Hypochlorite-induced ipso-substitution reactions of aromatic alcohols and related compounds

Article abstract of DOI:10.1055/s-0030-1261178

Organic solvent extracts derived from aqueous hypochlorite/phase-transfer catalyst solutions induce rapid and efficient ipso substitution of aromatic carbinols and related substrates. The key parameter impacting rates and yields is pH of the original hypochlorite/phase-transfer catalyst component. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261178

LETTER
2069
Hypochlorite-Induced Ipso-Substitution Reactions of Aromatic Alcohols and
Related Compounds
H
ypochlorite-Indu
e
c
ed Ipso-Su
c
bstitutionR
t
eactio
o
ns of
A
roma
r
tic
A
lcohols V. Carrillo,a Angelica Y. Rodriguez,a Robert G. Landolt,*a William H. Hendricksonb
a
Department of Chemistry, Texas Wesleyan University, Fort Worth, TX 76105, USA
Fax +1(871)5314275; E-mail: rlandolt@txwes.edu
b
Department of Chemistry, University of Dallas, Irving, TX 75062, USA
Received 13 May 2011
as conventional oxidation to ketones and b-scission reac-
tions occur competitively with 2° alcohols.6j,k The catalyst
does more than bring ionic material into the organic
phase. Specifically, b-scission conversion of the ROCl
from 2-phenyl-2-propanol and oxidation of the ROCl
from 1-phenylethanol to acetophenone were delayed until
the PTC was added to a two-phase alcohol–hypochlorite
mixture.
Abstract: Organic solvent extracts derived from aqueous hy-
pochlorite/phase-transfer catalyst solutions induce rapid and effi-
cient ipso substitution of aromatic carbinols and related substrates.
The key parameter impacting rates and yields is pH of the original
hypochlorite/phase-transfer catalyst component.
Key words: alcohols, electrophilic aromatic substitution, haloge-
nation, phase-transfer catalysis, solvent effects
In the present work, electrophilic ipso-substitution
reactions12 initially were observed to compete with oxida-
tion in dual phase, OCl–/PTC reactions of 4-methoxyben-
zyl alcohol (1a), facilitated by the electron-donating effect
of the methoxy group.13 Significantly, this substituent has
been found to have a deactivating effect on the OCl–/PTC
oxidation of benzyl alcohols.14 Reaction of 1a with aque-
ous NaOCl at pH 8–9, PTC and dichloromethane resulted
in ca. 30–40% yield of 4-methoxychlorobenzene [4-chlo-
roanisole (2a)] through ipso substitution in addition to 4-
methoxybenzaldehyde [anisaldehyde (3)], the expected
oxidation product.
For oxidation,1 chlorination,2 disinfection,3 or chemical
warfare agent decontamination,4 the reagent of choice
could be aqueous hypochlorite (OCl–). In addition to serv-
ing as a halogenating/oxidizing agent, hypochlorite is the
conjugate base of a weak acid, HOCl (pKa = 7.5).5 When
delivered as a basic aqueous solution, it is immiscible with
many organics, and reactions with the latter readily may
be achieved using phase-transfer catalysts (PTC). Howev-
er, as well as the reagent, water may react with organic
substrates or reaction intermediates either by competing
or consecutive pathways, giving rise to secondary prod-
ucts.
In contrast, use of a nontraditional, homogeneous
‘monophasic’, PTC-facilitated system was found to con-
sume the starting material much more rapidly than in the
two-phase approach, to yield 2a as the predominant prod-
uct (Scheme 1).
Reactivity and selectivity have been managed by adjust-
ing the pH value of aqueous solutions in hypochlorite-in-
duced reactions of polynuclear aromatics and chloroform
precursors, oxidative decarboxylations, competing oxida-
tion and b-scission of alcohols, and ipso substitutions of
aromatic halides.6 These reactions generally proceed
more rapidly at pH 8–9 than at pH >11, except for the ha-
loform reaction, whose heightened reactivity at high pH
has been attributed to the role of slow formation of precur-
sor enolate.7 When the inverse PTC catalyst b-cyclodex-
trin was employed for haloform reactions with aqueous
hypochlorite to achieve miscibility with methyl ketones,8
no attempt was made to adjust or monitor the pH value.
Other efforts involving special technologies specifically
have used hypochlorite at approximately pH 9 for rutheni-
um-catalyzed oxidation of ethers and alcohols,9 polymer-
immobilized TEMPO for aerobic oxidation of alcohols,10
and selective oxidation of benzyl alcohols in ionic liq-
uids.11
CH2OH
Cl
CHO
monophasic PTC/OCl
CH2Cl2 extract
+
OMe
OMe
OMe
2a
1a
3
Scheme 1
Effective ipso substitutions were initiated by mixing the
phase-transfer reagent, tetra-n-butylammonium bisulfate
with aqueous hypochlorite, and adjusting the pH value to
8–9. A portion of dichloromethane was added, the dual
phase mixture was shaken, and the organic layer was
physically separated to provide a reactive, ipso-chlorinat-
ing solution. When this extract was added to a separate
dichloromethane aliquot containing 1a, GC analysis
revealed rapid production up to 80% of 2a, with only
modest formation of byproducts 3 and 2,4-dichloro-
methoxybenzene. Alternately, dual-phase reactions with
Under inert atmosphere at optimum pH, b-scission results
from hypochlorite/PTC reactions with 3° alcohols, where-
SYNLETT 2011, No. 14, pp 2069–2071
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261178; Art ID: S03711ST
© Georg Thieme Verlag Stuttgart · New York

2070
H. V. Carrillo et al.
LETTER
bleach layers pH > 11, with or without PTC, resulted in HOCl, Cl2O, or a PTC complex of HOCl and its conjugate
exclusive oxidation to aldehyde 3.
base. With suitably activated aromatics, research has re-
vealed that, for substrates lacking para-ipso leaving
groups, electrophilic substitution occurred under the mild,
monophasic conditions described above. Methoxyben-
zene (anisole), or 1,3,5-trimethylbenzene (mesitylene),
yielded relatively clean, ring-chlorination products, con-
clusively identified by GC-MS to be 2a and 2-chloro-
1,3,5-trimethylbenzene, respectively. Reactivity of these
substrates also depended on pH of PTC solutions in aque-
ous hypochlorite used to provide CH2Cl2 extracts. This
opens the prospect that monophasic chlorination may be
feasible for a variety of substances that respond to control
parameters in degree yet to be determined.
In less than 5 minutes, ‘monophasic’ reaction of 1a with
an extract derived from pH 8–9 hypochlorite induced the
ipso substitution at ambient temperatures. Subsequently,
similar monophasic treatment showed 75–79% ipso-prod-
uct 2a from 4-methoxybenzoic acid [anisic acid (4)] with-
in the same time frame; however, the aldehyde 3 was
relatively inert to these conditions (Scheme 2).
2a
CO2H
1a
OMe
Table 1 Hypochlorite-Induced Ipso-Substitutions of 1-X-4-Y-ben-
3
zenes
4
Scheme 2
1
Y
X
Yield of 2a Yield of
(%) ketone (%)
Evidence that ipso-product 2a was derived directly from
1a also came from isolation of formaldehyde as the dime-
done derivative, (1,3,1¢,3¢-tetraketo-5,5,5¢,5¢-tetramethyl-
4,4¢-dicyclohexylmethane)15 from aqueous extracts of
dichloromethane reaction solutions.
1b
1c
1d
1e
1f
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OPh
CH(OH)Me
CH(OH)Et
CH(OH)Ph
53–73
2–20
6–10
67–92
73–75b
1–10
CH(OH)(4-MeOC6H4) 69–70c
21–23
The ipso-enhancing effect of the methoxy and other elec-
tron-donating substituents also was evidenced in
monophasic reactions of methoxy-substituted secondary
and tertiary aromatic alcohols 1b–f and carboxylic acid
and acid derivatives 1g–j, as indicated as 1-X-4-Y-ben-
zenes in Table 1. Ketones expected from secondary alco-
hol oxidations were detected as minor products.
C(OH)Me2
C(=O)Cl
34–47
70–80
48
1g
1h
1i
C(=O)O(=O)(4-Ans)a
CO2H
100
95
1j
t-Bu
C(C=O)Cl
Other substrates thought to be plausible candidates for
ipso substitution were subjected to reaction under condi-
tions shown in Table 1. Those with electron-donating
substituents, including 4-acetoxybenzoic acid, 4-methox-
ybenzamide, 4-methoxybromobenzene, 4-tert-butylben-
zoic acid, 2-methoxybenzyl alcohol, 4-methoxy-
benzylamine, methoxytrityl alcohol, and 4-methylben-
zoyl chloride showed trace production of ipso products to
GC analysis. Benzoic acid, benzoyl chloride, and 2-phe-
nyl-2-propanol were inert. These reactions typically ex-
hibited poor mass balances, involving either substrates
and/or potential non-ipso products not characterizable by
GC. Further mechanistic studies are in progress
a Anisic anhydride; co-products (fate of X).
b Recovered benzaldehyde (from leaving group): 71–75%.
c Recovered 4-methoxybenzaldehyde (from leaving group): 57–65%;
pH 8–9 of bleach/PTC aqueous layer.
General Procedure
Tetra-n-butylammonium bisulfate (0.6082 g, 1.79·10–3 mol) and
NaCl (10 g) were dissolved in 6% aq hypochlorite (50 mL, Clorox
bleach, ca. 4·10–2 mol, pH 11.45). The pH value was adjusted with
6 M HCl to 8–9. This solution and CH2Cl2 (20 mL) were shaken
thoroughly using a separatory funnel. The CH2Cl2 extract layer was
added to a CH2Cl2 solution (20 mL) containing substrate alcohol
(2.6·10–3 mol) and chlorobenzene (2.6·10–3 mol, internal standard)
previously analyzed by capillary gas chromatography (GC) to es-
tablish a starting material concentration. Progress of reactions was
followed by GC and GC-MS. All reactions were conducted at am-
bient temperatures. Best results were obtained using distilled
CH2Cl2.
Heightened reactivity near pH 9 in biphasic systems with
PTC has lead others to propose either the intermediacy of
chlorine monoxide (Cl2O)1,2 or enhanced efficiency of co-
extraction of hypochlorous acid with hypochlorite by cat-
alyst at bleach pH near the pKa of HOCl.16 b-Scission
products and other evidence from both secondary- and ter-
tiary-alcohol reactions with hypochlorite are indicative of
the active involvement of alkyl hypochlorites, ROCl, as
intermediates in these processes.17
Acknowledgment
Research described herein was supported by Chemistry Departmen-
tal Grants from the Welch Foundation to Texas Wesleyan Universi-
ty (AZ-003), to the University of Dallas (BA-0015), and by the
American Chemical Society’s Project Seed. The data in Table 1
were obtained by Welch summer research participants, Michael
We suggest that the monophasic processes occurred via
electrophilic aromatic substitution involving arenium ions
resulting from attack potentially by any of several chlori-
nating agents.18 The latter include but are not limited to
Synlett 2011, No. 14, 2069–2071 © Thieme Stuttgart · New York

LETTER
Hypochlorite-Induced Ipso-Substitution Reactions of Aromatic Alcohols
2071
McDaniel, Jose Melendes, Alexis Perez, Katheryn Davis, and Seed
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