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Electro-DeprotectionЧElectrochemical Removal of Protecting Groups.

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1181 A . I . Meyers, G. Knaus, and K . Kamata, J. Am. Chem. SOC.96, 268
(1974); A. I . Meyers and G. Knaus, ibid. 96, 6508 (1974); A . I . Meyers,
G. Knaus, K . Kamata, and M . E. Ford, ibid. 98, 567 (1976).
1191 Commercially available from the following sources: a) Parke-Davis
& Co., Industrial Products Division, Detroit, Michigan; b) Aldrich
Chemical Co., Milwaukee, Wisconsin; c) Elars Biochemical Co., Fort
Collins, Colorado.
[20] C. E. Whitten, M . E . Ford, and A. I . Meyers, unpublished results.
[21] A. I . Meyers and K . Kamata, J. Org. Chem. 39, 1603 (1974); A . I .
M e y r s and K . Kamata, J. Am. Chem. SOC.98. 2290 (1976).
[22] A. I . Meyers and C . E. Whitten, J. Am. Chem. SOC97, 6226 (1975).
[23] A . I . Meyrrs. E. D. Mihelich, and K . Kamata, J. Chem. Soc. Chem.
Commun. 1974, 768.
[24] A . I . Mryers, E. D. Mihelich, and R . L. Nolen, J. Org. Chem. 39,
2783 (1974).
[25] A . I . Meyers and E. D . Mihelich, Heterocycles 2, 181 (1974).
[26] A. I . Meyers and E. D. Mihelich, J. Org. Chem. 40, 1186 (1975).
1271 E. D. Mihelich, Ph. D. Thesis, Colorado State University 1975.
[28] U . Schollkopf and D. Hoppe, Angew. Chem. 82, 483 (1970); Angew.
Chem. Int. Ed. Engl. 9, 459 (1970).
[29] A. I . Meyers, G. Knaus, and P . M . Kendall, Tetrahedron Lett. 1974,
1301 A . I . Meyers and P . M . Kendall, Tetrahedron Lett. 1974, 1337.
[31] 0. Cervinka and 0 . Belousky, COIL Czech. Chem. Commun. 30, 2487
( 1 965).
1321 S. R . Landor, A. R . Tarchell, and B. Miller, J. Chem. SOC.Cl966,
2280; C1967, 197.
[33] G. M . Giongo, F . DeGregorio, N . Palladino, and W Marconi, Tetrahedron
Lett. 1973, 3195.
[34] G. Giacomelli, R . Menicagli, and L. Lardicci, J. Org. Chem. 38, 2370
[35] S. Yamaguchi and H . S. Mosher, J. Org. Chem. 38, 1870 (1973).
[36] A. I . Meyers and M . E . Ford, Tetrahedron Lett. 1974, 1341.
[37] 7: D. Inch, G. J . Lewis, G. L. Sainburg, and D. J . Sellers, Tetrahedron
Lett. 1969, 3657.
1381 J. D. Morrison and H . S . Mosher: Asymmetric Organic Reactions.
Prentice-Hall, Englewood Cliffs 1971, pp. 415-417.
[39] A. I . Meyers and E. W Collington, J. Am. Chem. SOC.92, 6676 (1970);
R. S. Brinkmeyer, E. W Collington, and A. I . Meyers, Org. Synth.
54, 42 (1 974).
[40] 0. H . Oldenziel and A. M . uan Leusen, Tetrahedron Lett. 1974, 163,
[41] For a general discussion of this concept termed “umpolung” see D.
Seebach and D. Enders, Angew. Chem. 87, I (1975); Angew. Chem.
Int. Ed. Engl. 14, 15 (1975).
[42] J . E. Dubois and C. Lion, C. R. Acad. Sci. C 274,303 ( 1 972); Tetrahedron
29, 3417 (1973); Bull. SOC.Chim. Fr. 1973, 2673; C. R. Acad. Sci.
C277, 1383 (1973).
[43] A . I . Meyers, E . M . Smith, and M . S. Ao, J. Org. Chem. 38, 2129
[44] A . I . Meyers and M . E. Ford, Tetrahedron Lett. 1975, 2861.
[45] K. Hirai, H . Matsuda, and I! Kishida, Chem. Pharm. Bull. 20, 2067
[46] A. I . Meyers and M. E . Ford, unpublished results.
[47] A . I . Meyers and M . E. Ford, Tetrahedron Lett. 1975,2861
[48] A. 1. Meyers, D. L. Temple, D. Haidukewych, and E . D. Mihelich, J.
Org. Chem. 39, 2787 (1974).
[49] W E. Parham and I! Sayed, J. Org. Chem. 39,2053 (1974).
[50] H . W Gschwend and A . Hamdam, J. Org. Chem. 40, 2008 (1975).
[51] A. I . Meyers and E. D. Mihelich. J. Org. Chem. 40, 3158 (1975).
[52] A. I . Meyers and E. D. Mihelich, J. Am. Chem. SOC.97, 7383 (1975).
1531 From the Gomberg reaction: W E. Bachman and R . A . Hojfmann,
Org. React. 2, 224 (1944); 0. C. Dermer and M . 7: Edison, Chem.
Rev. 57, 77 (1957); D. R . Augood and G. H . Williams, Chem. Rev.
57, 123 (1957). From the Ullman reaction: P . E. Fantan, Chem. Rev.
64, 613 (1964).
[54] W Wolfand N . Kharasch, J. Org. Chem. 30, 2493 (1965).
[55] E. C . Taylor, F . Kienzle, and A . McKillop, J. Am. Chem. SOC. 92,
6088 (1970); E. C . Taylor, H . W Altland, and A. McKillop, J. Org.
Chem. 40, 2351 (1975).
[56] J . F. W Keana and T. D . Lee, J. Am. Chem. SOC.97, 1273 (1975).
[57] R . R . Curris and R . G. Fenwick, Chem. Phys. Lipids I I , 1 1 (1973).
[58] J . F . Hanson, K . Kamata, and A. I . Meyers, J. Heterocycl. Chem.
10, 711 (1973).
[59] R . Andreasch, Monatsh. Chem. 5 , 33 ( I 884).
Electro-DeprotectionElectrochemical Removal of Protecting Groups[**]
By V. G . M a i r a n o v s k y [ * l
The reactions of electrochemical splitting may be successfully used for removal of protecting
groups. Theoretical and preparative aspects of the method of electro-deprotection are discussed,
and examples of its use are given. The removal often requires high potentials. The use of
modified protecting groups (“inner activation”) or of catalysts (electron carriers) which facilitate
electron transfer against the standard potential gradient (“external activation”), can greatly
increase the scope of the electrochemical method.
1. Introduction
Temporary blocking (protecting) of definite centers of a
molecule which prevents them from undesirable change in
the course of the reaction is a widely adopted method in
many syntheses, especially in peptide and carbohydrate
[*] Dr. V. G. Mairanovsky
All-Union Institute for Vitamin Research
1 17 246, Moscow (USSR)
[**I Basedon a report to the VIII All-Union Conference on Organic Electrochemistry (cf. also Ref. [l]).
Angew. Chem. I n t . Ed. Engl.
1 Vol. 15 (1976) No. 5
Removal of the protecting groups is usually carried out by more or less severe chemical treatment, frequently
at higher temperatures and in the presence of acids or bases
which may cause degradation or racemization.
As shown by recent investigations many protecting groups
used in the synthesis of organic compounds can be removed
by electrochemical reactions. Mild reaction conditions and
the possibility of smooth variation in the strength of reagent
(electrode)by merely changing its potential makes electrolysis
a very attractive method for such conversions. In principle
all reactions for the cathodic cleavage (electroreduction) of
chemical bonds could be used.
2. Electrolysis Conditions-Influence
pH Value
of Solvent and
Although the first instances of cathodic bond cleavage
(C-0 in hydro~yketones'~],
C-N in aminoketones and amin o n i t r i l e ~'I,[ ~C-S
in thionesf6I) were observed in solutions
with a high con&nt of orotoqdonors. in mapv cases,aDroticgolvents seem to be more suitable"]. Their high stability toward
electroreduction permits working at as highly negative potentials as are required for the removal of most protecting groups.
In addition, the low content of proton donors in the solution
helps to decrease the rate of competitive protolytic reactions.
The possibility of competition between two chemical reactions-bond
cleavage and protonation after an electron
transfer-was apparently first noted in the reduction of p,yunsaturated alcohols : sorbyl alcohol ( I ), cinnamyl alcohol
(2), and vitamin A (3)['].
The negligible difference in half-wave potentials for the
cathodic reduction of unsaturated alcohols of type ( 4 ) and
the unsaturated hydrocarbons R-CH=CH,
led us to the conclusion that the two reactions have a common intermediate
product-namely, the radical anion (5) [Eq. (a)][81.
R-CH=C H-C H i
[R-(C H
OA c
a$-Unsaturated sulfones" 3, I4l, pyridine carbonitriles'' 'I,
benzoin and furoin" 'I, chloromaleic and chlorofumaric
acids["], 2,2-dichloronorbornane and its chloro-bromo analogs[''], as well as 4-(chloro~tyryl)pyridines~'~~
and other compounds, were also reduced in this way.
A direct indication that the use of aprotic solvents is preferable in electroremoval of the protecting groups follows from
a comparison of the reduction of cinnamyl ethers ( 1 2 ) in
and in DMF: in methanol the cinnamyl moiety
evidently cannot be used as a protecting group (hydrogenation
of the ethylene bond is to be expected instead of C-0 bond
cleavage) but it can in DMF~Z'*221.
e. [Ha]
Predominant formation of the hydrocarbon (6) in the electrolysis of ( 4 ) in dimethylformamide (DMF) was ascribed
to the higher rate of C-0 bond cleavage in radical anion
(5) compared to the rate ofprotonation under these conditions
(DH =proton donor):
It was natural to expect that the increase of protonic activity
of the solution be accompanied by an increase in V, and
therefore that the yield of the desirable ("cleaved") product
(6) would decrease: when V, > V, the formation of the saturated alcohol (7) should predominate.
[*] Apparently, Given and Peouer were the first to observe the cleavage
of a C 4 bond in an aprotic medium during the electroreduction of 9,lO-anthracenediol in dimethylformamide [7].
Such a mechanism, in fact, was found to be of common
occurrence (see also Ref. [ S ] ) . Thus, in the electroreduction
of ubichromenol (8) (inner ether of a substituted cinnamyl
alcohol4yclic isomer of ubiquinone) or naphthochromenol
( 9 ) [a similarly derived vitamin K derivative; reaction (b)]
in D M F a corresponding hydroquinone derivative is formed
-.. - J ~ x ~ ~ ~ ? r n g L &
-ilt$~:?:r?: - ~ imukfrcxmc-id
ative was the main product of the electroreduction in the
presence of proton donors; this could also be obtained in
high yield["I.
It should be noted however that in some cases (for example
in the removal of tosyl or benzoyl protecting groups) the
use of an aprotic medium is not necessary. Protonation and
cleavage reactions d o not compete with each other here (see
Sections 3.1 and 3.2). In contrast electroreduction of the C-N
bond in a-aminoketones requires previous protonation of the
nitrogen atom[' - "1.
An important condition is maintaining the proper acidity
(basicity) of the medium during electrolysis. For example,
an increase in pH in the catholyte may not only change
the direction of the reaction but also result in the undesirable
removal of a protecting group, racemization etc. Monitoring
and control of the pH during the electrolysis are beset with
difficulties. Since the pH-meter reading can change by a few
hundred mV after the current is switched on either the electrolysis must be interrupted during the pH-measurements[281
or a complicated arrangement must be resorted to which
allows electrical isolation of the solutions in the electrolyzer
and in the pH-meter cell[29].
Angew. Chem. Int.
Ed. Engl.
Vol. I S ( 1 9 7 6 ) N o . 5
Assuming that this effect is for the most part brought about
by the drop in potential (iR)between the pH-meter electrodes
we decreased the distance between them. We succeeded in
almost completely eliminating the interferences, even in nonaqueous solvents, by using a special pH-meter sender. This
differed from the usual arrangement in that one end of the
electrolyte bridge of the reference electrode was in direct contact with the membrane of the glass electrode (Fig. 1).
toluenesulfinic acid in good yields (55-98 %). The process
was carried out without control of potential; S-0 and S-N
bond cleavage was explained by the action of tetramethylammonium amalgam formed at the cathode. In later work[32.331
a direct electrochemical reduction was proposed [Eqs. (d)
and (e)].
2 c.
Fig. 1. Electrode sender for pH control during electrolysis. 1 : glass electrode;
2: calomel electrode casing; 3: electrolytic bridge; 4: holder.
A pH-stat system[30]constructed with such a sender was
used in most of our experiments on electro-deprotection; the
working point mostly corresponded to the solvent (DMF)
acidity. Moreover, the consumption of acid and current was
recorded automatically, so we were able to determine continuously the number of electrons and protons consumed
during the process. (A detailed description of the arrangement
and examples of its use in studying the mechanism of electroorganic reactions is given in Ref. [30].)
Effective maintenance of the pH value necessitated vigorous
stirring of the solution. Sometimes buffer components (e.g.
phenol) were added to the solution to raise the efficiency
of the system.
In other respects the conditions of electrolysis did not differ
from those usually employed (mercury or lead cathode, glass
frit or alundum diaphragm, potentiostat, bubbling of inert
gas etc.). In some cases we were able to dispense with a
diaphragm; it was found that performing the electrolysis under
these conditions was not accompanied by large changes of
pH, probably because of partial neutralization of the basic
and acidic products formed at cathode and anode, respectively.
To prevent alkalinization of the catholyte during electrolysis
in a nonaqueous medium, Saueant and Su Khac Binh[”’] have
suggested carrying out the electrolysis without a diaphragm
at a platinated Pt anode with hydrogen bubbling.
Contrary to the usual methods of tosyl cleavage the process
was not complicated by side reactions and did not cause
a marked decrease in optical purity, as observed in the cases
of menthol, borneol and cholesterol derivatives.
According to our investigations[341the tosyl protecting
group (Tos) in amino acids and aromatic or aliphatic amines
and alcohols can also be cleaved in 70-90 % yield in an
aprotic solvent (solution of (AlkylkNI in DMF). The ease
of S-0 and S-N bond cleavage decreases in the following
sequence: Tos-0-Ar
> Tos-0-Alkyl,
> Tos-NH-CH(Alkyl)-COOHC‘I.
All these experiments show that it is possible to remove
0-tosyl groups by electrolysis without affecting N-tosyl groups
of amino acids and aliphatic amines. Mann et al. reported
the possibility of using another aprotic solvent (acetonitrile)
in the detosylation reactions[353
The formation of identical products during electrolysis in
different solvents does not mean that the mechanisms of the
reactions are identical. The demonstrated correlation between
substituent constants and polarographic half-wave potentials
in different media (DMF, dimethyl sulfoxide, acet~nitrile[~’I
pyridine, benz~nitrile[~~],
DMF in aqueous alcohol[391)does
not seem to be sufficiently informative.
On the contrary there are data indicating a significant
influence of the experimental conditions (including the nature
of the anion in the supporting electrolyte, and of the cathode
on the course of the electroreduction of arenesulfonates; the mechanism of the reaction evidently cannot be
concluded with absolute certainty.
Detection of toluene during electroreduction of alkyl tosylates in acetonitrile led the authors[351to conclude that two
parallel reactions occur: the S-0 bond cleavage(final products
are alcohol and sulfinic acid) and C-S bond cleavage (the final
products may be alcohol and toluene). The latter reaction
was predominant when arenesulfonamides were reduced in
aqueous, buffered solutions[401[**I.
3. Electrochemical Removal of Protecting Groups
3.1. Removal of the Tosyl Group
In 1965 Horner and N e ~ r n a n n ‘discovered
that the reduction of esters or amides of p-toluenesulfonic acid (TosOH)
at a mercury cathode in methanol in the presence of tetramethylammonium chloride led to free alcohols (or amines) and
Angew. Chem. Int. Ed. Engl.
1 Vol.
15 (1976) No. 5
[*] The -.E,,* values (us SCE) within the groups of substances mentioned
fluctuated between 1.99kO.03; 2.20i0.06; 2.55k0.08, 2.67k0.04V. In the
case of N-tosyl-a-amino acids a “hydrogen” wave was observed in the polarogram, its - E , , 2 value lies between 2.1 and 2.3 V (cf. also V. G. Mairanousky
and N. F. Loginova, Bioorg. khim., in press).
[**I There is evidence available that electroreduction of N-tosylamino acids
in acid/alcohol medium does not lead to free amino acids [41].
Two such parallel reactions (routes A and B) can also
be demonstrated in the case of homogeneous electron transfer
to arenesulfonates and arenesulfonamides; thus, e. g. in the
reduction of N-tosylamino acids or -peptides by Na in liquid
ammonia[421,in the reduction of tosylates by naphthalenesod i ~ m [or~ in
~ ]the reduction of tosylamides by arene radical
anions in dimetho~yethane[~~I.
No cleavage of the C-S bond has been observed, however,
in the electroreduction of ditosylates (TOS-O(CH~)~--OTos, n=2-6) in DMF[451and of arenesulfonamides in acetonitrile[361.Formation of toluene, which would indicate that
the reaction followed “route A”, was also not observed in
our experiments on electroreduction in DMF[341.
We do not wish to dwell on the possible reasons for the
above mentioned differenced’] but rather to discuss in more
detail the frequently occurring case where the reaction proceeds predominantly oiu “route B 1 3 34* 36,45*461.
It is usually accepted that the S-X bond in arenesulfonates,
arenesulfonamides and arylalkylsulfones is cleaved after the
transfer of a second electron [eec mechanism Eq. (f)][**].
The following scheme of reduction [Eq. (g)] seems the more
likely (ece mechanism):
Here Ez>El[’]; accordingly a two-electron wave is to be
expected in the polarogram. The radical anion [Ar-SO2XIe quickly dissociates when X = OR, NR’R” or Alkyl; when
X=C,H, dissociation does not take place on the polarographic time scale :
+ XQ
In Eq. (h) E z <El ; one can observe two one-electron waves
in the polarogrim.
In contrast to a number of other cases [see Section 2, Eqs.
electroreduction of tosyl derivatives in a protonic
medium (methanolt3‘I) leads exclusively to formation of cleavage products, because the stepwise protonation of the radical
anion [Ar-S02-X]B
(contrary to Eq. (a)) likewise leads to
cleavage [Eq. (i)].
HX + D@
where X=OR [46], N R R ‘ [36], Alkyl [47]
DH = proton donor (solvent or supporting electrolyte)
This equation also explains the formation of only one oneelectron wave in the reduction of NH-to~ylamides[~~]
the decrease in wave height is attributed to deactivation of
50% of the initial compound (NH-acid) as a result of acid-base
interaction with the anion Xe that is formed (here NHRe).
In addition one should take into consideration volume reactions such as (i) and (k).
- r
Ar- -X
The electrolytic method of removing tosyl groups has
already been applied to the synthesis of cis- and trans-4-mercapto-~-prolines~~*~.
Sensitivity of the pyrrolidine ring in proNevertheless Eq. (f), which demands that the two electrons
be transferred at exactly one and the same p ~ t e n t i a l [ ~ ~ . ~ ’ ] line towards acid media and the instability of the protecting
(a common two-electron wave in a polarogram) does not
group on sulfur under conditions of catalytic hydrogenolysis
seem convincing. In fact, proceeding from Eq. (f) it is dificult
limited the use of chemical methods to remove a tosyl group.
Recently, Japanese authors[49*501 showed the possibility of
to explain why two separate one-electron transitions occur[46)
reducing the cost of the procedure (a mercury electrode was
in the case of diarylsulfones (when X=Ar) but not in the
replaced by a lead electrode and Ke and Na@cations were
case of arylalkylsulfones (X=Alkyl). At the same time Eq.
used instead of tetraalkylammonium cations) and conducted
(f) predicts insuficient negative values of ElI2 for the reduction
the electrolysis of N-tosyl amino acids in aqueous methanol
of the radical anions [Ar-SOZ-Alkyl]e.
Thus it gives
on a lO’-gram
The necessity of strictly maintaining
Ell,= -2.36 Vl4’] (or even still less negative values) us SCE
for [H5C,j-s02-cH3]e,
while for [ H ~ C ~ - S O Z - C , ~ H ~ ] ~ , a pH value of 11 during the experiment was especially emphasized; the authors used an automatic titrator for this purpose.
which should be more easily reducible, a value of Ell,=
When the electrolysis was performed without pH control the
-2.52 V was measured[***].The data obtained in the experiments
yield dropped by more than half and racemization took
on delayed homogeneous electron transfer against a standard
potential gradient provide further evidence against Eq. (f)
Cox and Ozrnent[l’zland Horner and Me~er[’‘~]
have demon(see Section 4.2 and Table 1).
strated for the case of diarylsulfones a reaction mechanism
[‘I R. Gerdil [46] recently attempted to explain the different contributions
which differs from the mechanism proposed by us [Eqs. (9)
of processes “ A and “ B by their dependence on the proton donor properties
and (i)] in that it does not include cleavage of the radical anion.
of the medium.
e =electron transfer, c =chemical stage (cleavage).
[***I This J!?,,~value is taken from Ref. [46] and calculated relative to SCE.
-pans that potential E2 is less negative than E ,
Angew. Chem. Int. Ed. Engl.
Vol. I S ( I 976) No. S
3.2. Removal of the Benzoyl Group
Information on the polarographic activity of the amides
and esters of benzoic acid (Bz-NH2 and Bz-OR) first
appeared in the late fifties[51*
521. In connection with the problem of removing protecting groups Horner et al. pointed out
the possibility of reducing benzoyl derivatives electrochemicallyf3 331. Electrolysis of esters and amides in 1 M tetramethylammonium bromide in methanol afforded alcohols or amines
in 60-90% yield and benzyl alcohol (in approximately equivalent amounts).
Electrochemical removal of the benzoyl protecting group
from the carbohydrate (13) in DMF proceeds in good yield
and without attack at the benzylidene group[601.If both groups
are to be removed simultaneously from the carbohydrate,
then a more negative potential must be chosen for the electrolysis[601.
It has been found that benzoyl derivatives are slightly more
difficult to reduce than tosyl derivatives[33]"]; Eq. (n) shows
the possibility of selectively removing the tosyl protecting
group in presence of the p-anisoyl (p-methoxybenzoyl)
Horner's data for the electrochemical cleavage of C-N
bonds confirms the results recently obtained in a polarographic
study of benzamide and its derivatives in protonic
In contrast to literature dataf5*]we established that methyl
benzoate and benzamide can also be reduced in aprotic media,
the first stage being a one-electron
leading to
relatively highly stable radical anions[591.Nevertheless, during
the electrolysis of P-~-methyl-2-benzoyl-4,6-O-benzylidenegalactopyranoside (13) [see Eq. (q)] in DMF at the potential
of the first wave (generation of a benzoyl radical anion), it
was observed that the second benzoate wave gradually disappeared, thus indicating transformation of the radical anion
in the solution. Such a behavior is typical for ece-processes.
Formation of the debenzoylated carbohydrate ( 1 4 ) during
the electrolysis indicates that one of the chemical stages is
cleavage of a C-0 bond [Eq. (o)].
3.3. Removal of Trityl, Benzhydryl, Benzyl, Phenyl, and Cinnamyl Groups
The trityl (triphenylmethyl), benzhydryl (diphenylmethyl),
benzyl, and phenyl groups are used for the protection of
hydroxyl, amino, and carboxyl groups as well as phosphoric
2e. 2 [H"1
H3,C 5-C C-NH-C
H2-C H 2 0 H + C in-H
4 e . 4 [Ha]
H,,C ,,-CH=CH-C H-CH-CH,-O-Cin
+ 2 Cin-H
OH ih-CO-C15H3,
H3,C ,,-CO-NH-C
H,-C H,-O-Trt
2 e , 2 [Hal
+ HTrt
(t )
2 e, [Ha]
Like the tosyl radical, on electroreduction the benzoyl radical
Bz' can accept an electron either from the electrode or from
the benzoate radical anion [BzORIe ; in principle the radical
can still also undergo other reactions (dimerization, abstraction of H'from the medium, etc.). The reactions of the benzoyl
derivatives, like those of the tosyl derivatives, do not change
on going over to the use of protonic media (cf. Ref. [33]).
This means that the C-0 bond may also cleave after the
protonation [cf. Eq. (p) and Eqs. (i) and (k)].
(0H3C-C &-)3
+ H&6-CH3
2 e. [He]
+ H&&H3
[*] We have found that this is not the case in DMF (see Table 2).
Angew. Chem. Int. Ed. Engl.
1 Val. 15 (1976) No. 5
acid esters; we suggested the cinnamyl group (Cin, see Section
4.1) be used for the blocking of the hydroxyl group’611.
According to polarographic measurements cinnamyl[”. 8]
and trityl ethersc6’], benzyl and phenyl phosphates[63,641, as
well as trityl, benzhydryl, benzyl, and phenyl esters of carboxylic acids[65,661 are electrochemically active in the supporting
electrolyte (0.04 M tetraethylammonium iodide in anhydrous
or 95 % aqueous DMF). All of these protecting groups can
be removed under the conditions of preparative electrolysis.
Several examples of such transformations, e. g. with derivatives of N-(2-hydroxyethyl)palmitamide (16), erythro-N-palmitoylsphingosine (1 7) are given in equations (r)-(x); the
yields of the products were 70-90 % [ 6 1 - 6 5 1 .
The preparation of cellulose from 6-U-tritylcellulo~e[’~
also serve as an example of electrochemical removal of the
trityl protecting group [Eq. (y)]. The electrolysis was carried
out with 0.1 M tetraethylammonium iodide in DMF. Free
cellulose, which is very sparingly soluble in this solvent, precipitated out immediately it was formed; no decomposition products were observed. Electro-deprotection is very promising
for use in the synthesis of modified polysaccharides.
- 7 H-COOH
2 e. 2 [He]
ysis of N-acetyl-S-benzylcysteine results in formation of N acetylcysteine in good yield (82 %) [Eq. (z)].
The electrochemical method for removal of the S-benzyl
protecting group is especially promising for preparation of
complicated peptides, as chemical methods often lead to undesirable side reactions (see e.g. Ref. c7’1).
According to Horner’s and Neumann’s findings[”], which
have been confirmed by other a ~ t h o r s [ ~ * the
* ~ ~S-benzyl
protecting group is not removed by electroreduction in methanol. Evidently other reactions of type (t)-(y), which require
high cathodic potentials, cannot be carried out in this solvent.
In the reactions (r) and (s) there is the danger of possible
competitive protonation of an intermediate radical anion in
methanol in accordance with Eq. (a).
3.4. Removal of the Benzyloxycarbonyl Group
The reduction of ethers (Eqs. (r)-(t)) proceeds according
to the mechanism given in Eq. (a) (see Section 2). It must
be pointed out however that the residues of other unsaturated
alcohols investigated in Refs. [8, 91 may be also be used as
protecting groups.
Interest attaches to the difference in behavior of the esters
of aromatic and aliphatic carboxylic acids, e. g. isomeric methyl
benzoate ( 2 0 ) and phenyl acetate (21 )[66].The sites ofcleavage
are indicated. Compound (21 ) is reduced at a potential ca.
0.6V more negative than that at which ( 2 0 ) is reduced and
without separation of the one-electron stage (formation of
the radical anion) from the following stages. The different
behavior of ( 2 0 ) and (21 ) can be rationalized on a quantum
mechanical basis (position of the LUMO, degree of charge
delocalization in the radical anion, etc.). As an estimation
of the bond energies shows[661,the site of bond cleavage
in ( 2 1 ) does not coincide with the least stable bond of the
molecule in the ground state.
Benzyl derivatives of aliphatic alcohols are not reduced
below the discharge potential of tetraethylammonium iodide
in D M F (ca. -2.9V us SCE)[*]. At the same time we found
that alkylbenzyl sulfides[681are polarographically active due to
the electrochemical cleavage of the C-S bond[**].Thus electrol-
In DMF with (n-C.,H,),N@CIO,R as supporting electrolyte, alkyl benzyl
ethers are first reduced shortly before discharge of the electrolyte [67];
thus e . g . butyl benzyl ether has a half-wave potential of cu. -3.1 V in
this solution.
The electrochemical reduction of diaryl-, arylalkyl-, dibenzyl- [69], and
arylbenzhydryl sulfides [70] has also been reported.
The benzyloxycarbonyl group (Z) is one of the most important groups for blocking the amino function, e.g. in peptide
syntheses[72! Chemical methods cannot always be used for
its removal; this is so e. g. in the synthesis of some complicated
polyfunctional compounds (uide infra).
It has already been reported that the N-benzyloxycarbonyl
group cannot be removed by electrolysis in methanol solut i ~ n [ ~ ’ 491.
, ~ *We
, succeeded in removing this protecting group
in good yield (70-80 %)however by electroreduction in D M F
at a high negative potential[731.The reaction, which is revealed
in the polarogram by a rise in current before discharge of
the supporting electrolyte, can be formulated as in Eq. (aa)
(COzreduction is not included in the equation of the reaction).
Electrolysis can also be used for removal of the Z protecting
group from hydroxyl and thiol groups. Thus, in the reduction
of Z-protected butanol equivalent amounts of butanol (70 %)
and toluene are obtained[68!
The reduction of S-benzyloxycarbonylcysteine gives cysteine; the ease of removal of the protecting group increases
in the series: amine < alcohol < thiol (El,’ of the Z-derivatives
of n-butylamine, a-butanol and cysteine are -2.9, -2.7 and
- 2.62 V, resp., us SCE). The removal of the N-benzyloxycarbony1 group from amino acids in D M F was not accompanied
by marked racemization[’].
The electrochemical method for removal of the benzyloxycarbonyl group was used in the synthesis of glycerol phosphatides containing residues of unsaturated acids[64.741, which
naturally do not permit removal of the protecting group by
catalytic hydrogenolysis. An example is the preparation of
Angew. Chem. I n r . E d . Engl.
1 Vol. 1 5
(1976) No. 5
the phosphatidylserine derivative (23) from compound
(22)[741, in which all three protecting groups were removed
by electroreduction at - 2.9 V in the final stage of the synthesis.
3.5. Removal of the Benzylidene Group
This group, which is widely used in carbohydrate chemistry
for blocking hydroxyl groups, is usually removed by acid
hydrolysis or catalytic hydrogenation. We found that benzylidene derivatives of carbohydrates can be reduced polarographically in DMF at a potential at which discharge of the
supporting electrolyte (0.04 M tetraethylammoniumiodide) begins. Preparative electrolysis of j3-~-methyl-4,6-O-benzylidenegalactopyranoside ( 1 4 ) yielded the methylgalactoside (15)
and toluene [Eq. (ad), cf. Eq. (q)].
4 c . 4 [Hal
(14) -(15)
-2.9 v
A variant of this activation method is the introduction
of electron acceptors (A) at definite sites of the protecting
group[781.Taking into consideration the activating effect of
a nitro group on the reductive splitting of halogen, as was
observed in nitro halo alkane^[^^^ and later in nitrohalobenzenes[so-851,we tested the nitro
861 as activating substituent A.
The possibility of removing nitro-substituted protecting
groups by reduction at the potentials of the first polarographic
wave of the nitro group was first established in the case
of the p-nitrobenzyl ester of N-acetylglycine ( 2 4 ) , p-nitrobenzyloxycarbonylalanine (25), and N-(o-nitrophenylsulfeny1)phenylalanine (26). In order to avoid decomposition of the
substance by attendant bases the electrolysis was carried out
with pH-control at the “pH” of DMF. In all cases the protecting group could be removed and the corresponding amino
acid was formed in good yield [Eqs. (ae)-(ag)]r781.
It is interesting to note that C-0 bond cleavage during
the electroremoval of protecting groups from carbohydrates
occurs at rather less negative potentials than in the case of
protected aliphatic alcohols[60!
4. Electrodeprotection with Activation
As can be seen from the previous Sections electrochemical
removal of protecting groups requires rather high cathodic
potentials (from ca. -2.0 to ca. -3.OV us SCE). It should
be possible to extend the working range to less negative potentials and thus increase the scope of the method.
A similar effect was also demonstrated in the case of the
As in the activation by lengthening of
a conjugated system (benzyl + cinnamyl, vide supra) introduction of a p-nitro substituent shifts the potential necessary
for removal of the protecting group into an accessible range;
in the case of the butyl derivative ( 2 7 ) Eliz is shifted more
than 1.8V. The yield of butanol is 60%. The electrolysis
was performed at the “pH” of DMF.
4.1. Directed Modificationof Protecting Groups (“Inner Activation”)
This problem could be solved in principle by increasing
the electron affinity of the protecting group by introduction
or elongation of a conjugated chain. If the reaction proceeds
via formation of a relatively stable radical anion [RCH=CH-X]e
[Eq.(a)], the ease of removal of the protecting
group should compare to a first approximation with the ease
of reduction of the corresponding unsaturated hydrocarbon.
The dependence of the ease of reduction of unsaturated hydrocarbon on the parameters of the n-electron system (aroma761 or linear conjugated[77])
is described by known quantum mechanical correlations. An example is the use of the
cinnamyl moiety C6H5CH=CHCH2 instead of the benzyl
moiety C6H5CH2[6’1for blocking the hydroxyl group: the
former is removed smoothly at - 2 S V (us SCE) while the
latter remains secure until discharge of the supporting electrolyte (see however Footnote [*] in Section 3.3).
Angew. Chrm. Inr. Ed. Engl.
1 Vol. 15
(1976) No. 5
In principle the mechanism of reactions (ae)-(ah) does
not differ from the previously studied reduction of nitrohaloarenes[81.821
. However, our experiments on the use of cyclic
voltammetry showed that the radical anions [X-Ar-NO,]
formed here are much more stable (rate constant of decomposition <0.1 s- I). The slow decrease in current during electroreduction of nitro compounds at the potentials of the first
wave of the nitro group should be noted. It is evidently
connected with the participation of radical anions [ e . g.
in Eq. (ah)] in homogeneous electron
transfer reactions which regenerate a neutral compound (nitrotoluene). The starting substance (27), oxygen, and any other
impurities present in the solution, can all serve as electron
acceptors in such a catalytic conversion.
Besides the nitro group other electron accepting substituents
(carbonyl, nitrile, halogen, etc.) can also be used as activating
groups. The activating effect of a nitrile group manifests itself
by the easier removal of halogen from haloarenecarbonitriles;
for instance,
of chlorobenzene in D M F is ca. -2.8V,
and that ofp-chlorobenzonitrile is - 1.93 V (us SCE; calculated
from the data described in Ref. [87]). Similarly the p-cyanotoluenesulfonyl protecting group is removed at a much less
negative potential than the toluenesulfonyl
The activating effect of halogens is particularly well revealed
in the haloethoxy and haloethoxycarbonyl groups‘88!
Examples of the ready removal of such protecting groups
by electroreduction in methanol with 0.1 M LiC104 are given
in Equations (ai)-(ao). The potentials are referred to SCE;
the yields are 50-100 %[“I.
H & 6-CO-0-c
H2-CH Clz
H & 6 - c OOH
Hz-C C1,
P -H~C-CGH~-NH-CO-~-CH,-C C13
P - H3C-C 6H4-N H-C 0-0-C Hz-C HC 12
P-H3C-C 6H,-NH2
-2 15 v
P-H3C-C 6H4-N Hz
H ~ C ~ - C H ~ ~ C O - C + C H ZC1,
HsC6-C H2-S-C 0 - 0 - C H2-C C13
H,C 6-C H,SH
In these cases activator and protecting group are removed
together. It must be pointed out that transformations (ai)-(ao)
are similar to the electroreduction of vicinal haloethanes with
and of h a l o a l c o h ~ l s [ ~ The
~ ! homogeneous reduction of 2,2,2-trifluoroethyl ethers with naphthalenesodium proceeds in much the same way[’’].
CioHsQ, [@I
HzC=CE‘z + F@
One can consider that the scheme of “conjugated cleavage
of halogens” proposed by Feoktistou et al.[891 may also be
applied to the reactions (ai)-(ao), i. e. they may proceed via
a concerted mechanism.
In a detailed interpretation of the reaction mechanism the
formation of small amounts of dichloro from trichloro compounds [6% and 26%, reactions (aj) and (an)] observed by
Semmelhack and Heinsohn[881must be taken into consideration. The content of dichloro compounds changes slightly
depending on the solvent (MeOH or DMF) and type of acid
employed (acetic or trifluoroacetic).
These data indicate that here the cleavage of the C-0
bond [Eq. (aq)] and protonation of the radical anion [Eq.
(ar)] are not competitive reactions with participation of one
and the same species [cf. Eq. (a)]. On the contrary, in view of
the results of an investigation by Feoktistou et al. on the
electrochemical[92- 951 reduction of polyhaloethanes an alternative explanation can be suggested : whether the reaction
proceeds according to Eq. (aq) or (ar) depends on the confor288
mation of the participating species. [According to Refs. [92-941
Eq. (ar) can be ascribed to the reduction of the gauche conformer.]
Independently of the method (introduction of a conjugated
system or electron acceptor)modification of a protecting group
presents an opportunity to decrease the potential necessary
for the bond cleavage. The opening of the bond should be
practically irreversible and proceed rapidly in comparison
to the competing deactivation of the radical anion by protonation etc. If these conditions are not fulfilled the protecting
group may not be removed at all on account of its increased
electron-acceptor properties. Thus the p - and o-nitrotoluenesulfonyl derivatives of glycine and n-butanol could not be
split electrochemically on the preparative scale with pH control
(at “pH” of DMF)[ll.As comparative experiments have shown
(storage of the substance in basic D M F solution) the formation
of small amounts of butanol (up to 20 %, GLC) during the
electrolysis of butyl p-nitrotoluenesulfonate without pH-control is connected with the action of strong bases formed in
the cathodic space during the electrolysis.
The electroreduction of p-nitrobenzenesulfonamides in
D M F has recently been studied in detail by Asivuatham and
H a ~ l e y ‘ ~S-N
~ ’ . bond cleavage was found not to occur either,
and the authors suggested that removal of a hydrogen atom
takes place in the case of primary and secondary amides :
p - 02N-C6H4-SOz-NHR
& [ p - 02N-C ~H~-SOZ-NHR]’
- H’
The polarographic activity of trifluoroacetates could be
ascribed to cleavage of a C-0 bond with formation of trifluoroethanol and free alcohol in a four-electron
however, preparative electrolysis at the “pH” of D M F showed
it not to be connected with the removal of a trifluoroacetyl
protecting group but rather with partial defl~orination[’~~’~.
e . 2 [Hs]
+ 2 F@
Thus the introduction of a substituent A which facilitates
electron transfer to a molecule can simultaneously lower the
rate of bond cleavage since the negative charge no longer
prefers this bond. Another reaction takes place instead of
removal of the protecting group.
Utley et al. have demonstrated the cathodic cleavage of the
methoxycarbonyl-activated 0-benzyl protecting group[114!
An ESR study of the structure and kinetics of decomposition
of radical anions in reactions (aeHah) and (as) is reported in
Ref. [I151. The rate constants for bond cleavage are decreased
by introduction of the electron-acceptor substituent A. A
quantum mechanical description of the effect is proposed in
Ref. [116].
4.2. Use of Catalysts as Electron Carriers (“External Activation’’)
The role of an “inner activator” i. e. of an electron-acceptor
substituent is first of all that it facilitates transfer of electrons
to the system. The ensuing process may be regarded as a
very fast (up to 10-12-10- I4s) intramolecular transfer (redistribution) of charge, which provides the prerequisite high electron density on the R-XA bond prior to its cleavage.
Angew. Chem. l n t . Ed. Engl.
1 Vol. I S ( 1 9 7 6 ) No. S
In analogy to the above case (see Section 4.1) we investigated
the feasibility of homogeneous electron transfer from an
external activator A. This must have a high electron affinity
for the substrate S but not form any chemical compound
with it. Obviously the rate of charge transfer should decrease
significantly, for it now depends on the difference of the standard potentials AEo = E: - E$ of substrate S and activator A
and its upper limit is diffusion controlled. If the bond cleavage
is irreversible and both the electron transfer and the bond
cleavage are fast compared to the competitive transformations
of the radical anion A?, the reaction is both thermodynamically and kinetically favorable (cf. Refs. [I, 981).
We carried out electro-deprotection of the substrate (S),
N-(pnitrobenzyloxycarbony1)alanine (25), using 4-nitrobiphenyl in the form of its radical anion A 0 as activator. The
transformation, which proceeds analogously to Eq. (af), was
performed at A E o = -0.1 V (Ey12= -1.14V, E:,2=-1.05V)
in the absence of current and obtained the free amino acid
in quantitative yield"]. When the current was switched on
(i.e. with continuous generation of A?) a catalytic current
should appear similarly to that observed in the systems
quinone/hydroquinone/H,/Pd, nitro compound/camphor/
10: etc. (see review given in Ref. [99]).
This phenomenon predicted by us in 1973['], has in the
meantime been confirmed by three groups of investigators
working independently["'- '", 98,h71; it evidently also
in the experiments described by Margel and
~ ~ ~ ~ [[*I.
l 0 3 1
The transformation of substrate S can be described by
Equations (au)-(az)[',98, 'O', 'O1l.
A and A? are, respectively, the electroneutral and radical
anion forms of the activator, Pe and R H are products, DH is
a proton donor (solvent, electrolyte, etc.), and I the product
of a competitive deactivation of A?. When
AE,= E z - E!:
K 3 <O
the equilibrium constant K 3 is small, and the value K4 (thermodynamic factor) must be high; besides the kinetic condition
k3 > k6 must be fulfilled.
In principle the catalytic current allows determination
of the rate constant of the rate-determining s t e p t h i s is either
the cleavage of the bond (k,) or the electron transfer against the
standard potential gradient (k,). Koutecky's solution['041, for
which a convenient analytical function was recently developed['051,can be used to find k , (if k , is large, but very much
smaller than k,). Britton and Fry recently solved the problem in
[*] It is possible that Sease and Reed considered an analogous process
in 1970 (see reference to the author's report of Reed's thesis in Ref. [loo]).
Unfortunately the works [loll and [lOZ]. were first accessible to us after
contributions [98] and [67] had already been submltted for publication.
Anyew. Chem. Inr. Ed. Enyl.
1 Vol. IS ( 1 9 7 6 ) N o . 5
an analogous case (one irreversible step of type (av)+(aw),
k3 < k4) using the method of chronoamperometry with stepwise
change of potential['06]. We recently discussed the whole process (au)-(az) for arbitrary ratios of k3 and k4 and various
values of K3L1071.
The solution for average polarographic
currents was obtained with the help of a computer which
provided plots of(-&)= F (k,, k4, K 3 )(7, =kinetic limiting current, Td=diffusion current). We shall not go into an analysis
of the individual results['071here, but it must be noted that
the solutions quoted p r e v i o ~ s l y [1051
' ~ ~are
~ not suitable for
the determination of k3 and k4 when these constants are
of comparable order of magnitude.
Not only the cleavage of a bond [Eq. (aw)] can function
as a fast irreversible step but also protonation, for instance
in the activated hydrogenation of a difficultly reducible conjugated hydrocarbon S with the help of the easily reducible
activator A [Eqs. (ba)-(bf)][981:
SH@ + DH
s? + A
+ Do
+ Do
Several different aspects of such reactions have been discussed in the literature[98.l o o - 'OZ1.
Data on homogeneous catalytic electron transfer against the
standard potential gradient for the removal of different protecting groups are listed in Table 1. Electro-deprotection is carried
out at the reduction potentials of the activator; the required
potential can be lowered (by more than 0.6 V) and the process
essentially facilitated.
The use of inner activation by introduction of a conjugated
double bond was discussed in Section 4.1 for the removal
of the 0-benzyl protecting group. Table 1, No. 1 1, demonstrates
the use of external activators for this purpose. The transformation [Eq. (bg)] proceeds according to first order kinetics and
gives butanol and toluene in good yields (100 % and 90 %
re~p.)[~'!Thus one can succeed in carrying out electron
transfer in a potential range lying beyond the discharge
potential of the supporting electrolyte. Another example is
illustrated in Fig. 2.
The possibility is revealed (see examples 6 and 7 in Table
1) of using the "chemical factor", i.e. the different stability
of the radical anions SQ [that is the difference between constants k,, Eq. (aw)] for the selective cleavage of protecting
groups in addition to the electrochemical factor (the difference
in reduction potentials). In fact, despite the higher half-wave
potential (Table 2) the N-tosyl protecting group ( - 2.6 V) is
Table 1. Electron transfer reactions against potential gradient for the removal of protecting groups (in DMF, for conditions see original literature). Z(N0,) =p-nitrobenzyloxycarbonyl, Z = benzyloxycarbonyl, Tos = toluenesulfonyl, Bzl = benzyl.
Z-butylamine [a]
Ethyl toluenesulfonate
Tos-gl ycine
Benzyl isopropyl ether
Benzyl butyl ether
Methyl benzoate
Methyl benzoate
1 -Methylnaphthalene
< -0.38
< -0.38
< -0.23
< -0.33
< -0.25
< -0.32
< -0.38
< -0.63
< -0.43
Yield [%I
Alanine 100
Glycine 100
Glycine 100
Toluene 93
Butanol 100
Toluene 90
~ 7 1
[a] Benzyl-N-butylcarbamate.
[b] Polarographic experiment.
Table 2. Removal of protecting groups by direct electroreduction (for details see text). The values quoted are the average half-wave potentials E , , , in V (us SCE; in
DMF, supporting electrolyte (Alkyl),NmXe). If no value is quoted either the protecting group is not suitable for the molecule to be protected or the possibility of the
electroreduction has not been investigated.
group Y
2.2 [a]
2.3 [a]
2.0 [a]
1.7 [d]
2.2 [d]
1.5 [d]
1.5 [d]
1.7 [d]
1.9 [d]
0.7 [d]
In methanol.
N o removal of protecting group up t o the discharge potential of the supporting electrolyte
Reduction of molecule without removal of protecting group.
In methanol. The given potential is that at which the electroreduction was carried out
removed earlier in D M F than the 0-benzoyl group (-2.3 V),
since it is cleaved faster from the corresponding radical anion
Se. It is interesting that Horner and Singer observed the
same order in deprotection during electroreductions performed in methanol[331(N-tosyl, El,, = -2.2 V ; N-benzoyl,
E l l 2= -2.3 V), but in this case the electrochemical factor was
apparently determining [cf. Eq. (n)].
The directed modification of protecting groups and utilization of activators (electron carriers) permit variation of the
potential at which electro-deprotection takes place. This opens
new prospects for the use of electrochemical methods in preparative organic chemistry.
Different aspects of electron transfer reactions are touched
upon in Refs. [117-1191.
5. Conclusion
A great number of protecting groups (see Table 2) can
be removed by electrolysis. The essential advantages of the
method are:
Protected molecule
a) mild conditions in the electrochemical cleavage ;
b) high degree of selectivity ; the required potential can be
shifted into a favorable range by “inner” or “external” activation ;
c) uniform experimental technique in contrast to chemical
methods, i. e. the technique is the same for all protecting groups
to be removed. It permits removal of several different protecting
groups at one and the same time during the last stage of the
synthesis (compare Section 3.4) and furnishes the prerequisites
for working out standard methods.
The range of potential for removal of various protecting
groups extends from ca. - 1 to ca. - 3 V (us SCE). A general
regularity may be noted-the removal of one and the same
protecting group (Y) is facilitated along the series N-Y
0-Y < S-Y < C(0)O-Y, i.e. according to increasing
nucleophilicity of the blocking group. By “external activation”
the potential of deprotection may be essentially decreased
(by at least 0 . 5 4 . 7 V) compared to the potentials listed in
Table 2.
The protecting groups listed in Table 2 are universal. An
example of a special protecting group is the nitro group sugAngew. Chem. Int. Ed. Engl.
1 Vol. 15
(1976) No. 5
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u rv1
Fig. 2. Catalytic polarographic current in a system with electron transfer
against potential gradient beyond the supporting electrolyte discharge range.
1 :0.04M(C4H9)4NeC10f in D M F ; 2 : 1 . 6 ~
M benzyl-N-butylcarbamate
3: 4.1 x
M biphenyl (A);4: mixture of A and S (schematic): see Table 1, No. 3. Potentials referred t o
gested here for blocking the guanidine residue of arginine"
and which can likewise be removed by electroreducti~n['~~!
The possibility of using not only cathodic but also anodic
reactions for the removal of protecting groups can so far
be illustrated by only a few examples: The electrooxidative
cleavage of benzyl and benzhydryl ethers'' "1.
The yields of free alcohols are 60-70 %.
Weinreb et al. have discussed the anodic cleavage of the
benzyl protecting group['20!
Received: October 28, 1975 [A 109 IE]
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Angew. Chem. Int. Ed. Engl.
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