Competing reactions of secondary alcohols with sodium hypochlorite promoted by phase-transfer catalysis

Article abstract of DOI:10.1021/jo0490651

(Chemical Equation Presented) With aqueous hypochlorite and a phase transfer catalyst, secondary alcohols undergo hitherto unreported free radical reactions that compete with and effectively limit traditional ketone syntheses. Product mixture profiles are determined by reactant ratios, organic cosolvent, and availability of oxygen to the system. Under argon, over half of substrate alcohols, PhCH(OH)R, are converted to benzaldehyde and free radical products through β-scission of intermediate alkyl hypochlorites. Secondary alcohols with R containing three or more carbons also may undergo δ chlorination.

Full text of DOI:10.1021/jo0490651

Competing Reactions of Secondary
Alcohols with Sodium Hypochlorite
Promoted by Phase-Transfer Catalysis
SCHEME 1
Zack R. Bright, Cedric R. Luyeye,
Angela Ste. Marie Morton, Marina Sedenko,
Robert G. Landolt,* Matthew J. Bronzi,
Katherine M. Bohovic, M. W. Alex Gonser,
Theodore E. Lapainis, and William H. Hendrickson
Department of Chemistry, Texas Wesleyan University,
Fort Worth, Texas 76105, and Department of Chemistry,
University of Dallas, Irving, Texas 75060
rlandolt@txwes.edu
Received June 3, 2004
pochlorite, with research indicating free radical pathways
2
to be operable and dichlorine monoxide (Cl O) suggested
5
as a reactive intermediate. With PTC under biphasic
conditions, bromo- and iodoaromatics undergo substitu-
tion reactions with aqueous hypochlorite, yielding chlo-
rinated aromatics.6
Tertiary alcohols, when treated with aqueous hy-
pochlorite under phase transfer catalytic conditions, are
subject to radical chain decomposition of intermediate
7
alkyl hypochlorites. Products are formed by â-scission
of an intermediate alkoxy radical, leading to a ketone and
chloroalkane, as shown in Scheme 1. Similar to most
phase transfer reactions with hypochlorite, tertiary
alcohol reactions are facilitated by the aqueous phase
being maintained at pH 8-9. Radical pathways are
inhibited by oxygen.
Significantly, hitherto unrecognized â-scission and
other free radical reactions may compete under condi-
tions routinely utilized for two-phase oxidations of sec-
ondary alcohols with aqueous hypochlorite. The degree
to which these processes successfully compete will reduce
the efficiency of alcohol to ketone syntheses, and the
competing processes themselves provide insight into the
role of solvents, pH, PTC, and structural features. The
present paper identifies a series of substrates subject to
this competition and identifies control parameters that
may be employed to impact yields from competing
pathways.8
With aqueous hypochlorite and a phase transfer catalyst,
secondary alcohols undergo hitherto unreported free radical
reactions that compete with and effectively limit traditional
ketone syntheses. Product mixture profiles are determined
by reactant ratios, organic cosolvent, and availability of
oxygen to the system. Under argon, over half of substrate
alcohols, PhCH(OH)R, are converted to benzaldehyde and
free radical products through â-scission of intermediate alkyl
hypochlorites. Secondary alcohols with R containing three
or more carbons also may undergo δ chlorination.
Aqueous sodium hypochlorite has been cited widely as
an effective oxidant in the transformation of secondary
alcohols to ketones as well as for a range of other
1
reactions. Under basic conditions, the utilization of a
phase transfer catalyst (PTC) such as tetra-n-butylam-
monium hydrogen sulfate (TBAHS) facilitates secondary
alcohol to ketone transformation in two phase systems,
with ethyl acetate exhibiting better results than dichlo-
At ambient temperatures, using dichloromethane,
TBAHS, and aqueous hypochlorite at pH ∼9, secondary
alcohols PhCH(OH)R (1) produced substantial benzalde-
hyde (2) as well as the expected ketones (3, Table 1).
Benzaldehyde yields reflect lower limits of substrates
undergoing â-scission, since under the same conditions
the aldehyde is subject to conversion to benzoic acid.
2
romethane as the organic phase. Kinetic studies, con-
3
ducted in air, of substituted 1-phenylethanols as well
4
as benzyl alcohols have shown that such oxidations are
facilitated by electron withdrawing substituents and
point toward an ionic reaction mechanism.
Phase transfer catalysts also are known to enable two-
phase chlorinations of hydrocarbons by aqueous hy-
(
5) (a) Fonouni, H. E.; Krishnan, S.; Kuhn, D. G.; Hamilton, G. A.
*
Address correspondence to this author at Texas Wesleyan Uni-
J. Am. Chem. Soc. 1983, 105, 7672-7676. (b) Dneprovskii, A. S.;
Eliseenkov, E. V. Russ. J. Org. Chem. 1994, 30 (2), 235-240.
(6) (a) O’Connor, K. J.; Burrows, C. J. J. Org. Chem. 1991, 56, 1344-
1346. (b) Arnold, J. T.; Bayraktaroglu, T. O.; Brown, R. G.; Heiermann,
C. R.; Magnus, W. W.; Ohman, A. B.; Landolt, R. G. J. Org. Chem.
1992, 57, 391-393. (c) Bayraktaroglu, T. O.; Gooding, M. A.; Khatib,
S. F.; Lee, H.; Kourouma, M.; Landolt, R. G. J. Org. Chem. 1993, 58,
1264-1265.
versity.
(
1) Skarzewski, J.; Siedlecka, R. Org. Prep. Proced. Int. 1992, 24,
6
23-647.
(
2) (a) Lee, G. A.; Freedman, H. H. Isr. J. Chem. 1985, 26, 229-
2
7
34. (b) Mirafzal, G. A.; Lozeva, A. M. Tetrahedron Lett. 1998, 39,
263-7266.
(
3) Sakai, A.; Hendrickson, D.G.; Hendrickson, W. H. Tetrahedron
Lett. 2000, 41, 2759-2763.
4) Bradley, L. M.; Lesica, J. M.; Albertson, K. B. React. Kinet. Catal.
Lett. 1997, 62, 3-7.
(7) Dailey, J. I.; Hays, R. S.; Lee, H.; Mitchell, R. M.; Ries, J. J.;
Landolt, R. G.; Hussmann; H. H.; Lockridge, J. B.; Hendrickson, W.
H. J. Org. Chem. 2000, 65, 2568-2571.
(
10.1021/jo0490651 CCC: $30.25 © 2005 American Chemical Society
684
J. Org. Chem. 2005, 70, 684-687
Published on Web 12/18/2004

TABLE 1. Secondary Alcohol-Hypochlorite/PTC
TABLE 2. Impact of Solvent and Atmosphere on
Reactions of 1-Phenyl-1-propanol
Reactions
time, benzaldehyde, propiophenone,
solvent
CH Cl
atmosphere
air
min
%
%
2
2
15
10-22
trace
19-30
trace
0
54-56
47-58
44-51
39-48
84-90
19-37
1, R
residual 1, %
2, %
3, %
time, min
3
0
ethyla
propyl
butyla
14-16
8-10
5-13
5-15
0-13
trace
50-73 12-14
70-85 5-10
50-60 15-30
70-85 trace
42-61 23-36
40-60
60-80
40-60
30
Ar
15
a
30
30
ethyl acetate
air
Ar
a,b
10-30
38-44
2
1
1
,2-dimethylethyl
c,d
-methylethyl
-methylpropyl
120
a,b,d
65-70
6
30
provides results of comparative reactions of 1-phenyl-1-
propanol (1) wherein the levels of reactants and PTC
were constant at pH 8.5-9.5, but the organic solvent and
atmosphere were varied. Results showed clearly that
benzaldehyde formation/â-scission was favored by an
inert atmosphere. When an air atmosphere was employed
with either ethyl acetate or dichloromethane, ketone
formation was favored, but more aldehyde formed early,
along with limited ketone, when exposure to air was
minimized in either of these solvents.
a
-3
Except as noted, 1.3 × 10 mol of substrate and Ph-Cl in 40-
5
1
0 mL of CH2Cl2; aq 6% NaOCl, in 2-10 mL increments (1.6 ×
-2 -5
0
mol); TBAHS, 0.010-0.013 g (3 × 10 mol); under argon;
b
pH adjusted to 8.5-9 with aq NaOH or HCl. One portion of 40
-2
c
-3
mL aq NaOCl (3.2 × 10 mol) employed. Substrate (6.15 × 10
-
3
mol) and Ph-Cl (3.07 × 10 mol) in 15 mL of CH2Cl2 stirred with
-
2
4
1
0 mL of aq NaOCl (3.2 × 10 mol) containing NaHCO3 (8.0 ×
-3 -5 d
0
mol) and TBASH (0.029 g, 3.6 × 10 mol) at pH 9.0. Air
atmosphere.
Simple flushing of reaction mixtures with argon prior
to and during reactions proved effective in enhancing
conversion of 1-phenyl-1-propanol to benzaldehyde. Two
experimental approaches lead to maximization of ben-
zaldehyde production: (A) addition of hypochlorite to
-phenyl-1-propanol in increments (Table 1) and (B)
treatment of relatively high concentrations (2.0 M) of
-methyl-1-phenyl-1-propanol with 20% excess bleach
The ability of ethyl acetate to facilitate higher ketone
yields relative to reactions in dichloromethane, previously
9
2a
attributed to formation of a reactive intermediate, is
likely derived from the ester’s more aerated state as the
top layer in the two-phase system, enhancing its capacity
to supply radical-inhibiting oxygen to the system. With
ethyl acetate in air, hypochlorite treatment of 1-phenyl-
1
2
2
-propanol produced 1-phenyl-2-propanone in modest
under either air or argon, yielding 67-97% benzaldehyde
and only 2-4% ketone.
amounts (20-50%) and no benzyl chloride in 1 h. In
contrast, using argon, â-scission resulted in greater than
Simple R-Cl cleavage products projected to result from
â-scission of phenyl alkyl hypochlorite were indistin-
guishable from solvents by GC/GCMS under conditions
employed for these reactions. However, dichlorinated
cleavage byproducts were detected (1,3-dichloropropane
from 1-phenyl-1-butanol and 1,3-dichlorobutane from
6
0-78% benzyl chloride production in 30 min, along with
a substantial amount of chloroethyl acetate.
The occurrence of â-scission products along with ke-
tones in these reactions suggests that alkyl hypochlorites
are intermediates in the reactions of secondary alcohols
as well as for tertiary alcohols. Additional evidence for
alkyl hypochlorite intermediates is provided by the
reactions of secondary aliphatic alcohols having side
chains of three or more carbon atoms. Alkyl hypochlorites
formed from such alcohols undergo radical chain decom-
1
-phenyl-1-pentanol and 2-methyl-1-phenyl-1-butanol),
arising from δ-hydrogen abstraction-promoted chlorina-
tion (see below) followed by a second chlorination result-
ing after â-scission. Moreover, in air, hypochlorite/PTC
reactions of 1-phenyl-2-propanol in dichloromethane
produced 54-60% benzyl chloride, the expected chlori-
nated â-scission product, and less than 15% ketone
11
positions to produce δ-chloro alcohols (Scheme 3). Under
SCHEME 3
1
0
(Scheme 2).
SCHEME 2
Key reaction variables impacting â-scission include
reactant/PTC concentration ratios, solvent, pH, and
employment of an inert vs an air atmosphere. When
reactions were maintained at pH >11, no â-scission was
detected; substrates essentially were inert. Table 2
(8) Preliminary reports: (a) Angela Ste. Marie, DFW/ACS Section
Meeting-In-Miniature, April, 1994; (b) Marina Sedenko, DFW/ACS
Section Meeting-In-Miniature, April 2000; M. W. Alex Gonser, National
ACS Meeting, New Orleans, April 2003.
conditions of excess hypochlorite, the δ-chloro alcohols
would be oxidized to δ-chloroketones. In addition to
(
9) In attempts to enhance â-scission by rigorously excluding air
through freeze-thaw under vacuum and working under a blanket of
nitrogen, the conversion level to benzaldehyde and to ketone averaged
(11) (a) Walling, C.; Bristol, D. J. Org. Chem. 1972, 37, 3514-3516.
(b) Nedelec, J.Y.; Gruselle, A.; Triki, A.; LeFort, D. Tetrahedron 1977,
33, 39-44. (c) Cekovic, Z.; Djokic, G. Tetrahedron 1981, 37, 4263-
4268.
4
5% and 26% yields, respectively.
(
10) The â-scission product acetaldehyde (ethanal) would not have
been detected by the GC conditions employed.
J. Org. Chem, Vol. 70, No. 2, 2005 685

-
5
FIGURE 2. Reaction of 10 mL of 0.40 M 1-phenylethanol in
-5
FIGURE 1. Addition of 5.0 × 10 mol PTC to a reaction
mixture of 25 mL of 0.20 M 1-phenyl-1-ethanol in CH Cl with
0 mL of bleach at pH 9 after 448 min: [1-phenyl-1-ethanol]
CDCl
mol PTC: [1-phenyl-1-ethanol]gc (4), [1-phenyl-1-ethanol]NMR
2), [1-phenylethyl hypochlorite]tit (O), [1-phenylethyl hy-
pochlorite]NMR (b), [acetophenone]gc (]), [acetophenone]nmr ([),
3
with 20 mL of bleach at pH 9.0 catalyzed by 1.3 × 10
2
2
2
(
(
2), [1-phenylethyl hypochlorite] (b), [acetophenone] ([), total
f).
(
[
total]gc7(g), [total]NMR (f). See the Experimental Section for
details.
dichlorinated cleavage products from 1-phenyl-1-butanol,
-phenyl-1-pentanol, and 2-methyl-1-phenylbutanol, δ-hy-
drogen abstractions were observed for reactions of both
-nonanol and 2-octanol. For example, in reactions of
-octanol in dichloromethane in air, both 2-octanone (42-
4%) and 5-chloro-2-octanone (18-26%) were produced.
1
In contrast, acidified aqueous potassium iodide pretreat-
ment, prior to GC and GCMS analysis, induced reduction
of secondary alkyl hypochlorites back to the starting
alcohol.
5
2
7
In summary, PTC-catalyzed reactions of secondary
alcohols with sodium hypochlorite form alkyl hypochlorite
intermediates. These intermediates may either eliminate
HCl to form ketones or undergo radical chain decomposi-
tions typical of alkyl hypochlorites to give â-scission or
δ-hydrogen abstraction. Oxygen inhibits the chain de-
composition and favors ketone formation, while the chain
decomposition is enhanced by inert atmosphere or by
higher alcohol/oxidant ratios. â-Scission is more likely
when the alkyl radical that is split off is benzyl or more
highly substituted, while δ-hydrogen abstraction is likely
to occur for alcohols with a side chain of more than three
carbon atoms.
Reactions of aliphatic alcohols showed the same effects
of solvent and atmosphere as seen with aromatic alcohols,
e.g., higher amounts of radical products in dichlo-
romethane compared to ethyl acetate and under an argon
atmosphere compared to air.
Additional evidence for alkyl hypochlorite involvement
in biphasic reactions of secondary alcohols was derived
when aqueous hypochlorite at pH 8-9 was mixed with
dichloromethane solutions of secondary alcohols with no
7
PTC present. Similar to tertiary alcohols, titrimetric
analysis showed that a substantial portion of substrate
was converted to the secondary alkyl hypochlorite that
proved to be quite stable under ambient conditions,
especially in dichloromethane, until addition of the
phase-transfer catalyst (Figure 1). It is projected that
PTC-mediated participation by intermediates such as
chlorine monoxide and its precursor, hypochlorite ion,
effects decomposition of the alkyl hypochlorite.
Experimental Section
Materials and General Procedures. All organic compounds
employed were secured from commercial suppliers. Aqueous
hypochlorite, unless specified otherwise, was obtained in the
form of commercial Ultra Clorox, “6.0%”. In all cases the phase
transfer catalyst (PTC) used was tetrabutylammonium hydrogen
sulfate (TBAHS). Gas chromatographic (GC) instruments were
equipped with capillary columns and flame ionization detectors.
Except where noted, the pH values of aqueous layers of biphasic
systems were set and maintained at desired levels by the
addition of aqueous NaOH or HCl, and the pH was monitored
by pH meters. Progress of reactions was followed by GC, using
chlorobenzene or tert-butylbenzene as an internal standard. All
reactions were conducted at ambient temperatures.
Potassium iodide (KI) treatments consisted of mixing reaction
aliquots with 5% aqueous KI acidified with concentrated HCl.
The presence of active oxidants was clearly indicated by dark
pink to pinkish brown color development in both layers, con-
centrated in the organic phase.
Reactions of 1-Phenyl-2-propanol. Conditions given in
footnotes a and b of Table 1 were employed, except that 100 mg
of TBAHS was used.
To demonstrate further that alkyl hypochlorites are
reactive intermediates, a reaction of 1-phenyl-1-ethanol
1
with bleach in CDCl
3
was monitored by H NMR, GC,
and iodometric titration. The results given in Figure 2
show good agreement between alkyl hypochlorite mea-
1
sured by titration and H NMR. Also, the similarity of
the concentrations of alcohol and ketone determined by
1
H NMR and GC indicates that KI treatment of the
reaction samples provides reliable GC analysis.
Reactions of secondary alcohols with aqueous hy-
pochlorite shared a significant characteristic with tertiary
7
alcohols. With no catalyst present, solutions of the
secondary alkyl hypochlorite from 1-phenyl-1-propanol
underwent thermally promoted â-scission in the inlet and
on columns during gas chromatographic analysis: 38-
4
1
0% to benzaldehyde as well as oxidation, 13% to
-phenyl-1-propanone, with ∼30% substrate remaining.
Comparative Reactions of 1-Phenyl-1-propanol (Table
-
2
2). Aqueous hypochlorite (100 mL, 6.00 g, 8.1 × 10 mol)
686 J. Org. Chem., Vol. 70, No. 2, 2005

-
4
containing 0.200 g (5.8 × 10 mol) of PTC was adjusted to pH
buffered with 0.2 M NaHCO
aliquots of the organic layer were removed, diluted to 1.0 mL
with CDCl , washed with D O, dried over MgSO , and analyzed
by NMR. After NMR analysis, the aliquot was divided. Alkyl
hypochlorite concentration in one part was determined by
iodometric titration; the other part was quenched with KI and
analyzed by GC. Since treatment of KI converts alkyl hypochlo-
rite to alcohol, the [alcohol]gc points in Figure 2 were calculated
by subtracting the alkyl hypochlorite concentration from the
alcohol concentration after KI treatment.
3
at pH 9.0. At intervals, 0.20-mL
8
.5-9.5 that was maintained with concentrated HCl and the
solution was stirred magnetically with the substrate alcohol
3
2
4
-
3
(
1
0.700 g, 5.14 × 10 mol) and chlorobenzene(0.579 g, 5.13 ×
-3
0
mol) dissolved in 50 mL of organic cosolvent. Reactions
under Ar were conducted in a sidearm flask fitted for gas inlet
and exit, with each layer separately sparged with Ar for 20 min
prior to and during mixing. Aliquots were split and analyzed
with and without KI treatment prior to GC analysis. The identity
of all products was confirmed by GCMS.
Reaction of 2.0 M 2-Methyl-1-phenyl-1-propanol in
Reaction of 2-Octanol. A 20.0 mL dichloromethane solution
-
2
Dichloromethane. Sodium bicarbonate (3.78 g, 4.50 × 10
-3
-4
of 2-octanol (0.264 g, 2.04 × 10 mol), PTC (0.034 g, 1.0 × 10
mol) was added to 45 mL of aqueous hypochlorite (2.70 g, 3.6 ×
-3
mol), and chlorobenzene (0.118 g, 1.05 × 10 mol) was stirred
-2
-5
1
0
mol) containing 0.025 g (7.4 × 10 mol) of PTC. The pH of
with 20 mL of bleach buffered at pH 9 with 0.2 M NaHCO
Aliquots were quenched with KI and analyzed by GC. The
-chloro-2-octanol was identified by GCMS and by the compari-
3
.
this solution was 8.4. The 2-methyl-1-phenyl-1-propanol (4.55
-2
-4-
g, 3.03 × 10 mol) and chlorobenzene (0.338 g, 3.01 × 10 mol)
in 15 mL of dichloromethane were added to the magnetically
stirred bleach solution. After 15 min, an aliquot was taken and
quenched with KI. Analysis by GC showed 3% remaining alcohol,
5
son of retention times of products formed in the decomposition
of 1-methylheptyl hypochlorite by iron(II) sulfate according to
11c
the procedure of Cekovic and Djokic. Oxidation of the 5-chloro-
-octanol solution with bleach in ethyl acetate gave a solution
2
% isobutyrophenone, and 67% benzaldehyde. Reactions under
2
argon were done with the bleach solution in a three-necked
round-bottom flask equipped with a gas inlet connected to a
Firestone valve and an addition funnel containing the dichlo-
romethane solution. Both solutions were sparged with Ar for
2b
of 5-chloro-2-octanone. Retention times of chlorination products
in reactions of 5-nonanol were assigned in a similar manner.
2
0 min prior to mixing.
Acknowledgment. All phases of this work were
supported by Chemistry Departmental Research Grants
from the Robert A. Welch Foundation (AZ0003, Texas
Wesleyan, and BA0015, University of Dallas) and by the
O’Hara Chemical Sciences Institute of the University
of Dallas. The effort was made possible in part by
instrumentation supplied by the National Science Foun-
dation under an Instrumentation and Laboratory Im-
provement Grant to Texas Wesleyan (USE-9250391).
1H NMR Analysis of 1-Phenyl-1-ethanol Reaction (Fig-
ure 2). The chemical shifts of the methyl hydrogens of 1-phenyl-
1
-ethanol (d, 1.44 ppm) and 1-phenylethyl hypochlorite (d, 1.54
ppm) overlapped on the 60 MHz instrument to yield a triplet
centered at 1.49 ppm. However, the concentrations of the alcohol
and hypochlorite could be determined by integration of the
resolved outer peaks at 1.39 and 1.59 ppm, using tert-butylben-
zene (1.29 ppm) as an internal standard. The 1-phenyl-1-ethanol
-
5
(
0.494 g, 4.04 mmol), PTC (0.0044 g, 1.3 × 10 mol), and tert-
-3
butylbenzene (0.137 g, 1.02 × 10 mol) were dissolved in 10
mL of CDCl . The solution was stirred with 20 mL of bleach
3
JO0490651
J. Org. Chem, Vol. 70, No. 2, 2005 687