Transition metal-catalyzed oxidations. 11 : Para-selective chlorination and bromination of phenols with tert-butyl hydroperoxide and TiX(OiPr)3

Article abstract of DOI:10.1002/(SICI)1521-3897(199901)341:1<59::AID-PRAC59>3.0.CO;2-8

Mononuclear phenols 1-4 are chlorinated or brominated with high para-selectivity and in good yields to the halides 5-11 with the TiX_n(OiPr)_m/TBHP system (X = Cl or Br). WILEY-VCH Verlag GmbH, 1999.

Full text of DOI:10.1002/(SICI)1521-3897(199901)341:1<59::AID-PRAC59>3.0.CO;2-8

___________________________________________________________________________PROCEDURES/DATA
Transition Metal-Catalyzed Oxidations. 11 [1]
Para-Selective Chlorination and Bromination of Phenols with tert-Butyl
Hydroperoxide and TiX(OiPr)3
Karsten Krohn, Hagen Rieger, Klaus Steingröver, and Ingeborg Vinke
Paderborn, Universität-GH, FB 13- Fachbereich Chemie und Chemietechnik
Received October 20th, 1998
Dedicated to Prof. W. Pritzkow on the Occasion of his 70th Anniversary
Keywords: Bromine, Chlorine, Oxidations, Titanium, Peroxides, Phenol
Abstract. Mononuclear phenols 1–4 are chlorinated or bro-
minated with high para-selectivity and in good yields to the
halides 5–11 with the TiXn(OiPr)m/TBHP system (X = Cl or
Br).
OH
OH
OH
OH
Selectivity is a major goal in modern synthetic chemistry [2].
This goal is relatively difficult to achieve in some electrophilic
aromatic substitutions especially in the halogenation of
phenols. Mixtures of ortho- and para-substitution products
are usually formed which are often difficult to separate. We
now report on surprisingly clean chlorinations and bromina-
tions with interesting para-position selectivity in the reactions
of phenols with tert-butyl hydroperoxide (TBHP) in the
presence of halogenated transitionmetal alkoxides such as
TiX(OiPr)3 (X = Cl or Br; for a review on TBHP oxidations
see [3]). The halogenating power of the TiXn(OiPr)m/TBHP
system and the selectivities involved have not yet been
systematically investigated. Pertrifluoroacetic acid is known
to generate hypochlorite ions in the reaction with TiCl4 that
chlorinate phenol (1) with moderate ortho-selectivity (56:22)
[4]. A reverse, but also very poor para-selectivity (67.5:25)
is obtained when meta-chloroperbenzoic acid is used in
presence of HCl [5].
Our preliminary chlorination experiments of 2-methyl-
phenol (2) in dichloromethane at room temperature with
TiCl(OiPr)3/TBHP gave low yields but an interesting para-
selectivity encouraging further studies. The reaction was
finally (see Experimental for details) conducted in THF at
–30 ° C with 0.1 molar solutions of the phenols 1–3. In-
creasing the chlorine content of the titanium catalyst or the
addition of lithium or magnesium chloride did not improve
CH3
OCH3
OCH3
CH3
1
2
3
4
OH
OH
OH
OH
CH3
CH3
X
Br
X
X
5: X = Cl 7: X = Cl
6: X = Br 8: X = Br
9: X = Cl
10: X = Br
11
the conversions that were in the range of 90–95% by GC
analysis after 20 h of reaction time at –30 °C. The corres-
ponding para-chlorination products 5, 7 and 9 were the only
products detected by GC analysis; the isolated yields were
62, 58, and 47%, respectively [6]. For comparison, the most
successful reagents for regioselective para-chlorination are
listed in Table 1. With exception of a recent procedure of
Hirano et al. [7] using sodium chlorite and a manganese(III)-
salen complex in the chlorination of anisol some ortho-
chlorination products (3 – 8.7%) were always formed in the
described procedures.
Next, we turned our attention to the bromination of the
phenols 1–4. Initially, we observed that bromination products
Table 1 Selection of reagents for para-selective chlorination of phenol 1
Reagent
Ratio ortho/para
Dichloro product (%)
Yield para (%)
chlorodimethylsulfonium chloride [8]
N-chlorotriethylammonium chloride [9]
N-chloropyridinium chloride [9]
SO2Cl2, cat.: Ph2S, AlCl3 [10]
2,3,4,4,5,6-hexachlorocyclohexa-2,5-dienone [11]
sodium chlorite, cat.: (salene)-mangan(III)-complex [7]
3 : 97
3 : 97
3 : 97
8.7 : 91.3
–
–
–
–
10 )
0 )
84
97 b)
95 b)
89 b)
a
a
a
5.6 : 94.4 )
85 )
98 )
– a)
a
a
a) selectivity for the chlorination of anisol; b) based on chlorination equivalent
J. Prakt. Chem. 1999, 341, No. 1
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999 1436-9966/99/34101-59 $ 17.50 + .50/0
59

K. Krohn, H. Rieger, K. Steingröver, I, Vinke
PROCEDURES/DATA___________________________________________________________________________
para-selectivity. It should be noted in this connection that
electron-rich phenol ethers are also halogenated by the system
but without the position selectivity typical for the investigated
phenols.
were formed when lithium bromide was added to the
TiCl(OiPr)3/TBHP system. To exclude the simultaneous
formation of chlorides, we later used TiBr(OiPr)3 that was
prepared by mixing TiBr4 with three parts of Ti(OiPr)4
similarly as described for TiCl(OiPr)3. The reaction of 1–4
was conducted at –40 °C in THF, and Table 2 shows the results
of the GC analysis comprising all reaction products. It must
be mentioned that naphthol did not give clean halogenation
products due to oxygenations described earlier [12]. The para-
bromination products of 6, 8, 10, and 11 were formed in high
yields and selectivity (86–92%) with only small amounts of
starting material (3–8%), dibromination products (2–8%) or
very little ortho-product (3%, only one case). These results
are comparable with the best known reagents for selective
para-bromination compiled in Table 3. It should be stressed
that in the procedure described here, readily available com-
mercial reagents are used and environmentally safe (TiO2)
side products are formed.
The reason of the high para-selectivity was unclear, and
we performed a few experiments to rule out some mechanistic
alternatives. Although the redox potential is relatively unfa-
vourable, it cannot be excluded that electrophilic chlorine
species in particular hypochlorite or tert-butyl hypochlorite
are generated from TBHP and the titanium catalyst [20].
Therefore, sodium hypochlorite and tert-butyl hypochlorite
were treated with phenol (1) and the products carefully ana-
lyzed by GC. The results are summarized in Table 4. They
clearly demonstrate that ortho-chlorophenol is formed
predominantly with these reagents. However, it is possible
that para-selectivity is caused by steric shielding of the
phenolic ortho-positions after ligand exchange with the
titanium alkoxide to form the phenolate. Accordingly, tert-
butyl hypochlorite in combination with Ti(OiPr)4 or the
sterically even more bulky Zr(OtBu)4 was treated with phenol.
In fact, the amount of the para-product especially in the
presence of Zr(OtBu)4 increased showing that steric shielding
of the ortho-positions may be of some importance. However,
the ratio of nearly 1:1 is far away from that observed with the
TiCl(OiPr)3/TBHP or the related TiBr(OiPr)3/TBHP systems
(see Tables 1 and 3) and steric shielding by formation of the
titanium phenolate is not solely responsible for the observed
We thank the Deutsche Forschungsgemeinschaft for financial
support of this work.
Experimental
For general methods and instrumentation see [21].
Preparation of Chloro- and Bromotitanium Triisoprop-
oxides [14]
A solution of Ti(OiPr)4 (2.132 g, 7.5 mmol) in dry CH2Cl2
(10 ml) was treated at 0 °C with TiCl4 (0.474 g, 2.5 mmol) or
TiBr4 (0.919 g, 2.5 mmol) in dry CH2Cl2 (10 ml). The solutions
were then allowed to warm to room temperature, and stirring
was continued for 24 h. The 1 molar solutions can be used for
one month if stored at 4 °C.
Chlorination of Phenols (General Procedure)
A solution of the phenols 1 – 4 (1 mmol) in dry THF (10 ml)
was treated with TiCl(OiPr)3 (1 mmol, 1 mol/l in CH2Cl2).
The solution turned orange and was stirred 30 min and cooled
to –30 °C. A solution of TBHP (0.86 ml, 3 mmol, 3.5 mol/L
in CH2Cl2) was then added dropwise within 5 min. The yellow
mixture was stirred for 20 h at room temperature, quenched
by addition 10% H2SO4 (10 ml), and the phases were sepa-
rated. The aqueous phase was extracted twice with CH2Cl2
(each 5 ml), the combined organic phases washed twice with
10% H2SO4 (each 5 ml), dried (MgSO4), and the solvent was
evaporated at reduced pressure. The crude product was ana-
lyzed by GC (starting temperature 80 °C, heating rate
5 °C/min to 160 °C, then 10 °C/min). The products were puri-
fied by column chromatography (CH2Cl2/n-hexane 10:1) and
characterized by NMR and m.p.; for yields see Table 1; m.p.
5: 41 °C (Lit. [22] 43–44 °C) 7: m.p. 43– 44 °C (Lit. [23]
m.p. 48.5–49 °C); 9: m.p. 61–62 °C (Lit. [23] : m.p. 65–
68 °C).
Table 2 Bromination of the phenols 1–4
Substrate
ortho-Product (%)
para-Product (%)
Dibrominated product (%)
Starting material (%)
phenol (1)
3
–
–
–
88
92
90
86
6
3.5
2
8
3
4.5
8
6
2-methylphenol (2)
3-methylphenol (3)
2-methoxyphenol (4)
Table 3 Selected reagents for selective para-bromination of phenol 1
Reagent
Ratio ortho/para
Dibrominated product (%)
–
Yield para (%)
2,4-diamino-1,3-thiazol hydrotribromide [13]
tetrabutylammonium tribromide [14]
bis(dimethylacetamid) hydrotribromide [15]
4,4-dibrom-3-methylpyrazol-5-one [16]
benzyltrimethylammonium tribromide [17]a)
bromodimethylsulfonium bromide [18]
N-bromsuccinimid/DMF [18]
1 : 3
–
–
83
93
92
94
2.5
3
traces
–
–
–
7.6 : 92.4
8 : 92
3 : 97
–
85
70
80
hexabromocyclopentadiene [19]
–
a) bound on a polymeric matrix
60
J. Prakt. Chem. 1999, 341, No. 1

Para-Selective Chlorination and Bromination of Phenols
____________________________________________________________________________________________PROCEDURE
Table 4 Comparison of the selectivity of hypochlorites in the reaction with phenol 1
Reagent
ortho-product (%)
para-product (%)
dichloro product (%)
sodium hypochlorite
tert-butyl hypochlorite
tert-butyl hypochlorite/Ti(OiPr)4
tert-butyl hypochlorite/Zr(OtBu)4
77
60
53
49
18
38
46
49
5
2
1
2
tert-butyl hydroperoxide; regioselectivity
References
Bromination of Phenols (General Procedure)
A solution of the phenol (1 mmol) in THF (10 ml) was treated
with TiBr(OiPr)3 (1 ml, 1 mol) and stirred 30 min at room
temperature. A solution of TBHP (0.57 ml, 2 mmol, 3.5mol/l
in CH2Cl2) at –40 °C was then added within 5 min. The
cooling bath was removed after 2 h at –40 °C, and stirring
was continued for 30 min. The orange mixture was quenched
by addition of 10% H2SO4 (10 ml), and the aqueous phase
was extracted twice with CH2Cl2 (each 7.5 ml). The combined
organic phases were extracted three times with 5% NaOH
(each 5 ml), the aqueous phase was acidified to pH 2 with
10% H2SO4 and then extracted three times with CH2Cl2 (each
5 ml). The combined organic phases were dried (MgSO4),
and the solvent was evaporated at reduced pressure. The crude
products were analyzed by GC (see Table 3); the pure
bromides were obtained by filtration through a batch of silica
gel and crystallization. 6: (75%) m.p. 62 °C (Lit. [24] m.p.
66.4 °C); 8: (73%) m.p. 34–35 °C (Lit. [25] m.p. 35–36 °C);
10: (78%) m.p. 61 °C (Lit. [18] m.p. 60–61 °C); 11: (80%)
m.p. 58 °C (Lit. [25] m.p. 61–62 °C).
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[20] We thank Prof. E. Pritzkow for drawing our attention to that
possibility.
A solution of the phenol (1 mmol) in CH2Cl2 (10 ml) was
treated at 0 °C with an aqueous solution of sodium hypo-
chlorite (5 ml, 11 mmol). The resulting emulsion was stirred
4 h at room temperature. The organic phase was washed twice
with 10% H2SO4 (5 ml), dried (MgSO4 ), and the solvent was
evaporated at reduced pressure. The crude oily residues were
analyzed by GC (comparison with authentic samples; ratio of
ortho- to para products see Table 4).
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Schulz, Liebigs Ann. Chem. 1994, 1093
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A solution of phenol (1) (1 mmol) in CH2Cl2 (10 ml) was
treated at 0 °C with tert-butyl hypochlorite [26] in CH2Cl2
(2 ml, 2.5 ml, 0.8 mol/L). The mixture was allowed to warm
to room temperature and was stirred for 24 h. The solution
was then extracted three times with 10% NaOH (each 5 ml),
acidified to pH 2 and again extracted three times with CH2Cl2
(each 5 ml). The solvent was evaporated at reduced pressure
and the ortho to para ratio analyzed by GC.
Address for correspondence:
Prof. K. Krohn
Fachbereich Chemie und Chemietechnik
der Univ.-GH Paderborn
Warburger Str. 100
D-33098 Paderborn
Chlorination of Phenol (1) with tert-Butyl Hypochlorite
in Presence of Ti(OiPr)4 or Zr(OtBu)4
The phenols were equilibrated for 30 min at room temperature
in CH2Cl2 (10 ml) with 1 mmol with Ti(OiPr)4 or Zr(OtBu)4.
The reactions were then performed as described above and
the ortho to para ratios analyzed by GC (ratio see Table 4).
FAX: internat. code (0) 5251-60-3245
E-mail: kk@chemie.uni-paderborn.de
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