Benzyloxy-2-methyl-6-
chlorobenzene
C 72.1(72.3);
H 5.8(5.6);
Cl 15.1(15.2)
232 (8%, [C14H13OCl]þz),
141 (8%, [C7H6OCl]þ),
91 (100%, [C7H7]þ),
77 (31%, [C6H5]þ),
65 (35%, [C5H5]þ),
51 (26%, [C4H3]þ),
39 (19%, [C3H3]þ)
212 (19%, [C15H16O]þ),
105 (100%, [C8H9]þ),
91 (6%, [C7H7]þ),
1H NMR d(CDCl3): 2.27 (s, 3H, CH3), 4.96 (s, 2H, Hd, He),
6.96 (dd, 1H, 3JHbHc¼3JHbHa¼7.8 Hz, Hb),
7.08 (d, 1H, 3JHbHc¼7.8 Hz, Hc),
7.24 (d, 1H, 3JHaHb¼7.8 Hz, Ha), 7.35–7.52 (m, 5H, Hf–j);
13C NMR d(CDCl3): 16.6 (C7), 74.4 (C8), 124.7 (C4),
128.1 (C6), 128.2 (C5), 128.2 (C11, C13), 128.5 (C10, C14, C12),
129.6 (C3), 133.7 (C2), 137.1 (C9), 153.1 (C1)
1-(4-Methylbenzyloxy)-2-
methylbenzene
C 84.9(84.9);
H 7.4(7.6)
1H NMR d(CDCl3): 2.27 (s, 3H, C7H3), 2.36 (s, 3H, C15H3),
5.04 (s, 2H, He, Hf), 6.85–6.89 (m, 2H, Ha, Hc),
7.12–7.16 (m, 2H, Hb, Hd),
77 (45%, [C6H5]þ),
65 (10%, [C5H5]þ),
51 (13%, [C4H3]þ),
39 (13%, [C3H3]þ)
7.19 (d, 2H, 3JHh,iHg,j¼7.8 Hz, Hh, Hi),
7.33 (d, 2H, 3JHg,jHh,I¼8.0 Hz, Hg, Hj); 13C NMR d(CDCl3):
16.4 (C7), 21.2 (C15), 69.8 (C8), 111.5 (C6), 120.5 (C4),
126.7 (C5), 127.2 (C2, C10, C14), 129.2 (C11, C13), 130.7 (C3),
134.7 (C12), 137.3 (C9), 159.7 (C1)
1-(4-Methylbenzyloxy)-2-
methyl-4-chlorobenzene
C 72.8(73.0);
H 6.0(6.1);
Cl 14.2(14.4)
246 (17.5%, [C15H15OCl]þz),
141 (10%, [C7H7OCl]þ),
105 (100%, [C8H9]þ),
77 (58%, [C6H5]þ),
1H NMR d(CDCl3): 2.23 (s, 3H, C7H3), 2.36 (s, 3H, C15H3),
5.01 (s, 2H, Hd, He), 6.78 (d, 1H, 3JHaHb¼8.6 Hz, Ha),
4
7.07 (d(d), 1H, 3JHaHb¼8.6 Hz, JHbHc¼2.6 Hz, Hb),
7.12 (d, 1H, 4JHcHb¼2.6 Hz, Hc), 7.19 (d, 2H, 3JHg,hHf,I¼7.9 Hz,
Hg, Hh), 7.30 (d, 2H, 3JHg,hHf,i¼7.9 Hz, Hf, Hi);
51 (23%, [C4H3]þ)
13C NMR d(CDCl3): 16.3 (C7), 21.2 (C15), 70.2 (C8),
112.6 (C6), 125.2 (C2), 126.3 (C5), 127.3 (C10, C14), 129.1 (C4),
129.3 (C11, C13), 130.5 (C3), 134.0 (C12), 137.7 (C9), 155.6 (C1)
1H NMR d(CDCl3): 2.26 (s, 3H, C7H3), 2.37 (s, 3H, C15H3),
4.92 (s, 2H, Hd, He), 6.96 (dd, 1H, 3JHcHb¼3JHaHb¼7.7 Hz, Hb),
7.07 (d, 1H, 3JHcHb¼7.7 Hz, Hc), 7.20 (d, 2H, 3JHg,hHf,I¼7.8 Hz,
Hg, Hh), 7.24 (d, 1H, 3JHaHb¼7.7 Hz, Ha), 7.40 (d, 2H,
3JHg,hHf,I¼7.8 Hz, Hf, Hi); 13C NMR d(CDCl3): 16.6 (C7),
21.3 (C15), 74.4 (C8), 124.7 (C4), 128.1 (C5), 128.1 (C6),
128.4 (C10, C14), 129.2 (C11, C13), 129.5 (C3), 133.7 (C2),
134.1 (C12), 138.0 (C9), 153.2 (C1)
1-(4-Methylbenzyloxy)-2-
methyl-6-chlorobenzene
C 73.0(73.0);
H 6.3(6.3);
Cl 14.1(14.4)
246 (19%, [C15H15OCl]þz),
141 (9%, [C7H7OCl]þ),
105 (100%, [C8H9]þ),
91 (7%, [C7H7]þ),
77 (52%, [C6H5]þ),
65 (8%, [C5H5]þ),
51 (20%, [C4H3]þ),
39 (11%, [C3H3]þ)
1-(4-Chlorobenzyloxy)-2-
methyl-4-chlorobenzene
C 59.9(62.9);
H 4.6(4.5)
266 (22%, [C14H12OCl2]þz),
125 (100%, [C7H6Cl]þ),
77 (35%, [C6H5]þ),
1H NMR d(CDCl3): 2.24 (s, 3H, CH3), 5.01 (s, 2H, Hd, He),
6.75, (d, 1H, 3JHbHa¼8.7 Hz, Ha), 7.08 (dd, 1H, 3JHbHa¼8.7 Hz,
4JHbHc¼2.2 Hz, Hb), 7.13 (d, 1H, 4JHbHc¼2.2 Hz, Hc),
7.35 (s, 4H, Hf–i); 13C NMR d(CDCl3): 16.3 (C7), 69.5 (C8),
112.5 (C6), 126.4 (C5), 128.5 (C11, C13), 128.8 (C10, C14),
130.6 (C3)
51 (24%, [C4H3]þ)
1-(4-Chlorobenzyloxy)-2-
methyl-6-chlorobenzene
C 63.0(62.9);
H 5.7(4.5);
Cl 26.3(26.5)
266 (5%, [C14H12OCl2]þz),
125 (100%, [C7H6Cl]þ),
63 (36%, [C5H3]þ),
1H NMR d(CDCl3): 2.26 (s, 3H, CH3), 4.92 (s, 2H, Hd, He),
6.97 (dd, 1H, 3JHbHc¼3JHbHa¼7.8 Hz, Hb), 7.08 (d, 1H,
3JHbHc¼7.8 Hz, Hc), 7.25 (d, 1H, 3JHbHa¼7.8 Hz, Ha),
7.37 (d, 1H, 3JHg,hHf,i¼8.5 Hz, Hg, Hh), 7.45 (d, 1H,
3JHg,hHf,i¼8.5 Hz, Hf, Hi); 13C NMR d(CDCl3): 16.6 (C7),
73.5 (C8), 124.9 (C5), 128.0 (C6), 128.1 (C4), 128.7 (C11, C13),
129.5 (C10, C14), 129.6 (C3), 133.5 (C2), 134.0 (C12),
135.6 (C9), 152.9 (C1)
51 (40%, [C4H3]þ)
1-(4-Trifluoromethylbenzyloxy)-2- C 67.5(67.7);
methylbenzene H 5.0(4.9)
266 (25%, [C15H13OF3]þz),
159 (100%, [C8H6F3]þ),
77 (10%, [C6H5]þ)
1H NMR d(CDCl3) 2.30 (s, 3H, CH3), 5.14 (s, 2H, He, Hf),
6.85 (d, 1H, 3JHbHa¼8.1 Hz, Ha), 6.90 (dd, 1H,
3JHbHc¼3JHcHd¼7.4 Hz, Hc), 7.13–7.19 (m, 2H, Hb, Hd),
7.56 (d, 2H, 3JHg,jHh,i¼8.1 Hz, Hg, Hj), 7.65 (d, 2H,
3JHi,hHg,j¼8.1 Hz, Hh, Hi); 13C NMR d(CDCl3) 16.4 (C7),
69.0 (C8), 111.3 (C6), 121.0 (C4), 125.5 (C11, C13), 126.8 (C5),
127.1 (C10, C14), 130.9 (C3), 141.6 (C9), 156.5 (C1)
1-(4-Trifluoromethylbenzyloxy)-2- C 59.7(59.9);
methyl-4-chlorobenzene
300 (17%, [C15H12OClF3]þz), 1H NMR d(CDCl3) 2.27 (s, 3H, CH3), 5.11 (s, 2H, Hd, He),
H 4.1(4.0);
Cl 11.8(11.8)
159 (100%, [C8H6F3]þ),
77 (16%, [C6H5]þ),
51 (9%, [C4H3]þ)
6.75 (d, 1H, 3JHbHa¼8.7 Hz, Ha), 7.09 (d(d), 1H,
4
3JHbHa¼8.7 Hz, JHbHc¼2.7 Hz, Hb), 7.15 (s(d), 1H,
4JHbHc¼2.7 Hz, Hc); 13C NMR d(CDCl3) 16.2 (C7), 69.3 (C8),
112.4 (C6), 122.8 (C12), 125.6 (C11, C13), 126.4 (C5),
127.1 (C10, C14), 129.0 (C2, C4), 130.7 (C3), 141.1 (C9),
155.1 (C1)
1-(4-Trifluoromethylbenzyloxy)-2- C 59.9(59.9);
H 4.15(4.0);
Cl 12.1(11.8)
300 (8%, [C15H12OClF3]þz),
159 (100%, [C8H6F3]þ),
140 (6%, [C8H6F2]þ),
77 (12%, [C6H5]þ),
1H NMR d(CDCl3) 2.29 (s, 3H, CH3), 5.02 (s, 2H, Hd, He),
6.99 (dd, 1H, 3JHbHc¼3JHbHa¼7.8 Hz, Hb), 7.10 (d, 1H,
3JHbHc¼7.8 Hz, Hc), 7.26 (d, 1H, 3JHbHa¼7.8 Hz, Ha),
7.64 (d, 2H, 3JHf,iHg,h¼8.5 Hz, Hf, Hi), 7.66 (d, 2H,
3JHg,hHf,i¼8.4 Hz, Hg, Hh); 13C NMR d(CDCl3) 16.5 (C7),
73.3 (C8), 122.0 (C12), 125.0 (C4), 125.4 (C11, C13),
127.9 (C10, C14), 128.2 (C5), 129.7 (C3), 133.4 (C2), 141.1 (C9),
152.9 (C1)
methyl-6-chlorobenzene
51 (10%, [C4H3]þ)

E. A. Bugnet et al. / Tetrahedron 58 (2002) 8059–8065
8063
Table 2 (continued)
Compound name
Microanalysis (%)
Found (required)
MS(EI) m/z
1H; 13C{1H} NMR d(CDCl3)
1-(4-Nitrobenzyloxy)-2-methyl-4- C 60.1(60.6);
chlorobenzene
277 (27%, [C14H12NO3Cl]þz), 1H NMR d(CDCl3) 2.28 (s, 3H, CH3), 5.16 (s, 2H, Hd, He),
H 4.6(4.4);
N 4.6(5.0)
136 (100%, [C7H6O2N]þ),
106 (38%, [C7H6O]þz),
78 (45%, [C6H6]þ),
63 (11%, [C5H3]þ),
51 (15%, [C4H3]þ)
6.74 (d, 1H, 3JHaHb¼8.7 Hz, Ha), 7.10 (d, 1H, 3JHbHa¼8.7 Hz,
4JHbHc¼2.6 Hz, Hb), 7.16 (s, 1H, 4JHcHb¼2.6 Hz, Hc),
7.60 (d, 2H, 3JHf,iHg,h¼8.9 Hz, Hf, Hi), 8.26 (d, 2H,
3JHg,hHf,i¼8.9 Hz, Hg, Hh); 13C NMR d(CDCl3) 16.3 (C7),
68.9 (C8), 112.4 (C6), 123.9 (C11, C13), 126.1 (C2), 126.5 (C5),
127.4 (C10, C14), 129.0 (C4), 130.9 (C3), 144.4 (C9),
147.7 (C12), 154.8 (C1)
1-(4-Nitrobenzyloxy)-2-methyl-6- C 60.4(60.0);
277 (45%, [C14H12NO3Cl]þz), 1H NMR d(CDCl3) 2.30 (s, 3H, CH3), 5.06 (s, 2H, Hd, He),
chlorobenzene
H 4.5(4.4);
N 4.9(5.0);
Cl 12.9(12.8)
136 (100%, [C7H6O2N]þ),
106 (63%, [C7H6O]þz),
78 (64%, [C6H6]þ),
63 (19%, [C5H3]þ),
51 (26%, [C4H3]þ)
7.01 (dd, 1H, 3JHbHc¼3JHbHa¼7.8 Hz, Hb), 7.11 (d, 1H,
3JHbHc¼7.8 Hz, Hc), 7.26 (d, 1H, 3JHbHa¼7.8 Hz, Ha),
7.70 (d, 2H, 3JHf,iHg,h¼8.8 Hz, Hf, Hi), 8.27 (d, 2H,
3JHf,iHg,h¼8.8 Hz, Hg, Hh); 13C NMR d(CDCl3) 16.5 (C7),
72.8 (C8), 123.7 (C11, C13), 125.2 (C4), 127.9 (C6),
128.1 (C10, C14), 128.3 (C5), 129.8 (C3), 133.3 (C2), 144.5 (C9),
147.7 (C12), 152.7 (C1)
ortho-chloro and some small yet constant amount of
dichloro-cresol. Reaction is considerably faster than for
the parent o-cresol with reactions proceeding to completion
within ca. 25 min. We used a slight (5%) excess of o-cresol
over SO2Cl2 in each reaction to ensure complete consump-
tion of the latter and hence avoid any problems of
adventitious over chlorination. In Table 1 are collected
together Rp/o values, conversions and reaction compositions
after 25 min in the chlorination of 40-XC6H4CH2OC6H4-2-
CH3 (X¼H, NO2, CF3, Cl, CH3) with SO2Cl2.
7.1 T magnet and 7 mm DBMAS probe. All spectra were
collected with cross polarisation (contact time 1 ms) and
therefore are not quantitative.
Merrifield resin (HL 100–200 mesh, loading 1.0–
1.6 mmol/g resin) was purchased from NovaBiochem.
Sample rotation was achieved using a Fisher Stuart
Scientific rotator, in 6 mL volume Isolute Filtration
Columns (SPE Accessories from Jones Chromatography)
and filtration on 12-Port Vacuum Manifolds (Alltech).
Resin pre-washing was performed using high-purity
dimethylformamide (DMF). An aliquot of resin (100 mg)
was placed in a 6 mL plastic-capped frit-cuvette containing
DMF (5 mL) and the cuvette rotated for 1 h. Subsequent
filtration on the cuvette under reduced pressure afforded dry
resin which was then treated identically a total of eight times
over 24 h followed by vacuum oven-drying to constant
mass.
It is clear from the position of structural modification that
steric effects are envisaged to play a minor, if any role, in
influencing regiocontrol. Moreover, even though the data in
Table 1 suggest that the nature of substitution has a
significant effect upon Rp/o values, we must approach such
results with care. The proportions of ortho and dichloro
products are small in each case and with normal
considerations of dynamic control effects on high resolution
NMR measurements making intensity measurements ,1%
unreliable, we are inclined to consider a reliability cut-off
Rp/o value of ca. 99. Nevertheless, what is incontrovertible is
that benzylation of o-cresols to afford substituted 1-
benzyloxy-2-methyl-benzenes, results in significant
increase in selectivity towards para-chlorination using
SO2Cl2, presumably due to the increased steric presence
of benzyl substituent blocking access to the remaining
phenolic ortho-position. Indeed, simple calculations suggest
values of Rp/o in the region of 50–60 based on the influence
of steric factors alone.†
Coupling step (i): In a 6 cm3 column, to the Merrifield resin
(600.5 mg, 0.81 mmol) in 2.6 mL of DMF were added o-
cresol (268 mg, 2.48 mmol), caesium carbonate (792 mg,
2.43 mmol) and sodium iodide (123 mg, 0.82 mmol). The
column was rotated at room temperature for 48 h and then
washed with 50 mL fractions of DMF, H2O, DMF, H2O,
acetone, THF and CH2Cl2. The resin was dried by vacuum
oven to constant mass m¼668.3 mg. (Coupling efficiency
87%).
Chlorination step (ii): In a 6 mL column, sulfuryl chloride
(27 mL, 0.333 mmol) was added to the o-cresol-coupled
resin (251.8 mg, 0.337 mmol) in 2 mL of CH2Cl2. The
column was rotated at room temperature for 2 h, washed
with CH2Cl2, and vacuum dried to constant mass
m¼265.3 mg.
Further studies where steric effects are exploited to
influence electrophilic aromatic chlorination, primarily
through non-covalent interactions, are in progress.
Decoupling step (iii): In a 6 mL column, trifluoroacetic acid
(1 mL) was added to the resin system above after cresol
chlorination (103.6 mg, 0.164 mmol) in 1 mL of CH2Cl2.
After 2 h rotation at ambient temperature, reaction was
quenched with water, the resin washed with both water and
CH2Cl2 and the filtrate extracted with CH2Cl2 (3£10 mL)
The organic extracts were then combined, dried over
3. Experimental
3.1. General resin methods and techniques
All 13C MAS-CP NMR spectra were collected at 75 MHz
with decoupling at 35 kHz and magic angle spinning at
4 kHz using a Bruker MSL-300 spectrometer equipped with

8064
E. A. Bugnet et al. / Tetrahedron 58 (2002) 8059–8065
MgSO4 and all volatiles removed to afford decoupled
chlorinated cresols which were analysed subsequently by
500 MHz NMR spectroscopy.
general numbering scheme illustrated below for 1-(para-
trifluoromethylbenzyloxy)-2-methyl-benzene and full data
are collected in Table 2.
Starting with Merrifield at 1.34 mmol/g loading; replace-
ment of chlorine by o-cresol would change theoretical
substitution to 1.22 mmol/g using the equation; Sth
¼
Ss=½1 þ ðSsWtaddÞ=1000ꢀ where each of the terms is as
described in Advanced Chemtech Handbook of Combina-
torial and Solid Phase Organic Chemistry, A Guide to
Principles, Products and Protocols, Advanced Chemtech,
Kentucky, 1998. Subsequently, coupling efficiency is
calculated from the equation Ceff¼Wtg/Wtex where Wtg
and Wtex are the measured and expected (100%) weight
gains, respectively.
3.4. Chlorination of benzyl systems
In a Schlenk equipped with a magnetic stirrer, the ether
(0.567 mmol) was dissolved in dry CH2Cl2 (0.5 mL).
Sulfuryl chloride (46 mL, 76.6 mg, 0.567 mmol) was then
added at ambient temperature and the mixture stirred under
dinitrogen. After 2 h the volatiles were removed under
reduced pressure to afford a mixture of benzyl ethers and
chlorinated benzyl ethers.
3.2. General synthetic chemistry
Solvents were HPLC grade and used as received except for
dichloromethane which was pre-dried and distilled from
calcium hydride and deoxygenated by purging with
dinitrogen gas prior to use. Rotation was achieved using a
Fisher Stuart Scientific rotator, in 6 mL volume Filtration
Columns Isolute, SPE Accessories Jones Chromatography,
and filtration on 12-Port Vacuum Manifolds from Alltech.
Silica gel used for column chromatography was Fisons
Scientific equipment 30–70 mesh, 0.200–0.500 nm. Micro-
analyses were carried out in the School of Chemistry
Microanalysis Laboratory. Mass spectrometric data col-
lected on a VG Autospec instrument (operating at 70 eV for
electron impact). Infrared spectra (KBr discs) were
collected on MIDAC FT-IR grating Spectrophotometer
(4000–600 cm21). NMR spectra were collected at 298 K on
Bruker ARX 250 instrument, Bruker DRX 500 and Bruker
AM 400. In all cases the solvent used for NMR was
deuterated chloroform CDCl3 (99.8%; 0.03% TMS) and the
chemical shifts referenced to residual protons in the solvent
or to tetramethylsilane for 1H and 13C. o-Cresol was
purchased from G.E. Speciality Chemical and purified by
distillation at 768C under reduced pressure. Sulfuryl
chloride was purchased from Fluka.
Analysis of this mixture was achieved through 500 MHz 1H
NMR spectroscopy as outlined above and was found to be
reproducible to within ^5% (when tested against average of
5 runs). Ratios R¼para/ortho were subsequently deter-
mined from integration of the peaks in the methyl region of
the o-cresol, followed by cross-checking against integration
of appropriate resonances in the aromatic region. Ratios
were calculated by dividing the integration of the methyl of
the para compound by the integration of the methyl of the
ortho compound. The percentage conversion is also
calculated from integrations of the methyl region of the
compounds. If A is the value of the integration of the methyl
group of the 4-chloro-o-cresol, and B of the 6-chloro-o-
cresol, and T, the sum of the integration of the methyl of
4-chloro, 6-chloro, 4,6-dichloro-o-cresol and the o-cresol,
so % conversion¼[(AþB)/T]100.
Acknowledgements
We thank the European Coal and Steel Community for
financial support (grant No. 7220-PR-049) and Dr Anne
Routledge (University of York) for many valuable discus-
sions. Full CPMAS NMR spectra and kinetic data for the
reactions between SO2Cl2 and 40-XC6H4CH2OC6H4-2-CH3;
X¼H, NO2, CF3, Cl, CH3 are available as Supplementary
Information.
3.3. Synthesis of substituted 1-benzyloxy-2-methyl-
benzene ethers
All ethers were prepared by refluxing the chloro-, trifluoro-,
nitro-, methyl-benzyl chloride (2 mmol) with an excess of
the appropriate o-cresol (2.2 mmol) in 5 mL of acetone, and
an excess of potassium carbonate in suspension. Reaction
times varied from 4 to 48 h. In each case, reaction was
quenched with 5 mL of diethylether and 10 mL of water.
The mixture was then extracted with diethylether
(2£20 mL), the extracts washed with water (2£20 mL)
followed by 10% potassium hydroxide (2£10 mL) to
remove excess of o-cresol and again with water
(2£10 mL). The ether extract was subsequently dried over
MgSO4, filtered and the volatiles removed under reduced
pressure. Purification was generally performed using flash
column chromatography on silica. 1-Benzyloxy-2-methyl-
benzene,15 1-(4-nitrobenzyloxy)-2-methyl-benzene,16
1-(4-chlorobenzyloxy)-2-methyl-benzene,17 1-benzyloxy-
4-chloro-2-methyl-benzene,18 have been described pre-
viously. NMR data for all new compounds reflect the
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