Regioselective synthesis of important chlorophenols in the presence of methylthioalkanes with remote SMe, OMe or OH substituents

Article abstract of DOI:10.1080/17415993.2018.1493111

Various methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes have been used as regioselectivity modifiers in the chlorination reactions of various phenols at room temperature. The process involves the use of a slight excess of sulfuryl chloride in the presence of aluminum or ferric chloride as an activator. Methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes having 2 and 3 methylene groups as a spacer were found to be good for the para-selective chlorination of o-cresol and phenol. On the other hand, methylthio alcohols, methoxy(methylthio)alkanes and bis(methylthio)alkanes having 6 and 9 methylene groups were found to be good for the selective para-chlorination of m-xylenol and m-cresol. Calculations using density functional theory on bis(methylthio)alkanes have suggested two different types of stable chlorinated intermediates depending on the number of methylene units as a spacer.

Full text of DOI:10.1080/17415993.2018.1493111

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Regioselective synthesis of important
chlorophenols in the presence of
methylthioalkanes with remote SMe, OMe or OH
substituents
Keith Smith, Ali J. Al-Zuhairi, Mark. C. Elliott & Gamal A. El-Hiti
To cite this article: Keith Smith, Ali J. Al-Zuhairi, Mark. C. Elliott & Gamal A. El-
Hiti (2018): Regioselective synthesis of important chlorophenols in the presence of
methylthioalkanes with remote SMe, OMe or OH substituents, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2018.1493111
To link to this article: https://doi.org/10.1080/17415993.2018.1493111
Published online: 04 Jul 2018.
Submit your article to this journal
Article views: 2
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gsrp20

JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2018.1493111
Regioselective synthesis of important chlorophenols in the
presence of methylthioalkanes with remote SMe, OMe or OH
substituents
a
∗a
a
b
Keith Smith , Ali J. Al-Zuhairi , Mark. C. Elliott and Gamal A. El-Hiti
a
b
School of Chemistry, Cardiff University, Cardiff, UK; Cornea Research Chair, Department of Optometry,
College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Various methylthio alcohols, methoxy(methylthio)alkanes and bis
Received 20 December 2017
Accepted 12 June 2018
(methylthio)alkanes have been used as regioselectivity modifiers
in the chlorination reactions of various phenols at room tem-
perature. The process involves the use of a slight excess of sul-
furyl chloride in the presence of aluminum or ferric chloride as
an activator. Methylthio alcohols, methoxy(methylthio)alkanes and
bis(methylthio)alkanes having 2 and 3 methylene groups as a
spacer were found to be good for the para-selective chlorination
of o-cresol and phenol. On the other hand, methylthio alcohols,
methoxy(methylthio)alkanes and bis(methylthio)alkanes having 6
and 9 methylene groups were found to be good for the selective
para-chlorination of m-xylenol and m-cresol. Calculations using den-
sity functional theory on bis(methylthio)alkanes have suggested two
different types of stable chlorinated intermediates depending on the
number of methylene units as a spacer.
KEYWORDS
Regioselective chlorination;
methylthio alcohols;
methoxy(methylthio)alkanes;
bis(methylthio)alkanes;
phenols
OH
OH
SO Cl , FeCl or AlCl
3
2
2
3
+
others
MeS (CH2)n XR1
R
R
Cl
R = H, 2-Me, 3-Me, 3,5-di-Me
1
major
X = O, S; R = H or Me; n = 2, 3, 4, 6, 9
1. Introduction
Chlorinated phenols are important intermediates for many pharmaceutical and industrial
products [1,2]. Also, they act as commercial disinfectants and household active ingredients
CONTACT Keith Smith
Place, Cardiff CF10 3AT, UK; Gamal A. El-Hiti
Optometry, College of Applied Medical Sciences, King Saud University, PO Box 10219, Riyadh 11433, Saudi Arabia
smithk13@cardiff.ac.uk
School of Chemistry, Cardiff University, Main Building, Park
gelhiti@ksu.edu.sa
Cornea Research Chair, Department of
*Current address: College of Engineering – Al-Musayab, University of Babylon, Iraq
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2018.1493111
©
2018 Informa UK Limited, trading as Taylor & Francis Group

2
K. SMITH ET AL.
and have to be isomerically pure to avoid problems associated with the use of chlorinated
phenol mixtures. Therefore, the development of selective chlorination processes for sim-
ple phenols is highly desirable, both in its own right and to reduce the waste from use of
traditional procedures [3–5].
Various procedures have been reported for improving the selectivity of chlorination
reactions of phenols. For example, chlorination of phenol over an Al-pillared montmo-
rillonite clay using freshly distilled sulfuryl chloride (SO Cl ) in 2,2,4-trimethylpentane as
2
2
solvent at 25°C gave 4-chlorophenol in 76% yield and a para/ortho ratio of 5.7, while reac-
tion under similar conditions in the presence of partially cation-exchanged L-type zeolite
gave 4-chlorophenol in 85% yield and a para/ortho ratio of 8, compared to a para/ortho
ratio of only 1.7 when reaction was carried out in the absence of the clay [6]. Chlorination
of o-cresol attached to Merrifield resin with sulfuryl chloride in dichloromethane (DCM),
followed by a trifluoroacetic acid decoupling step, was more selective, giving p-chloro-o-
cresol in high yield with a para/ortho ratio of ca. 50 [7]. However, the reaction has been
applied on only a very small scale (0.33 mmol of o-cresol) and also involves several steps,
solvents, reagents and a relatively large quantity of Merrifield resin; so it is not attractive
for commercial applications. As a result of the commercial importance of the products,
regioselective halogenation of phenols continues to attract attention [8–16] and there is
still a need for convenient yet highly selective processes.
Chlorination of phenols over sulfur-containing compounds in the presence of metal
halides [17–19] offers considerable potential for regioselectivity. For example, the use
of diphenyl sulfide in the presence of aluminum chloride (AlCl ) in chlorination of o-
3
cresol with sulfuryl chloride gave mainly p-chloro-o-cresol with a para/ortho ratio of ca.
2
0 [17,18]. We have previously shown that simple aliphatic sulfides can also improve
para-selectivity in chlorination reactions of phenols with sulfuryl chloride [20,21]. Unfor-
tunately, some examples of such sulfides are volatile and not desirable for use in commercial
applications. However, such volatility was overcome by the use of modified Merrifield
resins or dithiaalkanes [22,23]. As part of our continued interest in the use of solid cat-
alysts in regioselective aromatic electrophilic substitution reactions [24–27], we recently
showed that cyclic or polymeric disulfides could also be used to improve regioselectivity
in chlorination of phenols [28].
The conventional wisdom is that sulfur compounds give greater para-selectivity in
chlorination of phenols by forming bulky chlorosulfonium salts that can more readily
approach the more distal para-position than the proximal ortho-position of the phenol
[
17]. However, some of our results did not appear to fit very well with this conventional
understanding. Therefore, we decided to investigate the use of different sulfur-containing
compounds that could help probe the effect of sulfur groups in chlorination reactions
of phenols. In the present work, we report the use of a range of methylthio alcohols,
methoxy(methylthio)alkanes and bis(methylthio)alkanes in chlorination reactions of var-
ious phenols. We have also attempted to understand the chlorinated intermediates that
might be formed when bis(methylthio)alkanes are used as additives by the use of density
functional theory (DFT) calculations of the structures of the reactive intermediates.
2. Results and discussion
The ability of the hydroxyl group of phenols to interact through hydrogen bonding with
electronegative atoms has been utilized in selective ortho- or para-chlorinations of phenol

JOURNAL OF SULFUR CHEMISTRY
3
[
29]. One working hypothesis for some of the unexpected results that we had observed
previously with dithiaalkanes was that there was an interaction between the phenolic OH
group and one sulfur atom, which resulted in a chlorosulfonium group located at the other
end of a spacer group being located closer to one potential reaction site than to another.
However, the hydrogen bonding between a phenolic OH group and a methylthio group is
not expected to be very strong and a stronger interaction (and perhaps greater regioselec-
tivity as a result) might be expected from a methoxy or hydroxyl group. Therefore, we have
prepared a range of methylthioalkylene derivatives with different alkylene spacer groups
and three different remote substituents, namely OH, OMe and SMe (Figure 1), and inves-
tigated their use as additives in the chlorination of phenols. We would expect the three
different substituents to show different hydrogen bonding abilities, which would presum-
ably cause different regioselectivity in chlorination reactions moderated by the different
compounds. In particular, we would expect the hydrogen bonding to a phenolic hydroxyl
group to diminish in the order OH, OMe, SMe.
Methylthio alcohols [30–33] having 2–9 methylene groups (Figure 1) were prepared
from the corresponding hydroxyalkylenethiols using one mole equivalent of methyllithium
followed by the addition of one mole equivalent of iodomethane, while the correspond-
ing methoxy(methylthio)alkanes [34,35] were prepared from the same starting materials
using two mole equivalents of MeLi followed by the addition of two mole equivalents of
MeI. bis(Methylthio)alkanes [36,37] having 2–9 methylene groups (Figure 1) were pre-
pared from the corresponding dithiols using two mole equivalents of MeLi followed by the
addition of two mole equivalents of MeI.
In view of the importance of 4-chloro-3,5-dimethylphenol (para-chloro-meta-xylenol,
PCMX) as a commercial disinfectant, we first attempted chlorination of m-xylenol
(
50 mmol) with sulfuryl chloride (57.7 mmol) (Scheme 1) in the presence of methylthio
alcohols (30 mg) and FeCl (25 mg) in DCM (25 mL). FeCl was chosen instead of AlCl
3
3
3
as the Lewis acid because the commercial specification for the product requires a low Al
content. The results obtained are recorded in Table 1, which also includes baseline results
for chlorination of m-xylenol in the absence of any additive for comparison.
The results recorded in Table 1 clearly indicate that 6-(methylthio)hexanol (n = 6)
and 9-(methylthio)nonanol (n = 9) gave better para/ortho ratios and higher yields of the
Figure 1. The structures of methylthioalkyl sulfides, ethers and alcohols prepared in this study.
Scheme 1. Chlorination of m-xylenol.

4
K. SMITH ET AL.
Table 1. Chlorination of m-xylenol in the presence of methylthio alcohols and FeCl3.a
Yield (%)b
MeS(CH2)nOH (n)
MX
OCMX
PCMX
DCMX
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
3.0 (4.5)
2.0
2.9
2.8
2.2
10.0 (11.3)
14.0
15.0
15.5
4.6
84.6 (82.0)
80.0
80.0
79.3
90.0
0.2 (1.0)
4.0
2.5
2.1
3.2
8.4 (7.2)
5.7
5.3
5.1
19.5
19.4
98.8 (98.3)
100.0
100.4
99.7
100.0
99.7
0.8
4.7
91.0
3.2
aSO2Cl2 (4.66 mL, 57.7 mmol) was slowly added to a mixture of m-xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg) and the organic
additive (30 mg) in DCM (25 mL) at room temperature over 2 h and the mixture was stirred for 2 h before it was worked
up.
YieldpercentagewascalculatedusingquantitativeGC. Figuresinparenthesesareforthereactioncarriedoutintheabsence
b
of FeCl3.
c
Sum of the yields of all identified compounds.
para-isomer (90% and 91%, respectively) than when no additive was used. On the other
hand, additives where n = 2–4 behaved in a different manner and gave lower yields of
PCMX (ca. 80%) and lower para/ortho ratios even than for the reaction when no additive
was present.
Therefore, it did seem that the presence of the OH group had been influential in affect-
ing the selectivity of the additive. It seemed from these results that it was indeed possible
that the OH group was hydrogen bonding to the phenolic OH group. The longer spacer
group could then allow the SMe group, bearing the chlorine to be transferred to the ring,
to reach around to the distant para-position, allowing greater para-selectivity, if the reac-
tion is intramolecular. By contrast, the shorter spacer groups may restrict the reach of the
chlorine-bearing SMe group, thereby enhancing the ortho-isomer in comparison to the sit-
uation when there is no additive. However, a complicating feature could be that some of the
alcohol additives may have been converted to other species under the reaction conditions;
so methoxy(methylthio)alkanes (n = 2–4, 6 and 9) were next investigated as additives
under conditions similar to those used with methylthio alcohols. The results are recorded
in Table 2.
It is obvious from Table 2 that methoxy(methylthio)alkanes where n = 3, 6 or 9
gave higher para-selectivity than the ones where n was 2 or 4. In general, the addi-
tives with shorter spacer groups were not as low in para-selectivity as the corresponding
hydroxy(methylthio)alkanes, which could be consistent with the H-bonding hypothesis
(the methoxy additives being less tightly held). However, on the basis of that hypothesis,
Table 2. Chlorination of m-xylenol in the presence of methoxy(methylthio)alkanes and FeCl3.a
Yield (%)b
MeS(CH2)nOMe (n)
MX
OCMX
PCMX
DCMX
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
3.0 (4.5)
3.8
2.1
4.4
2.2
10.0 (11.3)
11.7
5.2
84.6 (82.0)
80.5
89.1
85.0
90.0
0.2 (1.0)
3.8
1.9
1.8
2.1
8.4 (7.2)
6.8
17.1
9.4
16.6
26.4
97.8 (98.8)
99.8
98.3
100.2
99.7
9.0
5.4
3.5
1.9
92.4
1.9
99.7
a,b,cSee footnotes to Table 1.

JOURNAL OF SULFUR CHEMISTRY
5
it is not clear why methoxy(methylthio)alkane additives with n = 3 and n = 9 would be
more para-selective than the corresponding hydroxy(methylthio)alkanes.
Next, bis(methythio)alkanes (n = 2–4, 6 and 9) were used as additives for the chlorina-
tion of m-xylenol. The results obtained are recorded in Table 3.
A complicating feature of the results in Table 3 is the relatively high proportion
of 2,4-dichloro-m-xylenol (DCMX) formed in several of the reactions under the stan-
dard conditions used. Since there is no information about the relative reactivity of the
two monochloroxylenols, namely o-chloro-m-xylenol (OCMX) and p-chloro-m-xylenol
(PCMX), some caution must be exercised in interpreting the actual p/o ratios. Notwith-
standing that caveat, Table 3 shows that the selectivity with bis(methylthio)alkanes having
n = 6 and 9, which gave yields of PCMX of 86.6 and 90% respectively, was similar to the
selectivity with both methylthio alcohols and methoxy(methylthio)alkanes with the same
spacer lengths. bis(Methylthio)alkanes with n = 2 and 3 gave similar results to reactions
without any additive, while the para-selectivity of bis(methylthio)butane (n = 4) was less
(
para/ortho ratio was 4.5) than for the case where no additive was used.
In summary, the general trend was for the para-selectivity to increase with increasing
spacer length from 2 to 9 for all three types of additives, which is broadly consistent with
the notion that hydrogen bonding between the phenolic OH group and the heteroatom
of the additive causes the active chlorination site on the remote sulfur atom to be located
more conveniently for intramolecular para-substitution for longer spacer groups. However,
the para-selectivity with methoxy(methylthio)propane was significantly higher than was
obtained from use of other types of additives where n = 3, while the selectivity obtained
from use of additives where n = 4 was lower in all cases than with the same type of addi-
tive with n = 3 or 6, and in two of the three cases was lower than for the reaction without
any additive. This latter result could be consistent with the hydrogen-bonding hypothesis
if a chain length of four methylene groups provides the optimum separation of the Cl-
bearing S atom from the H-bonded heteroatom for delivery of the Cl to the ortho-position,
although in all cases it should be noted that para-substitution still predominates. Alterna-
tively, perhaps the effect could be explained by the 4-carbon spacer having the optimal
length to allow interaction between the two heteroatoms in a pseudo-six-membered ring
(
Figure 2). In such cases, the heteroatom could interact via overlap between a lone pair
of electrons on the heteroatom and a vacant d-orbital on sulfur. This interaction could
shield the sulfur atoms so that they are less available for chlorination by SO Cl than for
2
2
an open chain arrangement, or alternatively, when the species is chlorinated by SO Cl
2
2
it could behave differently in terms of its steric hindrance than is the case when it is an
open chain.
Table 3. Chlorination of m-xylenol in the presence of bis(methythio)alkanes and FeCl3.a
Yield (%)b
MeS(CH2)nSMe (n)
MX
OCMX
PCMX
DCMX
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
3.0 (4.5)
6.2
5.8
3.1
3.9
10.0 (11.3)
9.7
10.0
16.0
4.4
84.6 (82.0)
76.6
75
73.0
86.6
0.2 (1.0)
7.3
9.0
7.3
4.9
8.4 (7.2)
7.8
7.5
4.5
19.6
15.2
97.8 (98.8)
99.8
99.8
99.4
99.8
1.9
5.9
90.0
1.9
99.7
a,b,cSee footnotes to Table 1.

6
K. SMITH ET AL.
Figure 2. Possible interaction between heteroatoms of additive in the presumed active species.
In order to investigate whether the distant heteroatom of the additive was a major cause
of the low selectivity for the cases when n = 4, or whether it was simply a reflection of
the overall size of the additive in those cases, chlorination of m-xylenol was carried out in
the presence of hexyl methyl sulfide (30 mg) as additive under similar conditions to those
reported in Tables 1–3. The ethyl unit at the end of the hexyl chain is roughly equivalent in
size to the OMe or SMe group of other types of additives, but would not be able to hydrogen
bond at all to the phenolic OH group. The hexyl methyl sulfide showed modestly improved
selectivity compared to baseline results, giving an 86% yield of PCMX and a para/ortho
ratio of 10.2 (equivalent to a para:ortho ratio of 20.4 if consideration is given to the fact
that there are two equivalent ortho positions and only one para-position in m-xylenol).
This result represents higher para-selectivity than for any of the other additives with n = 4,
consistent with the hypothesis that hydrogen bonding of the remote heteroatom to the
phenolic OH group (absent in hexyl methyl sulfide) enhances ortho-substitution, although
the result with methoxy(methylthio)butane as additive showed only a small difference from
methylthiohexane.
It was hoped that more clues might emerge following studies of the chlorination of other
phenols. We have previously shown that aluminum chloride and ferric chloride behave very
similarly in sulfur compound moderated chlorinations of phenols [21], but the reactions
with AlCl are generally slightly more para-selective. Therefore, reactions with phenols
3
other than meta-xylenol were conducted with AlCl as Lewis acid co-additive, rather than
3
FeCl . Also, since the other phenols studied were liquid or easily liquefied around ambient
3
temperature, the reactions were conducted in the absence of solvent, which would be more
akin to conditions used in commercial chlorinations.
Chlorination of o-cresol in the presence of the various additives was next undertaken.
A mixture of the additive (0.10 g), o-cresol (50 mmol) and AlCl (0.25 g) was treated with
3
sulfuryl chloride (57.7 mmol) in the absence of solvent (Scheme 2). The results are given
in Tables 4–6.
Scheme 2. Chlorination of o-cresol.

JOURNAL OF SULFUR CHEMISTRY
7
Table 4. Chlorination of o-cresol in the presence of methylthio alcohols and AlCl3.a
Yield (%)b
MeS(CH2)nOH (n)
OC
OCOC
PCOC
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
14.0 (15.0)
9.0 (9.3)
6.0
6.2
22.8
7.8
13.0
76.0 (75.6)
90.0
91.2
72.5
86.2
8.4 (8.1)
15.0
14.7
3.1
11.0
6.5
99.0 (99.8)
99.9
99.9
99.8
99.9
3.9
2.5
4.5
5.9
2.0
84.8
99.8
aSO2Cl2 (4.66 mL, 57.7 mmol) was slowly added to a mixture of o-cresol (5.41 g, 50.0 mmol), AlCl3 (0.25 g) and organic
additive (0.10 g) at room temperature over 2 h and the mixture was stirred for another 2 h before it was worked up.
YieldpercentagewascalculatedusingquantitativeGC. Figuresinparenthesesareforthereactioncarriedoutintheabsence
b
of AlCl3.
c
Sum of the yields of all identified compounds.
Table 5. Chlorination of o-cresol in the presence of methoxy(methylthio)alkanes and AlCl3.a
Yield (%)b
MeS(CH2)nOMe (n)
OC
OCOC
PCOC
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
14.0 (15.0)
9.0 (9.3)
4.7
5.4
8.6
5.0
76.0 (75.6)
94.0
93.4
86.0
93.5
8.4 (8.1)
20.0
18.0
10.0
18.7
8.0
99.0 (99.8)
99.7
100.0
99.8
1.0
1.6
5.2
1.2
3.3
99.7
99.8
10.7
85.8
a,b,cSee footnotes to Table 4.
Table 6. Chlorination of o-cresol in the presence of bis(methythio)alkanes and AlCl3.a
Yield (%)b
MeS(CH2)nSMe (n)
OC
OCOC
PCOC
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
14.0 (15.0)
9.0 (9.3)
4.5
2.4
10.5
6.0
14.3
76.0 (75.6)
94.4
95.0
88.1
92.0
8.4 (8.1)
20.9
39.5
8.3
15.3
5.7
99.0 (99.8)
99.8
99.8
99.9
100.0
99.9
0.9
2.4
1.3
2.1
2.7
82.9
a,b,cSee footnotes to Table 4.
It is clear from Tables 4 to 6 that the picture for chlorination of o-cresol is very dif-
ferent than for chlorination of m-xylenol. In the case of o-cresol, the general trend is for
para-selectivity to reduce as the length of the spacer group increases for all three types of
additives, exactly the opposite trend to that seen for m-xylenol, suggesting that H-bonding
is not the major contributor to the regioselectivity in this case. However, the para-selectivity
with additives having n = 4 is invariably lower than for the corresponding additives with
n = 3 or n = 6, showing again that the case of n = 4 is somewhat special. Chlorination of
o-cresol (50 mmol) was also carried out using hexyl methyl sulfide (100 mg) as an additive
in the presence of AlCl and gave PCOC in 82% yield with a para/ortho ratio of 8.2. These
3
results are similar to those obtained with no additive or with methoxy(methylthio)butane

8
K. SMITH ET AL.
or bis(methylthio)butane as additive, but 4-(methylthio)butanol was significantly less para-
selective than all of those cases, again consistent with the notion that the strongest hydrogen
bonding additive might increase the amount of attack at the ortho-position.
The various additives (0.10 g) were next investigated in chlorination of m-cresol
(
50 mmol) with sulfuryl chloride (57.7 mmol) in the presence of AlCl (0.25 g) and in the
3
absence of any solvent (Scheme 3). The results obtained are recorded in Tables 7–9.
From Tables 7 to 9, it is clear that the general trend with m-cresol is for increasing para-
selectivity as the spacer group length increases, which is the same as for m-xylenol but the
opposite of that observed for o-cresol. Again, the situation with additives having a tetram-
ethylene spacer group was out of line with the general trend; for two of the additive types,
the selectivity was lower with n = 4 than that observed for the corresponding additives
with either n = 3 or n = 6, while for bis(methylthio)butane the value was between the
values for bis(methylthio)propane and bis(methylthio)hexane. The bis(methylthio)alkane
Scheme 3. Chlorination of m-cresol.
Table 7. Chlorination of m-cresol in the presence of methylthio alcohols and AlCl3.a
Yield (%)b,c
MeS(CH2)nOH (n)
MC
OCMC
PCMC
p/o ratio
Mass balance (%)d
–
2
3
4
6
9
2.5 (3.2)
3.8
0.6
1.3
0.6
9.5 (10.0)
10.0
9.0
87.2 (86.0)
86.0
89.0
89.1
93.0
9.1 (8.6)
8.6
9.8
9.3
14.5
15.0
99.2 (99.2)
99.8
99.6
99.8
100.0
99.8
9.5
6.4
6.2
0.2
93.0
aSO2Cl2 (4.66 mL, 57.7 mmol) was slowly added over 2 h to a mixture of m-cresol (5.41 g, 50.0 mmol), AlCl3(0.25 g) and
organic additive (0.10 g) at room temperature and the mixture was stirred for another 2 h before it was worked up.
YieldpercentagewascalculatedusingquantitativeGC. Figuresinparenthesesareforthereactioncarriedoutintheabsence
b
of AlCl3.
c
The two ortho-chlorinated products have been grouped under the banner OCMC because the two isomers could not be
separated with the GC system used.
Sum of the yields of all identified compounds.
d
Table 8. Chlorination of m-cresol in the presence of methoxy(methylthio)alkanes and AlCl3.a
Yield (%)b,c
MeS(CH2)nOMe (n)
MC
OCMC
PCMC
p/o ratio
Mass balance (%)d
–
2
3
4
6
9
2.5 (3.2)
4.2
2.3
4.0
0.7
9.5 (10.0)
10.7
8.0
87.2 (86.0)
85.0
89.6
87.0
93.2
9.1 (8.6)
7.9
11.2
9.6
15.5
15.3
99.2 (99.2)
99.9
99.9
100
99.9
100.0
9.0
6.0
6.1
0.0
93.9
a,b,c,dSee footnotes to Table 7.

JOURNAL OF SULFUR CHEMISTRY
9
Table 9. Chlorination of m-cresol in the presence of bis(methythio)alkanes and AlCl3.a
Yield (%)b,c
MeS(CH2)nSMe (n)
MC
OCMC
PCMC
p/o ratio
Mass balance (%)d
–
2
3
4
6
9
2.5 (3.2)
4.8
5.0
1.9
0.5
9.5 (10.0)
10.3
8.5
87.2 (86.0)
84.7
86.4
90.5
93.9
9.1 (8.6)
8.2
10.6
12.2
17.3
18.0
99.2 (99.2)
99.8
99.9
99.8
99.8
7.4
5.4
5.2
0.2
94.0
99.4
a,b,c,dSee footnotes to Table 7.
additives were generally a little more para-selective than the other two types, except for
those with the shortest spacer groups, for which all three types were rather similar. With
methyl hexyl sulfide (0.10 g) as additive in the presence of AlCl (0.25 g) the yield of PCMC
3
was 92% and the para/ortho ratio was 18.4; i.e. selectivity was almost as good as with the
best of the other additives, suggesting that hydrogen bonding was not the primary factor
influencing selectivity.
The chlorination of phenol (50 mmol) was next investigated in the presence of the
various organic additives and of AlCl (Scheme 4). The results are recorded in Tables
3
1
0–12.
From Tables 10 to 12, it is clear that methylthio alcohols and methoxy(methylthio)
alkanes exhibit similar trends in selectivity for chlorination of phenol, but with the methoxy
compounds possibly being somewhat more para-selective. In both series the selectivity
was higher when n = 2, 6 and 9, for which cases they provided significantly greater para-
selectivity than for the chlorination of phenol in the absence of any additive, while the
Scheme 4. Chlorination of phenol.
Table 10. Chlorination of phenol in the presence of methylthio alcohols and AlCl3.a
Yield (%)b
MeS(CH2)nOH (n)
P
OCP
PCP
DCP
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
6.0 (6.5)
1.0
0.0
5.2
3.1
19.0 (20.2)
13.0
32.0
23.0
13.0
73.0 (71.0)
83.0
64.0
69.3
82.1
2.0 (1.5)
2.8
3.7
2.3
1.5
3.8 (3.5)
6.3
1.9
3.0
6.3
100.0 (99.2)
99.8
99.8
99.8
99.7
99.8
2.0
12.7
83.1
2.0
6.5
aSO2Cl2 (4.66 mL, 57.7 mmol) was slowly added to a mixture of phenol (4.71 g, 50.0 mmol), AlCl3 (50 mg) and the organic
additive (50 mg) at room temperature over 2 h and the mixture was stirred for another 4 h before it was worked up.
b
YieldpercentagewascalculatedusingquantitativeGC. Figuresinparenthesesareforthereactioncarriedoutintheabsence
of AlCl3.
c
Sum of the yields of all identified compounds.

10
K. SMITH ET AL.
Table 11. Chlorination of phenol in the presence of methoxy(methylthio)alkanes and AlCl3.a
Yield (%)b
MeS(CH2)nOMe (n)
P
OCP
PCP
DCP
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
6.0 (6.5)
2.3
3.0
0.6
3.3
19.0 (20.2)
11.6
18.0
13.0
11.0
73.0 (71.0)
83.5
76.0
84.6
85.0
2.0 (1.5)
2.3
2.1
1.6
0.0
3.8 (3.5)
7.1
4.2
6.5
7.7
100.0 (99.2)
99.7
99.1
99.8
99.3
100
1.0
9.5
88.0
1.6
9.2
a,b,cSee footnotes to Table 10.
Table 12. Chlorination of phenol in the presence of bis(methythio)alkanes and AlCl3.a
Yield (%)b
MeS(CH2)nSMe (n)
P
OCP
PCP
DCP
p/o ratio
Mass balance (%)c
–
2
3
4
6
9
6.0 (6.5)
4.4
3.7
0.6
2.0
19.0 (20.2)
8.3
7.7
8.2
12.0
9.7
73.0 (71.0)
87.3
88.4
88.8
84.5
2.0 (1.5)
0.0
0.0
2.3
1.5
3.8 (3.5)
10.5
11.4
10.2
7.0
100.0 (99.2)
99.7
99.8
99.9
100
99.7
1.5
87.0
1.6
9.2
a,b,cSee footnotes to Table 10.
lowest selectivity in both series was for a spacer group length of n = 3. Indeed, methylth-
ioalcohols with n = 3 and 4 gave even lower para/ortho ratios than when no additive was
used (para/ortho = 3.5–3.8). By contrast, the para-selectivity of bis(methylthio)alkanes
peaked when n = 2–4 and was higher than for the other two types of additives for the
same spacer group length in almost all cases.
Chlorination of phenol in the presence of methyl hexyl sulfide under comparable con-
ditions gave PCP in 81% yield and a para/ortho ratio of 6.5, which is comparable to the
selectivity with methoxy(methylthio)butane, but less than that withbis(methylthio)butane,
each of which is roughly equivalent in overall size. The additives with spacer groups hav-
ing n = 4 were not so out of line with those having other spacer group lengths in the
chlorination of phenol as they were for chlorination of the methyl-substituted phenols.
If the results for all four phenols are considered together, some trends emerge. First, in all
four cases, the trends for the methylthio alcohols and the methoxy(methylthio)alkanes are
very similar and generally the methoxy compounds give somewhat higher para-selectivity
than the alcohols, although the variation in selectivity is not significant enough to allow
firm conclusions to be drawn, especially if the possibility of the alcohols reacting to some
extent under the reaction conditions is considered. Therefore, the results cannot definitely
rule out the hydrogen bonding and intramolecular transfer of chlorine hypothesis, but they
do not really support the view that H-bonding between the distant heteroatom and the
phenolic OH group helps deliver the active chlorine to a location appropriately distant
from the phenolic OH group. Furthermore, bis(methylthio)alkanes are often more para-
selective than either of the other types of additives, although the methylthio group would
be the weakest at H-bonding to the phenolic OH.
Second, the trends for m-xylenol and m-cresol are rather similar, with the highest para-
selectivity being observed with the longer spacer groups (n = 6 and 9). By contrast, the

JOURNAL OF SULFUR CHEMISTRY
11
trend for o-cresol is almost the opposite. Although the differences are less marked, the
best para-selectivity for this substrate is observed with the short spacer groups (n = 2
and 3). The situation with phenol itself is less clear cut. The trends for methythio alcohols
and methoxy(methylthio)alkanes are similar to those for m-xylenol and m-cresol (highest
para-selectivity for n = 6 or 9), while with the bis(methylthio)alkanes the trend is more
like that for ortho-cresol (selectivity better for short spacer groups).
Third, in the cases of methyl-substituted phenols, there is a dip in the para-selectivity
for additives with tetramethylene spacer groups (n = 4) for almost all additives with each
of the substrates. However, the situation is not as clear cut for chlorination of phenol.
2
.1. Computational study
Since these trends are not easy to interpret in terms of any single factor, they may sug-
gest that different influences are bearing on the reactions in different cases. Although the
differences in observed selectivity are synthetically significant, the implied differences in
transition state energies are rather small. Given the complexity of the systems (up to 13
non-H atoms in an open chain additive, together with a phenol, a chlorination source
and a Lewis acid) and the small energy differences that would need to be explained, it
was not possible to get meaningful transition state information by use of calculations.
However, it was possible to attempt to gain further insight into the nature of the active
species by use of calculations using the Spartan ’10 computational package and since the
bis(methylthio)alkanes are generally the most para-selective of the additives, they were
chosen for the study.
Potential intramolecular interactions between the heteroatoms were initially probed
using semi-empirical calculations (AM1 and PM6). Gas phase calculations on mono-
+
chlorinated bis(methylthio)alkanes ([MeS(CH ) SMe]Cl ) suggested two different types
2
n
of a stable chlorinated intermediate. Optimization of the lowest energy structure of each
Figure 3. The more stable type of the chlorinated bis(methylthio)alkane intermediates with n = 2, 3, 4,
6
and 9 according to DFT calculations.

12
K. SMITH ET AL.
Table 13. S–S–Cl and S–Cl–S energy differences for
+
[
MeS(CH2)nSMeCl] .
+
−1
)
n in [MeS(CH2)nSMeCl]
Energy difference (B3LYP) (kJ mol
2
3
4
6
9
S–Cl–S not found
S–Cl–S not found
35.7 (S–S–Cl more stable)
23.1 (S–Cl–S more stable)
45.5 (S–Cl–S more stable)
type using DFT at the B3LYP/6-31G* level suggested that for compounds having shorter
spacer groups (n = 2–4) the more stable intermediates would involve S–S–Cl interactions
(
Figure 3), while the intermediates in the cases of the longer spacer groups (n ≥ 6) would
involve S–Cl–S interactions (Table 13). On the suggestion of a referee, we repeated these
calculations using a larger basis set [6-311 + G(3D,3P)], through the Gaussian suite of
programs. The calculated energy differences between the two types of intermediates were
somewhat altered (generally the S–S–Cl form was lowered in energy relative to the S–Cl–S
form compared to the calculations using the smaller basis set), but the differences were not
great enough to affect the conclusions.
It is possible that different kinds of reactive intermediates such as these may offer some
insights into why additives with longer spacer groups are more para-selective than those
with shorter spacer groups for certain phenols (e.g. m-cresol and m-xylenol), while those
with shorter spacer groups are more para-selective for other phenols (e.g. o-cresol). These
ideas would justify further investigation in future.
3. Conclusion
The spacer group lengths of the prepared compounds play important roles in the selectivity
properties displayed when those compounds are used as additives in chlorination reactions
of various phenols. For example, methylthio alcohols, methoxy(methylthio)alkanes and
bis(methylthio)alkanes with n = 2 and 3 are good for the selective para-chlorination of
o-cresol, while the corresponding compounds with n = 6 and 9 are good for the selective
para-chlorination of m-xylenol and m-cresol.
The computational study of the structures of the chlorinated bis(methylthio)alkanes
with different spacer group lengths has suggested that the chlorinated sulfide additives
with n = 2 and 3 have an S–S–Cl structure while those with n = 6 and 9 have an S–Cl–S
structure. This difference might be responsible for the different performances with differ-
ent phenols of these two groups of additives, but it is not entirely clear how the structures
bring about those differences. Further research is needed in order to provide an under-
standing of the selectivity effects of the different spacer group lengths in these kinds of
species.
4. Experimental
4.1. General
Chemicals and phenol derivatives were purchased from Aldrich and Lancaster Chemicals
and used without further purification. All GC analyses were carried out on a Shimadzu

JOURNAL OF SULFUR CHEMISTRY
13
GC-2014 Gas Chromatograph using a capillary ZB Carbowax column (30 m, 0.32 mm ID).
The GC conditions used for analysis were as follows: 40°C for 3 min, ramped to 220°C
at 10°C/min and held for 8 min. The injection temperature was 300°C and the detection
temperature 250°C. Tetradecane was added as an internal standard to allow quantification.
All of the expected products from chlorination of phenols were purchased from Aldrich
Chemical Company and used to determine retention times and response factors relative to
tetradecane (average from four injections) for each product.
Methythio alcohols [30–33], methoxy(methythio)alkanes [34,35] and bis(methythio)
alkanes [36,37] were prepared based on literature procedures and their spectroscopic data
were consistent with those reported [30–37].
4.2. Typical experimental procedure for the chlorination of m-xylenol
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h, via a
pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl3
(
(
25 mg, 0.154 mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask
50 mL). The mixture was stirred at room temperature for a further 2 h and the reaction
was quenched with water (20 mL). The organic components were extracted with ether
(
3 × 30 mL). The ether layers were removed, combined and dried over MgSO . The drying
4
agent was filtered and the solvent was removed under reduced pressure. The crude product
was weighed and then analyzed by quantitative GC in the presence of tetradecane as added
internal standard.
4
.3. Typical experimental procedure for the chlorination of o-cresol and m-cresol
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mix-
ture of o-cresol or m-cresol (5.41 g, 50 mmol), AlCl (0.25 g, 1.875 mmol) and an additive
3
(
100 mg) in a round bottomed flask (50 mL). The mixture was stirred at room temperature
for a further 2 h, then worked up and analyzed by GC as shown for m-xylenol.
4.4. Typical experimental procedure for the chlorination of phenol
Freshly distilled sulfuryl chloride (4.66 mL, 57.7 mmol) was added slowly over 2 h to a mix-
ture of melted phenol (4.7 g, 50 mmol), AlCl (50 mg, 0.375 mmol) and an additive (50 mg)
3
in a round bottomed flask (50 mL). The mixture was stirred at room temperature for a
further 2 h then worked up and analyzed by GC as shown for m-xylenol.
4.5. Computational methods
Calculations were carried out using Spartan ’10 running on a Mac Pro computer at the
B3LYP/6-31G* level of theory.
Acknowledgements
Professor Bakthan Singaram is thanked for useful discussions.

14
K. SMITH ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Cardiff University, Iraqi Government, and King Saud University,
Deanship of Scientific Research, Research Chairs.
References
[
[
1] Cremlyn R. Pesticides, preparation and mode of action. Chichester: Wiley; 1978.
2] Grant MH. Kirk-Othmer encyclopaedia of chemical technology. 4th ed. New York (NY): Wiley
Interscience; 1992.
[
[
[
[
[
[
[
3] Nishihara A, Kato H. Chlorination of phenols. Japanese Patent JP4,9035,344A, 1974; Chem
Abstr. 1974;81:120196.
4] Gibson GP. CLXXXV. – the monochloro-derivatives of m-cresol. J Chem Soc. 1926;129:1424–
1
428.
5] Sah PPT, Anderson HH. The preparation and properties of three isomeric n-hexyl cresols and
their chlorinated derivatives. J Am Chem Soc. 1941;63:3164–3167.
6] Gnaim JM, Sheldon RA. Shape-selective para-chlorination of phenol using sulfuryl chloride
with the aid of microporous catalysts. Tetrahedron Lett. 2004;45:9397–9399.
7] Bugnet EA, Brough AR, Greatrex R, et al. On the para-selective chlorination of ortho-cresol.
Tetrahedron. 2002;58:8059–8065.
8] Wang M, Ma J, Che J. Method for preparing 2,4-dichlorophenol from phenol via directional
catalytic chlorination. Chinese Patent CN103435453A, 2013; Chem Abstr. 2013;160:101060.
9] Sun X, Sun Y, Zhang C, et al. Room-temperature Pd-catalyzed C–H chlorination by weak coor-
dination: one-pot synthesis of 2-chlorophenols with excellent regioselectivity. Chem Commun.
2
014;50:1262–1264.
[
10] Singh PP, Thatikonda T, Kumar KAA, et al. Cu-Mn spinel oxide catalyzed regioselective
halogenation of phenols and N-heteroarenes. J Org Chem. 2012;77:5823–5828.
11] Bovonsombat P, Ali R, Khan C, et al. Facile p-toluenesulfonic acid-promoted para-
selective monobromination and chlorination of phenol and analogues. Tetrahedron.
[
2
010;66:6928–6935.
[
12] Priya V, Mathiyalagan N. Chlorination of phenol and p-nitrophenol by N-chloronicotinamide
in aqueous acetic acid medium, kinetic and mechanistic study. Asian J Chem. 2010;22:5218–
5
222.
[
[
[
[
[
[
[
[
13] Geetha S, Namrata P. Effect of acetic acid on chlorination of some phenols by Chloramine-T:
a kinetic approach. Res J Chem Sci. 2014;4:86–89.
14] Xiong Y, Duan H, Meng X, et al. Highly selective synthesis of chlorophenols under microwave
irradiation. J Chem. 2016;2016:960414.
15] Georgiev D, Saes BWH, Johnston HJ, et al. Selective and efficient generation of ortho-
brominated para-substituted phenols in ACS-grade methanol. Molecules. 2016;21:88.
16] Maddox SM, Dinh AN, Armenta F, et al. A practical Lewis base catalyzed electrophilic
chlorination of arenes and heterocycles. Org Lett. 2016;18:5476–5479.
17] Watson WD. Regioselective para-chlorination of activated aromatic compounds. J Org Chem.
1
985;50:2145–2148.
18] Watson WD. Chlorination with sulfuryl chloride. US Patent US3,920,757A, 1975; Chem Abstr.
976;84:43612.
19] Binns JS, Braithwaite MJ. p-Chlorophenol. Ger Offen DE2,726,436A1, 1977; Chem Abstr.
1
1
978;88:120784.
20] Tzimas M, Smith K, Brown CM, et al. Chlorination of aromatic compounds and catalysts
therefor. European Patent EP0866049A2, 1998; Chem Abstr. 1998;129:260219.

JOURNAL OF SULFUR CHEMISTRY
15
[
[
[
[
[
[
[
[
[
21] Smith K, Tzimas M, Brown CM, et al. Dialkyl sulfides as selective catalysts for the chlorination
of phenols. Sulfur Lett. 1999;22:89–101.
22] Tzimas M, Smith K, Brown CM, et al. Chlorination of aromatic compounds and catalysts
therefor. European Patent EP0866048A2, 1998; Chem Abstr. 1998;129:275696.
23] Smith K, Tzimas M, Brown CM, et al. Dithia-alkanes and modified Merrifield resins as selective
catalysts for the chlorination of phenols. Sulfur Lett. 1999;22:103–123.
24] Smith K, El-Hiti GA. Catalytic, green and regioselective Friedel-Crafts acylation of simple
aromatics and heterocycles over zeolites. Curr Org Chem. 2015;19:585–598.
25] Smith K, El-Hiti GA. Use of zeolites for green and para-selective electrophilic aromatic
substitution reactions. Green Chem 2011;13:1579–1608.
26] Smith K, El-Hiti GA. Regioselective electrophilic aromatic substitution reactions over reusable
zeolites. Curr Org Chem. 2006;10:1603–1625.
27] Smith K, El-Hiti GA. Regioselective control of electrophilic aromatic substitution reactions.
Curr Org Synth. 2004;1:253–274.
28] Smith K, Al-Zuhairi AJ, El-Hiti GA, et al. Comparison of cyclic and polymeric disulfides as
catalysts for the regioselective chlorination of phenols. J Sulfur Chem. 2015;36:74–85.
29] Guy A, Lemaire M, Guetté J-P. Halogenation regioselective en serie aromatique – I: Chlo-
ration des phenols et de leurs ethers a l’aide de reactifs mettant en jeu des interactions
donneur-accepteur. Tetrahedron. 1982;38:2339–2346.
[
30] Field L, Giles PM. Organic disulfides and related substances. XXVIII. Analogs of o-(2-
protoaminoethyldithio)benzoate as antiradiation drugs. J Med Chem. 1970;13:317–319.
31] Ausín C, Kauffman JS, Duff RJ, et al. Assessment of heat-sensitive thiophosphate protect-
ing groups in the development of thermolytic DNA oligonucleotide prodrugs. Tetrahedron.
[
2
010;66:68–79.
[
[
[
32] Bennett GM, Gudgeon H. The formation of large ring monosulphides from halogenated
sulphides with extended carbon chains. J Chem Soc. 1938:1891–1897.
ꢀ
33] Brown R, Maggridge RCG. The methyl thioethers derived from 2:2 -dichlorodiethyl sulphide
and its analogues. Part III. Synthetic experiments. J Chem Soc. 1946:816–819.
34] Pau JK, Ruggera MB, Kim JK, et al. On the electron-donating properties of oxygen vs. sul-
fur. A study of the gas-phase ion chemistry of methoxymethylthioalkanes. J Am Chem Soc.
1
978;100:4242–4248.
[
35] Clark RJH, McAlees A. Chemistry of methyltitanium trichloride. II. Variable-temperature
nuclear magnetic resonance and infrared spectra of some complexes of methyltitanium trichlo-
ride and of titanium tetrachloride with unsymmetrical bidentate ligands. J Inorg Chem.
1
972;11:342–348.
[
36] Lissel M, Schmidt S, Neumann B. Dimethylcarbonat als methylierungsmittel unter phasen-
transfer-katalytischen bedingungen. Synthesis. 1986:382–383.
[37] Anklam E. Synthese von α-halogen-ω-alkylthio-alkanen und α,ω-bisalkylthio-alkanen. Syn-
thesis. 1987:841–843.