Review 6: organic peroxides in radical synthesis ... - Acros Organics

REVIEW 6
Organic Peroxides in
Radical Synthesis Reactions
Organic Peroxides
Organic Peroxides
New from Acros Organics
J. Meijer, A.H. Hogt and B. Fischer
Akzo Nobel Polymer Chemicals Laboratory Deventer
Zutphenseweg 10, PO Box 10, 7400 AA Deventer, The Netherlands.

Organic Peroxides in Radical Synthesis Reactions
J. Meijer, A.H. Hogt and B. Fischer
Akzo Nobel Polymer Chemicals Laboratory Deventer
Zutphenseweg 10, PO Box 10, 7400 AA Deventer, The Netherlands.
Contents
I. Introduction
II. Reactivity of organic peroxides
III. Oxidation reactions with organic peroxides
IV. Radical reactions with organic peroxides
V. Functionalization reactions with organic peroxides
VI. Concluding remarks
VII. References
VIII. Table of abbreviations
IX. Listing of Organic peroxides from Acros Organics
1

I. Introduction
Radicals can be used as synthetic intermediates in reactions which are often difficult
to accomplish by other means and which can selectively occur under very mild conditions.
The protection of functional groups, often essential for synthetic sequences of ionic reactions,
is mostly not required for radical reactions [Curran e.a., 1996].
Organic peroxides are a very versatile source of radicals that are formed after the
thermally induced homolysis of the peroxide bond. The major radical-molecule reactions are
additions and SH 2 –reactions, e.g. H-abstraction, atom transfer, unimolecular reactions, e.g.
decarboxylation, β-scission and rearrangements, e.g. 1,5-H-abstraction [Ingold, 1973]. In
synthesis reactions, undesired radical-radical reactions such as radical combination and
disproportionation can be avoided by proper choice of the type of peroxide and reaction
conditions. Another major application of organic peroxides in syntheses is oxidation, which is
a non-radical reaction [Rao and Mohan, 1999].
II.
Reactivity of organic peroxides
Organic peroxides can have a variety of characteristics depending on their chemical
structure and reactivity. The reactivity of the peroxides depends on the peroxide group
configuration and on the type of substituents. Organic peroxides can be classified into
different groups depending on their chemical structures (see Fig. 1).
Type of peroxide
Structure
Hydroperoxides R O O H
Ketone peroxides
Peroxyacids
R1
H O O O O H
O
R O O
R2
H
n=1,2
Dialkylperoxides R O O R
Peroxyesters
Peroxycarbonates
Diacylperoxides
Peroxydicarbonates
Peroxyketals
Cyclic ketone peroxides
O
R1 O O
Figure 1. Types of peroxides and general chemical structures.
R1
R
O
O
O
O
O
O
O
O
R2
O
R
R2
O
R O O O O R
R1
R O O O O R
R1
R2
O
R2
O
n=2,3
2

The thermally induced homolysis of the peroxidic bonds yield oxy-radicals. The
decomposition rate of peroxides does not only depend on the class of peroxide but on the
type of R-group as well. The reactivity and the sensitivity of the peroxides to radical attack
(induced decomposition) is strongly related to its structure. Therefore, organic peroxides are
radical initiators with a very broad range of reactivities [Akzo Nobel PC product catalogue].
This is illustrated in Figure 2, which shows the half-life time (t_) of a number of peroxides
against temperature.
10
EHP
TBPB
Half life time (h)
1
TBPP
LPO
DTBP
TBHP
BPO
0,1
0 50 100 150 200 250
Temperature (°C)
Figure 2. Half-life times of various organic peroxides as function of temperature (see: Abbreviations).
The thermal decomposition of organic peroxides is a first order reaction. Increase in
temperature of about 10°C results in a 2-3-fold increase in decomposition rate. In the case of
peresters and diacylperoxides, the reactivity of organic peroxides is affected to a high degree
by the type of substituents on the carbon atom adjacent to the peroxy bond. Increasing alkyl
substitution on a given peroxyester shortens the half-life by a factor of more than 60, on
diacylperoxides by a factor of 9000. This substitution effect is much less prominent for other
peroxides such as peroxy (di) carbonates and dialkylperoxides where substituents are varied
on the ß-position to the peroxy group. An extensive review on peroxy compounds is reported
by Sheppard [Sheppard, 1985].
Decomposition rates of peroxides are in principle depending on the solvent used,
mainly due to differences in polarity. For example, the one-hour half-life temperature of di-tertbutyl
peroxide (DTBP) increases about 20 degrees changing from chlorobenzene to an
aliphatic solvent [Akzo Nobel - internal information].
The viscosity of the medium can also have an effect on the rate of peroxide decomposition
[Lazar, 1983; Van Drumpt and Oosterwijk, 1976].
III.
Oxidation reactions with organic peroxides
Peroxyacids are mostly used for the epoxidation of unsaturated compounds. Most
important are the Baeyer-Villiger reaction of carbonyl compounds, oxidation of nitrogen and
sulfur compounds (see Fig. 3) [Rao and Mohan, 1999]. It is generally accepted that such
oxidations are non-radical reactions.
3

R 3 N(O)
R 3 N
O
EPOXIDATION
O
R O O H
PEROXY ACID
R 2 S
R 2 S(O) n=1,2
R 1 C(O)R 2
R 1 C(O)OR 2
BAEYER-VILLIGER
Figure 3. Oxidation via peroxy-compounds.
IV.
Radical reactions with organic peroxides
Through homolytic scission organic peroxides primarily generate oxy-radicals: alkoxy-
, acyloxy- and/or oxycarbonyloxy-radicals [Kochi, 1973 -a].
Oxy-radicals can also be generated from peroxyesters, diacylperoxides and hydroperoxides
by redox systems [ Kochi, 1973 -b]. (see Fig. 4).
O
*
O
*
DTAP
DCP
O
DTBP
BPO
O *
O *
R 1 OOR 2
O
O
CPDC
BPIC
C 16 H 33 O O * O O *
H
MPDC
TBCPDC
C 14 H 29
O
O
O *
O
O
*
O
Figure 4. Generation of oxy-radicals via peroxy-compounds.
4

An important reaction of alkoxy-radicals is β-scission, and of acyloxy-radicals
decarboxylation, both reactions resulting in the formation of carbon-radicals. In contrast,
alkoxycarbonyloxy-radicals do not show decarboxylation [Kochi, 1973-a]. (see Fig. 5).
C 2 H 5
DTAP
DTBP
CH 3 *
*
*
H
TBPIB
TBPP
*
R 1 OOR 2
BPO
TBPEH
* *
LPO
BTMHP
C 11 H 23 *
*
Figure 5. Generation of carbon-radicals via peroxy-compounds.
In the presence of a substrate, oxy-radicals (R-H) generate substrate-radicals which
may undergo combination reactions, addition reactions to unsaturated compounds or atomtransfer
reactions. Examples of such reactions in practical applications are (see Fig. 6):
combination of phenylisopropyl-radicals to 2,3-dimethyl-2,3-diphenylbutane, applied as flameretardant
synergist [Regitz and Giese, 1989 -a], addition of methylphosphorous monoisobutyl
ester to vinylacetic acid ethylester, used in the synthesis of the glufosinate herbicide
[Meiji Seika Kaisha, 1982], and atom transfer of bromine to a substituted tolyl-radical, yielding
a flame retardant [Tosoh, 1999]. In addition, oxy-radicals can be used for the racemization of
optically active chrysanthemic acid or its ester used for the synthesis of pyrethrine
insecticides [Sumitomo, 1992].
5

R 1 OOR 2
R 1 O * * OR 2
R-H
ABSTRACTION
R 1 OH + HOR
2x
2
X-Y
R-R R*
R-X + Y *
COMBINATION
ATOM TRANSFER
H
Br
R
H
X
H
[Regitz and Giese, 1989-a]
ADDITION
[Tosoh, 1999]
O
O
P
O
O
[Meiji Saika Kaisha, 1982]
Figure 6. Reactions of oxy-radicals with substrates R-H.
Oxy-radicals can add to unsaturated compounds. They may also undergo competitive
reactions such as β-scission in case of alkoxy-radicals, and decarboxylation in case of
acyloxy-radicals. The formed carbon-radicals will in most cases also add to the unsaturated
compounds [Kochi, 1973-Oxy-radicals; Regitz and Giese, 1989 -b].
6

V. Functionalization reactions with organic peroxides
Some organic peroxides with particular structures have a specific performance in
functionalization reactions. Examples are peroxides with unsaturated groups, hydroxyl groups
and acid groups and multi-functional peroxides with unsaturated and acid groups (see Fig. 7).
Peroxide CAS nr. Structure
tert-butyl-1,1-dimethylpropenyl
peroxide
114041-94-0
O
O
tert-butylperoxy
allylcarbonate
65700-08-5
O
O
O
O
tert-butylperoxy-6-
hydroxyhexanoate
(not yet
assigned) O O
O
O
H
tert-butylperoxy-3-
carboxypropanoate
28884-42-6
O
O
O
O
O
H
tert-butylmonoperoxymaleate
1931-62-0
O
O
O
O
O
H
Figure 7. Functional peroxides.
With particular unsaturated peroxides, functional groups can be incorporated in a
substrate after an induced decomposition reaction and subsequent rearrangement (see Fig.
8). Epoxide groups have been introduced in various substrates such as cyclohexane, furan,
methylproprionate, acetonitrile and dichoromethane, by allylic peroxides, e.g. t-butyl-1,1-
dimethyl-propenyl peroxide [Montaudon e.a., 1987]. Crown ethers have been functionalized
with cyclic carbonate groups using t-butylperoxy allylcarbonate [Maillard e.a., 1989].
R-H
+ O
* R * +
O H
R *
O
O
R
O
*
O
R * +
O
R
O
O O O
++
O O
Figure 8. Functionalization via unsaturated peroxy-compounds.
O
*
Tert-butylmonoperoxymaleate and t-butylperoxy-3-carboxypropanoate are capable of
incorporating acid and/or anhydride groups in substrates, probably via H-abstraction and an
addition or combination reaction [Manning and Moore, 1997]. Primary hydroxyl functions can
be introduced using t-butylperoxy-6-hydroxyhexanoate via a decarboxylation and addition
reaction to unsaturated substrates [ Akzo Nobel, 2001].
7

VI.
Concluding remarks
There are several important parameters for the choice of a peroxide for use in
chemical syntheses. The physical and chemical stability affects the storage and handling
properties, the temperature-dependent rate of decomposition determines the reactivity at the
process conditions. The radicals formed after decomposition must be efficient for the desired
radical reaction. Peroxides may also be selected for specific rearrangements or specific
coupling reactions, which can introduce functional groups into substrates. Decomposition
products of the peroxides have to be taken in account during the purification process.
Organic peroxides are well established synthetic agents in the manufacture of many
pharmaceutical intermediates, herbicides, insecticides and various other fine chemicals.
Organic peroxides offer opportunities to reduce the number of reaction steps in synthetic
routes applying classical synthetic procedures. Moreover, introduction of functional groups
can be achieved by using special organic peroxides. In many cases these reactions are
unprecedented in non-radical chemistry.
Organic peroxides combine a number of interesting features for the application in organic
synthesis:
! High purity
! Good solubility on most organic systems, enabling homogeneous reaction conditions
! Well defined and temperature controlled reactivity
! High efficiency
! Favorable cost/performance ratio
8

VII.
References
Curran, D.P., Porter, N.A., Giese, B., Stereochemistry of Radical Reactions, VCH
Verlagsgesellschaft, Weinheim, Germany (1996), pp. 1-22.
Rao, A.S. and Mohan, H.R., in: Burke, S.D. and Danheiser, R.L., Handbook of Reagents for
Organic Synthesis, Oxidizing and Reducing Agents, Wiley, Chichester, UK (1999), pp. 84-89.
Ingold, K.U., Rate constants for free radicals in solution, in: Kochi, J.K. (Ed.), Free Radicals,
Vol. I, Wiley, New York (1973), Chapter 11, pp. 37-112.
Akzo Nobel PC Product Catalogue.
Sheppard, Ch. S., in: Mark, H.F., Bikales, N.M., Overberger, C.G. and Menges, G. (Eds.),
Encyclopedia of Polymer Science and Engineering, Vol. 11, Wiley, New York (1985), p. 1.
Akzo Nobel, internal information.
Lazar, M., in: Patai, S (Ed.), The Chemistry of Functional Groups, Peroxides, Wiley, New York
(1983), p. 177.
Van Drumpt, J.D. and Oosterwijk, H.H.J., J. Polym. Sci., Polym. Chem. Ed., 14 (1976), 1495.
Kochi, J.K., Oxygen radicals, in: Kochi, J.K. (Ed.), Free Radicals, Vol. II, Wiley, New York
(1973), Chapter 23, pp. 665-710 (a).
Kochi, J.K, Oxidation-reduction reactions of free radicals and metal complexes, in: Kochi, J.K.
(Ed.), Free Radicals, Vol. I, Wiley, NY (1973), Chapter 11, pp. 591-684 (b).
Regitz, M. and Giese, B. (Eds.), C-Radikale Band E19a, Methoden der Organischen Chemie
(Houben-Weyl), Thieme Verlag, Stuttgart (1989), pp. 547-548 (a).
Regitz, M. and Giese, B. (Eds.), C-Radikale Band E19a, Methoden der Organischen Chemie
(Houben-Weyl), Thieme Verlag, Stuttgart (1989), pp. 31-40 (b).
Meiji Seka Kaisha, Ltd, European patent EP18415 (1982).
Tosoh Corp., Japanese patent JP 11130708 (1999).
Sumitomo Chemical Company, Ltd, European patent EP282221 (1992).
Montaudon, E., Agorrody, M., Rakotomanana, F., Maillard, B., Intramolecular homolytic
displacements. 15. Free-radical reactions to β-ethylenic peroxides, Bull. Soc. Chim. Belg. 96
(10), 769-74 (1987).
Maillard, B., Bourgeois, M.J., Montaudon, E., Lalande, R., French patent FR2628107 (1989).
Manning, S.C. and Moore, R.B., Carboxylation of polypropylene by reactive extrusion with
functionalized peroxides for use as a compatibilizer in polypropylene/polyamide-6,6 blends,
Journal of Vinyl & Additive Technology, 3 (2), 184-189 (1997).
Akzo Nobel, patent WO 01/27078 (2001).
9

VIII.
Abbreviations
Code Chemical name* CAS nr.
BPIC Tert-butyl peroxy isopropylcarbonate (Trigonox BPIC) 2372-21-6
BPO Dibenzoyl peroxide (Lucidol, Cadet) 94-36-0
BTMHP Bis(3,5,5-trimethylhexanoyl) peroxide (Trigonox 36) 3851-87-4
CPDC Dicetyl peroxydicarbonate (Perkadox 24) 26322-14-5
DCP Dicumyl peroxide (Perkadox BC) 80-43-3
DTAP Di-tert-amyl peroxide (Trigonox 201) 10508-09-5
DTBP Di-tert-butyl peroxide (Trigonox B) 110-05-4
EHP Bis(2-ethylhexyl) peroxydicarbonate (Trigonox EHP) 16111-62-9
LPO Dilauroyl peroxide (Laurox) 105-74-8
MPDC Dimyristyl peroxydicarbonate (Perkadox 26) 53220-22-7
TBCPDC Bis(4-tert-butylcyclohexyl) peroxydicarbonate (Perkadox 16) 15520-11-3
TBHP Tert-butyl hydroperoxide (Trigonox A) 75-91-2
TBPB Tert-butyl peroxybenzoate (Trigonox C) 614-45-9
TBPEH Tert-butyl peroxy-2-ethylhexanoate (Trigonox 21) 3006-82-4
TBPIB Tert-butyl peroxyisobutanoate (Trigonox 41) 109-13-7
TBPP Tert-butylperoxy pivalate (Trigonox 25) 927-07-1
* Cadet, Laurox, Lucidol, Perkadox, Trigonox are tradenames of Akzo Nobel.
10

IX.
Listing of Organic peroxides from Acros Organics
Acros Cat no
Chemical Name
34988 Dicumyl peroxide, 99%
10515 2,2'-Azobis(isobutyronitrile), 98%
34993 Di-tert-butyl peroxide, 99%
21178 Dibenzoyl peroxide, 75%
34980 1,1-Di(tert-butylperoxy)cyclohexane, 50%
34996 Cumyl hydroperoxide, 80%
34974 Dilauroyl peroxide, 99%
34994 3,6,9-Triethyl-3,6,9-trimethyl-1,4,7-triperoxonane, 41%
34977 1,1--Di-(tert-Butylperoxy)-3,3,5-trimethylcyclohexane, 75%
34983 2,2-Di(tert-butylperoxy)butane, 50
34986 tert-Butyl peroxyacetate, 95%
17014 tert-Butyl peroxybenzoate, 98%
34985 tert-Butylperoxy 2-ethylhexyl carbonate, 95%
34975 2,2'-Azobis(2-methylbutyronitrile), 98%
34981 tert-Butyl peroxy-3,5,5-trimethylcyclohexane, 97%
34984 tert-Butylperoxy isopropyl carbonate, 75%
34989 di(tert-butylperoxyisopropyl)benzene, 96%
34991 tert-Butyl cumyl peroxide, 95%
34990 2,5-Dimethyl-2,5-di(tert-butylperoxy)hexane, 92%
18034 tert-Butyl hydroperoxide, 80%
34998 2,3-Dimethyl-2,3-diphenylbutane, 95%
34997 3,4-Dimethyl-3,4-diphenylhexane, 98%
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