SODIUM HYPOCHLORITE 1
at this pH to effect oxidation reactions in biphasic media.15 In
Sodium Hypochlorite1
general, tetraalkylammonium salts have been the phase-transfer
catalysts of choice for such applications. Below pH 11, the equi-
NaOCl
librium amount of HOCl becomes significant,6a and this form
of positive chlorine is soluble in polar organic solvents such as
CH2Cl2. No phase-transfer catalyst is necessary to effect oxida-
[7681-52-9] ClNaO (MW 74.44)
tion of substrates or catalysts dissolved in the organic phase of
InChI = 1/ClO.Na/c1-2;/q-1;+1
biphasic reactions in the pH range 10 11.6a Below pH 10, molec-
InChIKey = SUKJFIGYRHOWBL-UHFFFAOYAD
ular chlorine becomes a significant component of aqueous bleach
(versatile and easily handled oxidizing agent;1 can oxidize solutions, and the reactivity of these solutions can be attributed to
alcohols,2 aldehydes,3 electron deficient alkenes,4 amines,5 and that of Cl2.1b
transition metal catalysts;6 reagent for N-chlorination,7 oxidative
coupling,8 and degradation reactions9) ClO + Cl + H2OCl2 + 2 OH (1)
Physical Data: most commonly used in aqueous solution; NaOCl
ć%
·5H2O: mp 18 C.
ClO + H2O HOCl + OH (2)
ć%
Solubility: pentahydrate: 293 g L-1 in H2O(0 C).
Form Supplied in: commercially available as aqueous solutions
with 5.25 12.5% available oxidant (w/v) (0.74 1.75 M). Con-
Oxidation of Alcohols. Oxidation of alcohols by NaOCl can
centration is expressed in % available chlorine, since half of
be effected under a variety of conditions, and useful yields and
the chlorine in bleach is present as NaCl. The pH of commer-
selectivities are attainable for conversion of primary alcohols
cial bleach is typically 11 12.5, and it may be adjusted and
to aldehydes or carboxylic acids, or of secondary alcohols to
buffered.6a
ketones. The advantages of NaOCl oxidations over methods that
Analysis of Reagent Purity: active oxidant may be assayed by
employ stoichiometric CrVI include simplified waste disposal and
iodometric10 or potentiometric11 titration.
lower toxicity and cost. The earliest application of NaOCl as
Preparative Methods: solutions may be generated in situ by pass-
a practical synthetic reagent for alcohol oxidation involved its
ing Chlorine gas through aq Sodium Hydroxide solution,12 or
use in a two-phase system with a phase-transfer catalyst,16 or in
electrochemically.13
association with Ruthenium(IV) Oxide.17 More recently, two
Purification: commercial solutions are generally used without
improved methods for bleach-mediated oxidation of alcohols have
purification.
been developed, one of which employs acetic acid as solvent
Handling, Storage, and Precautions: higher concentration
in a monophasic system,18 and the other uses catalytic amounts
sodium hypochlorite (12.5%), sometimes referred to as  swim-
of 2,2,6,6-Tetramethylpiperidin-1-oxyl (TEMPO) in a buffered
ming pool chlorine, tends to decrease in concentration by 20%
biphasic medium.2b These variants are highly complementary
per month upon storage and therefore should be titrated prior
and can offer significant advantages over alternative methods for
to use.1b The concentration of oxidant in household bleach
alcohol oxidation.
(5.25%) tends to remain constant upon prolonged storage; titra-
R Secondary alcohols are cleanly oxidized to ketones with NaOCl
tion is generally not necessary with brand names (e.g. Clorox©).
in acetic acid in the absence of added catalyst (eq 3).18 Either
Solid NaOCl is explosive as the pentahydrate or the anhydride,
 swimming pool chlorine or household laundry bleach can be
and therefore it is very rarely employed in those forms. Aque-
used with similar success.19 Excess hypochlorite is quenched with
ous solutions are very stable. Bleach is a household item, and it
sodium bisulfite, and essentially pure ketone is obtained simply
is quite easy and safe to handle. Still, it is a strong oxidant, and
by extraction of the product into dichloromethane or ether.
precaution should be taken to avoid prolonged skin exposure or
inhalation.14 May react violently with NH3.
AcOH
OH O
NaOCl
(3)
96%
Original Commentary
Jennifer M. Galvin
Under these conditions, secondary alcohols can be oxidized in
University of Illinois, Urbana, IL, USA
the presence of primary alcohols with essentially absolute selec-
Eric N. Jacobsen
tivity (eq 4).20 No epimerization is observed in the oxidation of
Harvard University, Cambridge, MA, USA
alcohols bearing ²-stereocenters (eq 5). Kinetic studies have led
to the proposal that molecular chlorine is the active oxidant under
Composition of Aqueous Solution as a Function of pH. The
conditions of low pH such as those employed for these reactions.21
equilibrium composition of aqueous solutions of NaOCl is pH-
dependent (eqs 1 and 2), and so pH control can be a critical
consideration in many oxidation and chlorination reactions. Un- OH O
AcOH
der strongly alkaline conditions (pH > 12), OCl- is the predom-
NaOCl
OH OH
inant form of positive chlorine. Because hypochlorite ion is in- (4)
90%
soluble in organic solvents, phase transfer catalysts are needed
Avoid Skin Contact with All Reagents
2 SODIUM HYPOCHLORITE
HO NaOCl
HO
O
OH
(1.1 equiv)
+ CHO
AcOH CHO
NaOCl TEMPO, KBr 8
8
(5)
OH
97% crude
10%
68%
83% isolated
(10)
OH
NaOCl
HO 8
O
O O
(2.2 equiv)
CHO + CO2H
TEMPO, KBr 8 8
Primary and secondary alcohols can be oxidized by oxoam-
69% 14%
monium salts;22 hypochlorite oxidation of the reduced nitroxyl
radical regenerates the active oxoammonium salt. Thus the
Molecular chlorine generated from NaOCl appears to have a
nitroxyl radical agent TEMPO can be employed as an alcohol
detrimental effect on the oxidizing power of the N-oxoammonium
oxidation catalyst, with NaOCl as the stoichiometric oxidant.2b
salt in these reactions.26 A similar protocol to the one described
This protocol has rapidly achieved widespread use due to its
above, but using Sodium Bromite (NaBrO2) in place of NaOCl
selectivity, ease of application, and versatility. A biphasic system
may be superior in this context. Despite this caveat, there is ample
is employed consisting of CH2Cl2 or toluene as the organic phase,
precedent for the successful application of the NaOCl/TEMPO
and commercial bleach buffered to pH <"9 with NaHCO3 and con-
system with a variety of substrates, and the use of commercial
taining substoichiometric levels of KBr or NaBr (eq 6).23 Reaction
bleach solutions has significant practical advantages.
times are longer in the absence of bromide salts, indicating that
For further discussion of this oxidizing system, see 2,2,6, 6-
HOBr is the agent that oxidizes TEMPO to the nitrosonium ion.
Tetramethylpiperidin-1-oxyl. See also Dimethyl Sulfoxide Oxa-
Without added phase transfer catalyst, primary alcohols are oxi-
lyl Chloride, Pyridinium Chlorochromate, Pyridinium Dichro-
dized with excellent selectivity to the corresponding aldehydes.24
mate, Potassium Permanganate, Dipyridine Chromium(VI)
High stirring rates (>1000 rpm) help to minimize overoxidation to
Oxide, and Tetrapropylammonium Perruthenate.
the carboxylic acid.23 The stereospecificity of TEMPO-catalyzed
oxidations of primary alcohols bearing ²-stereocenters has been
Oxidation of Primary Alcohols to Carboxylic Acids. Sim-
investigated in detail, and it is absolute in all cases reported thus
ple incorporation of a tetraalkylammonium chloride phase-
far (eqs 7 9).23,24
transfer catalyst (PTC) to the catalyst recipe outlined above for
aldehyde synthesis leads to a useful protocol for oxidation of
primary alcohols to the corresponding carboxylic acids (eq 11).2b
N
(0.01 equiv) Similar selectivity for primary alcohols over secondary alcohols
O"
RCH2OH + NaOCl (6)
RCHO
is observed as in the absence of PTC.25 This has been exploited
KBr (0.10 equiv)
1 equiv 1.1 equiv R = alkyl, 88 93%
NaHCO3
in the oxidation of unprotected monosaccharide derivatives to the
0.3 2 M CH2Cl2 R = aryl, 75 90%
corresponding uronic acids (eq 12).27
NaOCl
TEMPO (0.01 equiv) NaOCl (2.5 equiv)
KBr (0.1 equiv) TEMPO (0.01 equiv)
CHO O
OH
(7)
Aliquat 336 (0.05 equiv)
NaHCO3 (11)
R OH R OH
CH2Cl2, 0 15 °C KBr (0.01 equiv)
100% ee
82 84% R = primary
NaHCO3
alkyl CH2Cl2, 0 15 °C
NaOCl
>90%
TEMPO (0.01 0.02 equiv)
NaBr (1 equiv)
CHO
Ph OH Ph
(8)
HO
NaHCO3
NHCbz NHCbz OH 1% TEMPO
HO2C
CH2Cl2, 0 °C
KBr
O
>99% ee OH
96%
NaHCO3
O
+ NaOCl (12)
O
Bu4NCl
NaOCl
O
O
CH2Cl2
BnO TEMPO (0.01 0.02 equiv) BnO CHO
O
OH
64%
NaBr (1 equiv)
(9)
NaHCO3
CH2Cl2, 0 °C
77%
>98% ee The mildness of the oxidizing medium in TEMPO-catalyzed
oxidations by NaOCl is illustrated by the high yield oxidation of
Although both primary and secondary alcohols are oxidized
(2-hydroxyethyl)spiropentane to the corresponding acid (eq 13).28
with this catalyst system, moderate-to-good selectivity for the pri-
Jones oxidation conditions lead to extensive decomposition of the
mary position is obtained in oxidation of diols (eq 10).25 The diol
spiropentane residue of the same substrate.
must have nearly complete solubility in the organic phase for these
oxidations to occur cleanly. This selectivity for primary alcohols
NaOCl (pH 9)
is in direct contrast with monophasic NaOCl oxidations in acetic
1% TEMPO
KBr
acid (see above). Thus, proper choice of reaction conditions
OH (13)
allows selective oxidation by NaOCl of either or both the primary CO2H
Aliquat 336
or the secondary carbinol in diols.
92%
A list of General Abbreviations appears on the front Endpapers
SODIUM HYPOCHLORITE 3
NaOCl, Bu4NBr
See also Chromium(VI) Oxide, Potassium Dichromate, Potas-
pH 8 9
O
sium Permanganate, and Oxygen Platinum Catalyst. Ph
Ph (18)
S
S
CH2Cl2
O 80% O
Oxidation of Aldehydes. Sodium hypochlorite oxidizes
aromatic aldehydes to the corresponding acids in the presence of a
pyridine
C8H17 O O
+ NaOCl
phase-transfer catalyst.3 Best results are obtained at pH 9 10 with
Bu4NHSO4 as phase-transfer catalyst (eq 14). In this pH regime,
HOCl is present in significant concentrations, and phase-transfer
OH
C8H17 O O
CO2H
catalysts are generally not necessary.6a It has been suggested that 65 °C
C8H17
(19)
in this system, however, the phase-transfer catalyst helps to solubi-
O O
lize HOCl in the organic phase through hydrogen bonding.3 Direct
oxidation of aliphatic and aromatic aldehydes to the correspond-
See also Sodium Hypochlorite N,N -Bis(3,5-di-tert-butyl-
ing methyl esters is accomplished with methanol in acetic acid
salicylidene)-1,2-cyclohexanediaminomanganese(III) Chlo-
and 1 2 equiv of NaOCl.20 This reaction, which affords esters in
ride, Hydrogen Peroxide, tert-Butyl Hydroperoxide, and
moderate-to-good yield, probably proceeds via oxidation of equi-
Dimethyldioxirane.
librium concentrations of methyl hemiacetals. Poor results are
obtained with electron-rich aromatic aldehydes and unsaturated
Other Oxidation Reactions. Several other substrate classes
aldehydes, each of which undergo competitive chlorination.20
also undergo oxidation reactions with sodium hypochlorite. Dike-
tones may be oxidatively cleaved to give the corresponding diacids
Bu4NHSO4
ClCH2CH2Cl
(eq 20).33 Oxidation of hydroquinones and catechols34 and oxida-
Ph CHO + NaOCl Ph CO2H (14)
tive cyclization of phenols (eq 21)8 have also been realized.
87%
pH 9 10
CO2H
O
O NaOCl
See also Potassium Permanganate, Ozone, and N-
Br Br
H2O, THF
Bromosuccinimide.
OC
CO OR OR (20)
96%
Epoxidation. Sodium hypochlorite is an effective, although
CO2H
infrequently utilized, reagent for epoxidation of enones and poly-
NaOCl, TBAB
cyclic arenes. Careful control of pH is necessary for good yields in
Br
pH 8
these reactions. Polycyclic aromatics can be oxidized to epoxides
EtOAc
at pH 8 9 (eq 15).29 Phenanthridine is oxidized to the correspon-
OH OH
74%
ding lactam, presumably via an oxaziridine intermediate (eq 16),
Br
without formation of N-oxide.29 The optimum pH for this reaction
Br
is 8 9, and phase transfer catalysts are required. O
(21)
O
O
Br
NaOCl
Bu4NBr
pH 8 9
(15)
Oxidative Degradation. Treatment of carboxylic acids with
CHCl3
90%
sodium hypochlorite can lead to decarboxylation to afford alde-
hydes with one less carbon atom (eq 22).35 The mechanism of
O
this reaction is likely to involve methylene oxidation to the chlo-
NaOCl
N NH
Bu4NBr
ride or the alcohol followed by decarboxylation and oxidation to
pH 8 9
the aldehyde. This method has primarily been applied to sugar
(16)
CHCl3 degradation (eq 23).9,36
NaOCl, OH
CHO
Enones,4,30 particularly chalcones,31 also react with sodium 100 °C
CO2H
(22)
hypochlorite to form epoxides (eqs 17 19). These reactions gen-
71%
erally exhibit a strong dependence on the pH of the aqueous phase;
chlorination reactions can be competitive.30a The mechanism for CHO
1. NaOCl
these reactions has been proposed to involve production of the H OH CHO
pH 11, 20 h
HO H
ClO· radical species; this proposal was made on the basis of data HO H 2. NaOCl
pH 4.5 5, 10 h
from the chlorination of hydrocarbons, selectivity of epoxidation H OH H OH
(23)
reactions, and Hammett Á values for the chlorination of toluene.32 H OH H OH
35%
CH2OH CH2OH
O O
NaOCl
CCl3
+ (17)
pH 8 8.5
O
O O
Reaction with Amines. Reactions of sodium hypochlorite
70% 7%
with amines can yield ketones, cyclization products, or, in the
Avoid Skin Contact with All Reagents
4 SODIUM HYPOCHLORITE
case of amino acids, degradation products. The mechanism of Amine Coupling Reactions. Hydrazines44 and alkylhydra-
each of these processes involves initial N-chlorination.37 Chlo- zines (eq 30)45 are formed by the action of bleach and amines.
rinated intermediates have been identified spectroscopically, and Azoethanes are toxic, and therefore care should be taken in their
in some cases isolated, providing access to chlorination products production and handling.
as well. Treatment of aliphatic amines under phase transfer con-
NaOCl, NaOH
ditions yields ketones or nitriles.15,16a The initial product is the
EtNH2 + SOCl2
(EtNH)2SO2
H2O
N-chloro imine, with the carbonyl being released upon hydrolytic
workup (eq 24).
Et Et
NaOCl
HN N
(30)
HN N
NH2 NaOCl N O
H3O+
Bu4NBr Cl
Et Et
(24)
51 54%
CH2Cl2
98%
Reaction of Ä…- or ²-amino acids with NaOCl leads to the
Chlorination. Several types of organic nucleophiles undergo
corresponding aldehyde or methyl ketone containing one less
reaction with sodium hypochlorite to afford chlorination products.
carbon.38 The mechanism postulated for this Strecker-type degra-
N-Chlorination of primary and secondary amines is a represen-
dation of amino acids again involves N-chlorination, followed by
tative and widely-used example of this reaction class (eq 31).46
decarboxylation to yield the imines. Aldehydes and ketones are
Either mono- or dichlorinated products can be obtained selectively
released by hydrolysis (eq 25).39 This method has been applied to
through control of the relative stoichiometry of the amine and
degradation of Ä…-methyl DOPA (eq 26).40
NaOCl.47 A two-step chlorine-shuttle pathway for the selective
chlorination of electron-rich aromatics has been developed which
R CO2H R CO2Na R CO2Na
relies on initial N-chlorination with NaOCl.46 Intramolecular
NH2 NHCl NH cyclization of amines via the Hofmann Loffler reaction may also
be accomplished by effecting the requisite N-halogenation with
R NaOCl (eq 32).48
(25)
RCHO
NH
O O
NaOCl
MeO MeO
NaOCl
(31)
86 88%
(26) N N
H2N CO2H
O
60 75%
MeO MeO H Cl
NHMe
Oxidative Cyclization of Amines. Treatment of nitro
5.5% NaOCl
anilines with sodium hypochlorite under alkaline conditions af-
CH2Cl2
fords benzofuroxans as cyclization products (eq 27).41 Spectro-
scopic evidence suggests an initial chlorination of the amino
HO
group, followed by cyclization. In addition, chlorinated intermedi-
ates have been prepared independently and submitted to the reac- NClMe
1. CF3CO2H, h½
tion conditions to show that cyclization products are formed.37
2. KOH
The cyclization reaction requires addition of base, as azo prod-
84% overall
ucts are formed at neutral pH. Oxadiazoles (eq 28)42 and chloro-
diazirines (eq 29)43 are also formed by oxidative cyclization in
HO
moderate-to-good yields. The key intermediate for both of these
Me
reactions is also proposed to be an N-chloro imine.
N
N
NH2 NaOCl
KOH
O (32)
(27)
+
N
NO2 80%
O
HO
H Cl
N O N O Chlorination of indoles (eq 33),7,49 amides, and ureas50 occurs
NaOCl
at the nitrogen center, while oximes51 are chlorinated at carbon.
R1 N R2 R1 N R2
75 90%
Selective chlorination of nicotinic acids (eq 34),52 chromones,53
H H
and polymers54 has also been achieved. Substitution of chlorine
N O
for other halides occurs upon treatment of certain aromatic halides
R1 R2 (28)
with sodium hypochlorite solution.55
N
NaOCl
Cl
NH
NaOCl pentane
N Cl N
(33)
(29)
90%
NN
R NH2 LiCl R NH2 60% R
N
DMSO H Cl
A list of General Abbreviations appears on the front Endpapers
SODIUM HYPOCHLORITE 5
CO2H Cl CO2H
to the hydroxyl group. Recent advances in this area have been
NaOCl
(34)
directed toward the immobilization/entrapment of TEMPO on
60 75%
N OR N OR
solid supports, which allows for ease of workup and product purifi-
cation. This has been accomplished with the polyamine oligomer
Chimassorb 944 (PIPO),59 silica (SiO2),60 poly(ethylene glycol)
(PEG),61 and Sol-Gel (SG)62 to name a few (eqs 36 39).
First Update
PIPO-TEMPO (1 mol %)
Michael Palucki
NaOCl (1.25 equiv)
Merck Research Laboratories, Rahway, NJ, USA
KBr (0.5 equiv)
KHCO3
CH2Cl2
General Considerations of Sodium Hypochlorite. Sodium
Me OH
99%
hypochlorite (NaOCl or bleach) is a strong oxidant, and
accordingly, is primarily used in this manner. The benefits of using
O
Me (36)
commercial NaOCl in an oxidation reaction include the cheap and
readily available nature of commercial aqueous bleach, the ease of
PEG-TEMPO (1 mol %)
handling and storage, and the fact that the by-product from spent
NaOCl (1.25 equiv, pH = 8.6)
NaOCl is NaCl.56 The primary detractor in using NaOCl is that
OH
CH2Cl2
commercial NaOCl is supplied as an aqueous solution, which in
Me
94%
Me
turn, can limit its use to nonwater sensitive systems. In the ma-
jority of reactions using aq NaOCl, the adjustment and control of
O
the pH was often beneficial and even critical to the success of the
(37)
Me
Me
reaction.
SG-TEMPO (2 mol %)
Oxidation of Alcohols to Aldehydes and Ketones. NaOCl
NaOCl (1 equiv, pH = 9.1)
continues to be an oxidant of choice for the oxidation of
KBr (1.25 equiv)
OH
alcohols to carbonyl compounds. The oxidation of alcohols Me
filter/dry/re-use
using NaOCl requires the addition of at least one of the follow- 7 runs
ing reagents/catalyst in order to promote the reaction: catalytic
O
(38)
Me
amounts of ruthenium, catalytic amounts of nitrosyl radicals such
as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) with and with-
SiO2-TEMPO (0.5 mol %)
out the addition of a bromide source, phase transfer catalysts, pH
KBr (10 mol %)
adjustments via addition of acids, or other miscellaneous addi-
NaOCl (1.25 equiv, pH = 9.1)
OH
tives. The background reaction of commercial bleach with alco- CH2Cl2
Me Me
hols is prohibitively slow.
97% yield on first run
up to 10 runs
The oxidation of nitrosyl radicals such as TEMPO by NaOCl
provides an oxoammonium ion, which in itself is a highly reactive
O
oxidant. Upon oxidation of an alcohol, the oxoammonium ion
(39)
is converted to a hydroxylamine, which is sequentially oxidized Me Me
back to the oxoammonium ion via the nitrosyl radical intermediate
(eq 35).
Oxidation of alcohols with NaOCl can also be performed in
NaOCl
the absence of nitrosyl radicals or a transition metal by the addi-
tion of certain promoters such as phase transfer catalysts (PTC),63
²-cyclodextrin,64 or the use of an ionic liquid as solvent.65 The
PTC/NaOCl protocol has emerged as the most convenient method
N+
N
(35)
of choice. A distinct advantage of the PTC/NaOCl protocol rela-
O
O.
tive to the NaOCl/AcOH procedure is the ability to oxidize pri-
alcohol
mary alcohols to aldehydes with minimal over oxidation to the
ester, and the ability to oxidize alcohol substrates selectively in
NaOCl
the presence of double bonds. In addition, the PTC conditions do
N
not require the use of chlorinated solvents and often afford fast
carbonyl product
rates of reaction at ambient temperature (eqs 40 and 41).
OH
The use of catalytic amounts of TEMPO in conjunction with NaOCl
EtOAc, H2O
NaOCl as a reoxidant, with and without added bromide, has
Bu4NBr
become a widely used and often preferred method for the oxi-
Me OH
86%
dation of alcohols to carbonyl products.57,58 The mild conditions
allow for good functional group compatibility as well as the abil-
O (40)
Me
ity to retain the stereointegrity of stereogenic centers adjacent
Avoid Skin Contact with All Reagents
6 SODIUM HYPOCHLORITE
Me
Me A tetra-n-propylammonium perruthenate (TPAP)-catalyzed
oxidation of 1,2:4,5-di-O-isopropylidene-²-D-fructopyranose was
NaOCl
Me
developed using NaOCl as the reoxidant in order to avoid the stan-
Me EtOAc, H2O
dard pyridinium chlorochromate oxidation method.67 The TPAP/
Bu4NBr
NaOCl method was found to be applicable to a range of substrates.
72%
In addition, the metal catalyst can be recycled up to four times with
HO
minimal loss of activity (eqs 46 and 47).
Me
Me
O
Me
TPAP (1 mol %)
Me
O
Me
NaOCl (3 equiv)
(41) Me
O pH = 9.5
MTBE
OH
O
90%
O
O
Me
Me
Mechanistic studies have shown that PTC/NaOCl oxidation of
O
Me
O
secondary alcohols proceeds through an alkyl hypochlorite in-
Me
O
termediate, which can either eliminate HCl to form the desired
(46)
O
ketone product, or undergoes radical chain decomposition.66 It
O
was shown that reactions run in the presence of oxygen favored O
Me
ketone formation, whereas reactions run under an inert atmosphere
Me
enhanced the radical pathway (eq 42).
TPAP (1 mol %)
NaOCl (3 equiv)
O
-HCl
pH = 9.5
OH
EtOAc
R R2
99%
Me Me
Cl
OH O
NaOCl/PTC
(42)
O
pH = 9
R R2 R R2
(47)
Me Me
O.
+ Cl.
R R2
Oxidation of Primary Alcohols to Carboxylic Acids. The
radical chain
TEMPO-catalyzed NaOCl oxidation of primary alcohols to car-
decomposition
boxylic acids is an effective method for their preparation.68 The
addition of a catalytic bromide source was found to accelerate
The use of ²-cyclodextrin as a promoter in the NaOCl
the reaction via in situ generation of the more active oxidant
oxidation of certain alcohols is an ideal  green oxidation proto-
hypobromite. The use of buffered aq NaOCl was found to be key
col given that water is the solvent and that the ²-cyclodextrin can
for the oxidation of primary alcohols to sodium carboxylates in
be recycled (eqs 43 and 44). The mild protocol allows inclusion
the absence of any organic solvent (eqs 48 and 49).69 Studies
of allylic alcohols as substrates. Not surprisingly, this water-based
indicate the oxidation in buffered aqueous systems proceed
system does not work well with relatively bulky hydrophobic sub-
through a hydrated aldehyde intermediate.70
strates such as 2-octanol, cyclohexanol, and 2-adamantol.
TEMPO (0.5 mol %)
²-cyclodextrin
NaBr (15 mol %)
NaOCl, H2O
O
(43) NaOCl (2.4 equiv)
OH
ONa
99%
H2O (pH = 10)
(48)
OH
>99% O
N ²-cyclodextrin
N
OH (44)
NaOCl, H2O
O
99%
OH
TEMPO (0.5 mol %)
Ionic liquids have distinct physical properties that can
NaBr (15 mol %)
often affect chemical reactivity and selectivity. Using an ionic
NaOCl (2.4 equiv)
OH
liquid based on a cyclic guanidinium cation as solvent, an effec- H2O (pH = 10)
O
HO
tive NaOCl oxidation of alcohols was accomplished without the >95%
OH
requirement of other additives (eq 45). n
(starch)
NaO
NaOCl (pH = 8-9)
O
ionic liquid
OH
O (45)
(49)
95% Bu
N+ -
OH
PF6
O
ionic liquid:
HO
N N
OH n
A list of General Abbreviations appears on the front Endpapers
SODIUM HYPOCHLORITE 7
The TEMPO/NaOCl oxidation of primary alcohols contain- A rationally designed chiral binaphthyl-based PTC was devel-
ing an electron-rich aromatic group can often yield by-products oped for enantioselective epoxidation of Ä…, ²-unsaturated ketones
resulting from chlorination of the aromatic ring. This issue was in good enantioselectivity and yield.76 The successful identifi-
circumvented by using NaClO2 as the stoichiometric oxidant and cation of an optimal catalyst was based on the ability to utilize
NaOCl/TEMPO in catalytic amounts.71 It is proposed that the ini- stereoelectronic effects to fine tune the catalyst structure. The
tial amount of NaOCl oxidizes TEMPO to N-oxoammonium ion, high degree of chiral recognition by the PTC is attributed to
which in turn, oxidizes the substrate alcohol to an aldehyde. The hydrogen bonding of the PTC to the enone substrate as well as the
aldehyde product is subsequently oxidized by NaClO2 to gener- hypochlorite oxidizing agent prior to the key C O bond forming
ate the desired carboxylic acid and an equivalent of NaOCl.72 step. The end result is an epoxidation system that affords high
In the absence of the initial catalytic amounts of NaOCl, the enantioselectivities and yields for a wide range of enones (eq 53).
reaction rates are sluggish. The absence of chlorinated aromatic
Ar
by-products is due to the low concentrations of NaOCl throughout
Ar Ar
the course of the reaction. The use of the weaker NaClO2 oxidant,
OH
relative to NaOCl, in stoichiometric amounts renders this proce-
Br
N
dure significantly milder than using stoichiometric NaOCl (eqs 50
and 51).
OH
TEMPO (7 mol %)
Ar
Ar
Ar
NaClO2 (2 equiv)
NaOCl (10 mol %)
(Ar = 3,5-Ph2-C6H3)
O
(3 mol %)
pH = 6.7 (phosphate) OH
OH
MeCN
13% aq NaOCl
R1 R2
(50)
O
toluene, 12-24 h, 0 °C
96%
O
OMe
OMe O
R1 R2 (53)
TEMPO (7 mol %)
R1 R2 ee (%) Yield (%)
NaClO2 (2 equiv)
Ph p-Cl-C6H4 96 99
NaOCl (10 mol %)
O
O
HO O 96 99
p-Cl-C6H4 n-Hex
pH = 6.7 (phosphate)
HO
MeCN t-Bu Ph 89 87
N
N
(51)
Ph
95% 91 80
t-Bu n-Hex
Ph
O
O
Me
Me
Other Oxidation of Olefins. Iodohydroxylation of a termi-
nal olefin was accomplished via in situ generation of hypoiodous
acid (HOI) using the combination of NaOCl, NaI, and careful pH
Epoxidation of Olefins. The enantioselective epoxidation of
control.77 The careful control of pH allows generation of the eva-
Ä…,²-unsaturated ketones using NaOCl as the terminal oxidant can
sive HOI species while suppressing iodine formation, which can
be accomplished in high selectivity by the addition of certain chiral
result in by-products (eq 54).
phase transfer catalysts (PTC).73 The use of N-anthracenylmethyl
derivatives of cinchona alkaloids as catalyst has been shown to
NaOCl (2 equiv)
Me
NaI (1.8 equiv)
Ph Me
provide product epoxides with good enantioselectivity and in high
O NaHCO3
yields (eq 52).74 Studies show that toluene is the preferred organic
pH = 8-9.5
N
solvent, with as little as 0.5 1.0 mol % of the PTC required to
93%
obtained complete conversion of substrates.75 Kinetic studies have
O
shown that the reaction is first order in NaOCl and PTC.
Me
Ph
Me
N Me O
OH
I N
N
(54)
H
PTC =
OBn
O
Br
96% de
O
(1 mol %)
R1 R2
15% aq NaOCl (2 equiv)
The osmium-catalyzed asymmetric dihydroxylation (ADH) of
toluene, 12-24 h, 25 °C
olefins using NaOCl as the terminal oxidant was developed as a
O
O
more practical method relative to the protocols using K4[Fe(CN)6]
R1 R2 (52) or NMO (N-methylmorpholine N-Oxide) as oxidants.78 A wide
range of olefins were found to undergo rapid and highly enantio-
69-92% ee
75-98% yield
selective dihydroxylation in good yield (eqs 55 57).
Avoid Skin Contact with All Reagents
8 SODIUM HYPOCHLORITE
K2[Os)2(OH)4] (0.4 mol %)
Reaction with Amines. Studies on the NaOCl oxidation of
(DHQD)2PHAL (5 mol %)
aliphatic amines to produce N Cl compounds reveal that the op-
tBuOH/H2O/K2CO3
timal pH for obtaining the best reaction rates is pH = 9.82 The
NaOCl (1.5 equiv)
reaction is first order in amine and oxidant. Chlorination of pri-
88%
mary and secondary amines proceeds via initial proton transfer
HO
followed by Cl-transfer, whereas chlorination of tertiary amines
HO
(55)
proceeds through direct attack of the amine nitrogen on the oxidant
to generate a charged product species.
N-Chlorination of nitrogen heterocycles is a convenient way
95% ee
to oxidize N-heterocyclic compounds. The NaOCl oxidation of
K2[Os)2(OH)4] (0.4 mol %)
3-pyrrolines can be efficiently carried out to produce N-chlo-
(DHQD)2PHAL (5 mol %)
rinated lactams (eq 61).83 The reaction protocol is straightfor-
tBuOH/H2O/K2CO3
ward. The resulting N-chlorinated lactam can be dechlorinated
NaOCl (1.5 equiv)
(56)
TMS OH
using AcCl/MeOH. Similarly, N-chlorination of 1,3-oxazolidines
TMS
87%
OH with NaOCl provides 3-oxazolines after HCl elimination under
80% ee basic conditions (eq 62).84
K2[Os)2(OH)4] (0.4 mol %)
(DHQD)2PHAL (5 mol %)
Me Me
Me Me
Me
Me
tBuOH/H2O/K2CO3
NaOCl (10 equiv)
NaOCl (1.5 equiv)
MeOH, rt
Me
93% O
N
N
OTBS
OTBS
Cl
OH
Me
(57) Me Me
AcCl
Me
OH
MeOH
(61)
49% over two steps
95% ee
O
N
OTBS
H
Other Oxidations. A one pot alcohol oxidation and Baeyer-
Me
Me
Villiger reaction sequence was developed for the conversion of
NaOCl (1.0 equiv) KOH/EtOH
Ä…-hydroxy-²-lactams to Ä…-amino acid N-carboxy anhydrides.79
O N
O NH
72%
The reaction involves the oxidation of the alcohol to the ketone
83% Cl
using an aq TEMPO/NaOCl protocol carried out in a phosphate-
Et Me
Et Me
buffered (pH = 6.9) biphasic system (eq 58).
Me
TEMPO (1 mol %)
Boc
Boc
(62)
NaOCl (pH = 6.9
O N
N
N
KBr (10 mol %)
O
H
H H
Et Me
CH2Cl2
HO
(58)
95% O
N
N
Bn
O Bn
O
NaOCl oxidation of N-alkylaminoacetonitriles provides N-
alkylformimidoyl cyanides in good yields via N-chlorination
The Ru-catalyzed Ä…-oxidation of ethers to esters can be carried
followed by HCl elimination (eq 63). The reactions are rapid,
out selectively by careful pH control of the NaOCl solution.80
straightforward, and require no organic solvent. NaOCl oxidation
A pH range of 8 9.5 was found to be optimal for activity and
of hydroxylamines provides nitrones in good yields (eq 64),85
selectivity in the biphasic reaction. The efficient use of NaOCl (2.0
whereas NaOCl oxidation of oximes provides nitrile oxides in
equiv relative to substrate) and the rapid rate of reaction render
good yield (eq 65). Nitrile oxides can undergo 1,3-dipolar cyclo-
this protocol superior to traditional procedures (eqs 59 and 60).81
additions to provide isoxazole-type products.
TPAP (0.25 mol %)
NaOCl (pH = 9.5)
CH2Cl2
O
O
(59)
R1 R1
77%
NaOCl (1.5 equiv)
O
67-97%
R2 N CN R2 N CN
7 examples
H
[RuCl2(dmso)4] (0.5 mol %)
Cl
NaOCl (pH = 9.5)
O O
O
CH2Cl2 R1
(60)
(63)
44%
R2 N CN
A list of General Abbreviations appears on the front Endpapers
SODIUM HYPOCHLORITE 9
NaOCl (1.3 equiv) 8. Tsuge, O.; Watanabe, H.; Kanemasa, S., Chem. Lett. 1984, 1415.
R1 N R2 R1 N R2 (64)
9. Whistler, R. L.; Yagi, K., J. Org. Chem. 1964, 26, 1050.
50-94%
OH O
10 examples
10. Lolthoff, I. M.; Belcher, R. Volumetric Analysis; Interscience: New York,
1957; p 262.
H N
OH NaOCl (1.6 equiv) 11. Lieu, V. T.; Kalbus, G. E., J. Chem. Educ. 1988, 65, 184.
Et3N
12. (a) Sanfourche, M.; Gardent, L., Bull. Soc. Chem. Fr. 1924, 35, 1088. (b)
CH2Cl2
Adams, R. A.; Brown, B. K., Org. Synth., Coll. Vol. 1932, 1, 309.
13. Robertson, P. M.; Oberlin, R.; Ibl, N., Electrochim. Acta 1981, 26, 941.
OTBDMS
14. The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989;
OCH3
p 1363.
15. Lee, G. A.; Freedman, H. H., Isr. J. Chem. 1988, 26, 229.
16. (a) Lee, G. A.; Freedman, H. H., Tetrahedron Lett. 1976, 1641. (b) Regen,
N
O
S. L., J. Org. Chem. 1977, 42, 875.
Ar 17. Wolfe, S.; Hasan, S. K.; Campbell, J. R., J. Chem. Soc., Chem. Commun.
1970, 1420.
6-63%
8 examples
18. Stevens, R. V.; Chapman, K. T.; Weller, H. N., J. Org. Chem. 1980, 45,
OTBDMS
2030.
OCH3
19. Perkins, R. A.; Chau, F., J. Chem. Educ. 1982, 59, 981.
20. Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.; Albizati, K.
O N
F., Tetrahedron Lett. 1982, 23, 4647.
OTBDMS
Ar
21. Kudesia, V. P.; Mukherjee, S. K., Indian J. Chem., Sect. A 1977, 15A,
(65)
513.
OCH3
22. Yamaguchi, M.; Takata, T.; Endo, T., J. Org. Chem. 1990, 55, 1490.
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5029.
24. Anelli, P. L.; Montanari, F.; Quici, S., Org. Synth. 1991, 69, 212.
Chlorination of Allylic Carbons. Chlorination of allylic
25. (a) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S., J. Org. Chem. 1989,
carbons can be accomplished using a NaOCl/CeCl3 protocol
54, 2970. (b) Siedlecka, R.; Skarzewski, J.; Mlochowski, J., Tetrahedron
(eq 66).86 The cerium trichloride is thought to promote the forma-
Lett. 1990, 2177.
tion of an electrophilic chlorine. The overall process is straightfor-
26. Inokuchi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S., J. Org. Chem.
ward and high yielding. A chlorinative one carbon ring expansion
1990, 55, 462.
of [2.2.1]- and [2.2.2]-bicyclic compounds can be achieved with
27. Davis, N. J.; Flitsch, S. L., Tetrahedron Lett. 1993, 34, 1181.
NaOCl in the presence of acetic acid (eq 67).87
28. Russo, J. M.; Price, W. A., J. Org. Chem. 1993, 58, 3589.
NaOCl (2 equiv)
29. Krishnan, S.; Kuhn, D. G.; Hamilton, G. A., J. Am. Chem. Soc. 1977,
CeCl3·7 H2O (2 equiv)
99, 8121.
CH2Cl2/H2O
(66)
Cl 30. (a) Wellman, G. R.; Lam, B.; Anderson, E. L.; White, V. E., Synthesis
R Me
R
60-98%
1976, 547. (b) Jakubowski, A. A.; Guziec, F. S., Jr.; Tishler, M.,
7 examples
Tetrahedron Lett. 1977, 2399.
31. Arcoria, A.; Ballistreri, F. P.; Contone, A.; Musumarra, G.; Tripolone,
Me OMe
Me OMe
NaOCl/HOAc M., Gazz. Chim. Ital. 1980, 110, 267.
H2O/CCl4
32. Fonouni, H. E.; Krishnan, S.; Kuhn, D. G.; Hamilton, G. A., J. Am. Chem.
(67)
Soc. 1983, 105, 7672.
OH 47-86% yield
6 examples
Me O 33. (a) Corey, E. J.; Pearce, H. L., J. Am. Chem. Soc. 1979, 101, 5841. (b)
Me
Me
Me
Neiswender, D. D.; Moniz, W. B.; Dixon, J. A., J. Am. Chem. Soc. 1960,
Cl
82, 2876.
34. Ishii, F.; Kishi, K., Synthesis 1980, 706.
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A list of General Abbreviations appears on the front Endpapers