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The effect of additives on organolithiums
Vo1.27, Tetrahedron Letters Printed in Great Britain
pp 331-334,
No.3
THE EFFECT OF ADDITIVES
1986
0040-4039/86 $3.00 + .OO 01986 Pergamon Press Ltd.
ON ORGANOLITHIUMS
Robert R. Fraser and Tarek S. Mansour Ottawa-Carleton Chemistry Institute, Ottawa, KlN 9B4, Canada
Abstract: The effect of additives versus
lithiated
amides
the most effective
The beneficial
effects
diazabicyclo[2.2.2]octane known agents
have frequently
diisopropylamide
Further
modulation
(6).
caused a significant
addition evidence,
effects
effect on reactivity
of an equivalent
of potassium
altered
Changing
t-butoxide
(13,14).
of
These additives
result of their long known to
of LDA, by the
It has been assumed,
without
direct
(14) and that the basicity
counterion.
(15), we have undertaken
(3).
by the addition
in reactions
is solely kinetic
331
of choice
the metal counterion,
by the type of solvated
of this assumption
as a
as metalating
and lithium -bis-
[DMPU(S)].
(11,12) has been achieved
that the effetzt of these "additives"
significance
the solvent
urea
have been
(3) such as lithium
[LTMP(5)]
rates, most probably (9,lO).
alkyllithiums
amines
of these amides has been achieved
1,4-
(TMEDA), and
basic alkyllithiums
is most frequently
is found to be
of triphenylmethane.
involving
2,2,6,6_tetramethylpiperidide
in metallation
aggregation
the amide is not significantly practical
strongly
[HMPA] and N,N'-dimethylpropylene
to influence
have an important
for reactions
by the less basic lithiated
Tetrahydrofuran
increase
TMEDA
(< 2 pK units).
such as tetramethylethylenediamine
More recently,
of the reactivity
hexamethylphosphoramide
abilities
lithium
of weak carbon acids as measured
the rates of deprotonation
as catalysts
been replaced
[LDA(4)]
trimethylsilylamide
of amines
(1,2).
acidities
is found to be small
in accelerating
(DABCO),
for over two decades
on the "apparent"
In view of the
the measurement
of the
of
332
acidities presence
of five carbon acids, of a variety
of the equilibrium
in equilibrium
of additives,
for the purpose
+
LiNR'* --z
The value of K in the equilibrium The value
N-methylimidazole, relative
presents
of the carbon acid only. the variation
of pK
coordinating
agent
aminopyrrole,
describing
The general
each versus
by LDA.
TMEDA.
of additives
the influence
Also included
from the results
Of the three,
deprotonation,
influence
increase
competitive
rate enhancements
fact that a true equtlibrium methane
using thiophene,
the earlier
estimate
of 34.6.
and N,N-dimethylConsequently,
acidity.
amines.
It can be seen,
by HMPA, DMPU, and
In addition
And for
to catalysing
the
that these three additives
of triphenylmethane
will
(19,20).
by LD.4 in the
of the pKa of triphenylmethane
by LDA (th = 13 hr) allowed catalysed
We have redetermined acid.
We
of triphenylmethane
(17,18) and stereoselectivity
pKA = 33.0 (22), as reference
the pK
amine or
is also the most effective.
The deprotonation,
had not been reached.
1
as follows:
to increase kinetic
are provided
Our intial measurement
to occur.
Table
as influencing
salt, tertiary
rates for two other hindered
in the rate of deprotonatton
hydrolysis
(pK = 35.8).
on the rates of deprotonation
(21) was, in fact, in error as the slow deprotonation unmeasured
to diisopropylamine
way by the use of additives.
in their ability
on regioselectivity
the two weak
N,N-dimethylaminopyrrole,
varied by more than one pK unit.
on the basis of recent work,
of TMEDA has proven useful.
between
In fact, only thioanisole
and the safest, TMEDA,
previously
The first two acids were assessed
than LDA, TMEDA should be used routinely.
it can be expected,
The forty-fold
thfoanisole,
in a significant
of these additives
are comparative
also have a significant
presence
acidity
thus remains
the cheapest
difference
trend in all cases can be summarized
in Table 2, that useful
bases more hindered
by 13~ NMR as described
the effect of each addition
tetramethylpiperidine,
one does not alter the thermodynamic
have compared
on the position
[II
to bis-trimethylsilylamine
is never more than 2.1 pK units.
The importance
each in the
HNR12
of the carbon acid as a result of inorganic
a
amine,
their effects
(pK, = 37.3) the next two relative
relative
arbitrarily
the results,
include
and 4-benzylpyridine.
to 2,2,5,5_tetramethylpiperidine
(pK, = 35.7) the 4-benzylpyridine
+
the ApK or the acidity
The carbon acids studied diphenylmethane,
RLi
has been determined
for -log K then provides
acids RH and R'*NH.
of determining
lithiated
as well as on the rates of metalation.
[l],
RH
(16).
with the appropriate
by TMEDA
some revealed
the
the pKA for triphenyl-
The revised value of 32.9 replaces
333
TABLE 1 pKA VALUES
IN THF-Et20a
CARBON ACID Ph$H2
Additive
PhSCHB
N-N('=B)Z
None
38.1b
37.1=
35.3d
LiCl
38.9
37.7
35.6
LiBr
38.2
38.1
34.9
TMEDA
31.5
37.3
34.6
33.7
24.8
DABCO
37.6
37.2
24.6
37.48 i
37.78 _i
35.0 _ g,h
34.0
HMPA
34.01
25.2
K t-BuO
36.8g
36.48
K t-BuOk
36.9'
37.1
DMPU
/-\ NvN-CHB
33.7c _f
25.1e 25.2 25.3
34.d
24.8
34.58
33.78
24.6
34.8
aThe lithiated amine was produced by adding methyllithium in ether (1.1 ml) to a solution of amine in THF(2 ml). An equivalent of carbon acid and additive were then added and so_lution d examined by 13C NMR. bRef. 21, versus TMP. 'Ref. 22 versus diisopropylamine. Ref. 21 versus f diisopropylamine. eRef. 23 versus bistrimethylsilylamine. broad peaks prevented accurate h measurement. gdetermined at -6O'C to avoid decomposition. Equilibrium not attained. i j Additional peaks suggested addition to DMPU. The pK was essentially the same (34.2) at -7OOC. k Solid Li -t-BuO filtered off before measurement.
TABLE 2 EFFECT OF "ADDITIVES" (1 eq.) ON HALF LIFE (mins.) FOR DEPROTONATION OF TRIPHENYLMETHANE
LDA
784
LTMP
2020
LDA-LiBr
863
LTMP-TMEDA
148
LDA-DABCO
LDA-DMPU
LDA-HMPA
LDA-TMEDA
695
41
27
18
R3SiNRza
5800
aThe base was lithiated i-propyl trimethylsilylamine(24).
334
REFERENCES AND NOTES
1.
G.G. Eberhardt and W.A. Butte. J. Org. Chem., 3
2.
E.J. Corey and D. Seebach. J. Org. C&em., 2,
3.
For a very recent discusson of the practical aspects of carbanion techniques, including a
2928 (1964).
4097 (1966).
review of the various metalating agents, see "Techniques in Carbanion Chemistry", T. Durst in Comprehensive Carbanion Chemistry, Part B.
Elsevier Science Publishers BV., Amsterdam,
The Netherlands, 1984. 4.
G. Wittig and H. Reiff. Angew. Chem. Int. Ed. 1, 7 (1968).
5.
R.A. Olofson and C.M. Daugherty, J. Amer. Chem. Sot., 2,
582 (1973).
6.
U. Wannagat and H. Niederpriim. Chem. Ber. 9&
7.
H. Normant. Angew Chem. Int. Ed. 6, 1046 (1967), see also D. Seebach and D. Enders. Angew. Chem. Int. Ed. l&
1540 (1961).
15 (1975).
a.
T. Mukhopadhyay and D. Seebach. Helv. Chim. Acta. 65, 385 (1982).
9.
The acidities reported herein involve equilibria between a lithiated amine and a weak carbon acid. It is known that both the lithiated hydrocarbons and the lithiated amines can form aggregates in solution; W. Bauer and D. Seebach. Helv. Chim. Acta., z,
10.
1972 (1984).
Recent work on butyllithium in THF has established the presence of a dimer-tetramer equilibium [D. Seebach, R. Hassig and J. Gabriel. Helv. Chim. Acta, E,
308 (1983)], and a
greater reactivity of the dimer (J.F. McGarrity, C.A. Ogle, 2. Brich and H.-R. Loosli. J. Am. Chem. Sot., 107, 1810 (1985). 11.
A. Streitwieser,Jr. and R.A. Caldwell. J. Am. Chem. Sot., 87, 5394 (1965).
12. E.A. Symons, M.F. Powell, J.B. Schnittker and M.J. Clermont., J. Am. Chem. Sot., 101, 6704 (1979). 13. B. Ranger, H. Hugel, W. Wykypiel and D. Seebach, Chem. Ber., 111, 2630 (1978). 14.
S. Raucher and G.A. Koolpe, J. Org. Chem., z,
15.
Intuitively, one could expect to alter the position of an acid-base equilibrium
3794 (1978).
significantly if the addition could selectively deaggregate and thereby stabilize one of the two lithio derivatives. 16. R.R. Fraser, M. Bresse and T.S. Mansour, J. Am. Chem. Sot., 105, 7790 (1983). 17. C.L. Liotta and T.C. Caruso, Tetrahedron Letters, 1599 (1985). 18. L.M. Jackman and T.S. Dunne, J. Am. Chem. Sot., 107, 2805 (1985). 19. R.R. Fraser and F. Akiyama and J. Banville. Tetrahedron Letters, 3929 (1979). 20. M. Eyer and D. Seebach, .I.Am. Chem. Sot., 107, 3601 (1985). 21. R.R. Fraser, M. Bresse and T.S. Mansour, J. Chem. Sot. Chem. Commun., 621 (1983). 22. R.R. Fraser, T.S. Mansour and S. Savard, Can. J. Chem., in press. 23.
R.R. Fraser, T.S. Mansour and S. Savard, J. Org. Chem., 2,
24. R.R. Fraser and T.S. Mansour, J. Org. Chem., 2, (Received
in USA
19 August
1985)
0000 (1985).
3442 (1984).
pp 331-334,
No.3
THE EFFECT OF ADDITIVES
1986
0040-4039/86 $3.00 + .OO 01986 Pergamon Press Ltd.
ON ORGANOLITHIUMS
Robert R. Fraser and Tarek S. Mansour Ottawa-Carleton Chemistry Institute, Ottawa, KlN 9B4, Canada
Abstract: The effect of additives versus
lithiated
amides
the most effective
The beneficial
effects
diazabicyclo[2.2.2]octane known agents
have frequently
diisopropylamide
Further
modulation
(6).
caused a significant
addition evidence,
effects
effect on reactivity
of an equivalent
of potassium
altered
Changing
t-butoxide
(13,14).
of
These additives
result of their long known to
of LDA, by the
It has been assumed,
without
direct
(14) and that the basicity
counterion.
(15), we have undertaken
(3).
by the addition
in reactions
is solely kinetic
331
of choice
the metal counterion,
by the type of solvated
of this assumption
as a
as metalating
and lithium -bis-
[DMPU(S)].
(11,12) has been achieved
that the effetzt of these "additives"
significance
the solvent
urea
have been
(3) such as lithium
[LTMP(5)]
rates, most probably (9,lO).
alkyllithiums
amines
of these amides has been achieved
1,4-
(TMEDA), and
basic alkyllithiums
is most frequently
is found to be
of triphenylmethane.
involving
2,2,6,6_tetramethylpiperidide
in metallation
aggregation
the amide is not significantly practical
strongly
[HMPA] and N,N'-dimethylpropylene
to influence
have an important
for reactions
by the less basic lithiated
Tetrahydrofuran
increase
TMEDA
(< 2 pK units).
such as tetramethylethylenediamine
More recently,
of the reactivity
hexamethylphosphoramide
abilities
lithium
of weak carbon acids as measured
the rates of deprotonation
as catalysts
been replaced
[LDA(4)]
trimethylsilylamide
of amines
(1,2).
acidities
is found to be small
in accelerating
(DABCO),
for over two decades
on the "apparent"
In view of the
the measurement
of the
of
332
acidities presence
of five carbon acids, of a variety
of the equilibrium
in equilibrium
of additives,
for the purpose
+
LiNR'* --z
The value of K in the equilibrium The value
N-methylimidazole, relative
presents
of the carbon acid only. the variation
of pK
coordinating
agent
aminopyrrole,
describing
The general
each versus
by LDA.
TMEDA.
of additives
the influence
Also included
from the results
Of the three,
deprotonation,
influence
increase
competitive
rate enhancements
fact that a true equtlibrium methane
using thiophene,
the earlier
estimate
of 34.6.
and N,N-dimethylConsequently,
acidity.
amines.
It can be seen,
by HMPA, DMPU, and
In addition
And for
to catalysing
the
that these three additives
of triphenylmethane
will
(19,20).
by LD.4 in the
of the pKa of triphenylmethane
by LDA (th = 13 hr) allowed catalysed
We have redetermined acid.
We
of triphenylmethane
(17,18) and stereoselectivity
pKA = 33.0 (22), as reference
the pK
amine or
is also the most effective.
The deprotonation,
had not been reached.
1
as follows:
to increase kinetic
are provided
Our intial measurement
to occur.
Table
as influencing
salt, tertiary
rates for two other hindered
in the rate of deprotonatton
hydrolysis
(pK = 35.8).
on the rates of deprotonation
(21) was, in fact, in error as the slow deprotonation unmeasured
to diisopropylamine
way by the use of additives.
in their ability
on regioselectivity
the two weak
N,N-dimethylaminopyrrole,
varied by more than one pK unit.
on the basis of recent work,
of TMEDA has proven useful.
between
In fact, only thioanisole
and the safest, TMEDA,
previously
The first two acids were assessed
than LDA, TMEDA should be used routinely.
it can be expected,
The forty-fold
thfoanisole,
in a significant
of these additives
are comparative
also have a significant
presence
acidity
thus remains
the cheapest
difference
trend in all cases can be summarized
in Table 2, that useful
bases more hindered
by 13~ NMR as described
the effect of each addition
tetramethylpiperidine,
one does not alter the thermodynamic
have compared
on the position
[II
to bis-trimethylsilylamine
is never more than 2.1 pK units.
The importance
each in the
HNR12
of the carbon acid as a result of inorganic
a
amine,
their effects
(pK, = 37.3) the next two relative
relative
arbitrarily
the results,
include
and 4-benzylpyridine.
to 2,2,5,5_tetramethylpiperidine
(pK, = 35.7) the 4-benzylpyridine
+
the ApK or the acidity
The carbon acids studied diphenylmethane,
RLi
has been determined
for -log K then provides
acids RH and R'*NH.
of determining
lithiated
as well as on the rates of metalation.
[l],
RH
(16).
with the appropriate
by TMEDA
some revealed
the
the pKA for triphenyl-
The revised value of 32.9 replaces
333
TABLE 1 pKA VALUES
IN THF-Et20a
CARBON ACID Ph$H2
Additive
PhSCHB
N-N('=B)Z
None
38.1b
37.1=
35.3d
LiCl
38.9
37.7
35.6
LiBr
38.2
38.1
34.9
TMEDA
31.5
37.3
34.6
33.7
24.8
DABCO
37.6
37.2
24.6
37.48 i
37.78 _i
35.0 _ g,h
34.0
HMPA
34.01
25.2
K t-BuO
36.8g
36.48
K t-BuOk
36.9'
37.1
DMPU
/-\ NvN-CHB
33.7c _f
25.1e 25.2 25.3
34.d
24.8
34.58
33.78
24.6
34.8
aThe lithiated amine was produced by adding methyllithium in ether (1.1 ml) to a solution of amine in THF(2 ml). An equivalent of carbon acid and additive were then added and so_lution d examined by 13C NMR. bRef. 21, versus TMP. 'Ref. 22 versus diisopropylamine. Ref. 21 versus f diisopropylamine. eRef. 23 versus bistrimethylsilylamine. broad peaks prevented accurate h measurement. gdetermined at -6O'C to avoid decomposition. Equilibrium not attained. i j Additional peaks suggested addition to DMPU. The pK was essentially the same (34.2) at -7OOC. k Solid Li -t-BuO filtered off before measurement.
TABLE 2 EFFECT OF "ADDITIVES" (1 eq.) ON HALF LIFE (mins.) FOR DEPROTONATION OF TRIPHENYLMETHANE
LDA
784
LTMP
2020
LDA-LiBr
863
LTMP-TMEDA
148
LDA-DABCO
LDA-DMPU
LDA-HMPA
LDA-TMEDA
695
41
27
18
R3SiNRza
5800
aThe base was lithiated i-propyl trimethylsilylamine(24).
334
REFERENCES AND NOTES
1.
G.G. Eberhardt and W.A. Butte. J. Org. Chem., 3
2.
E.J. Corey and D. Seebach. J. Org. C&em., 2,
3.
For a very recent discusson of the practical aspects of carbanion techniques, including a
2928 (1964).
4097 (1966).
review of the various metalating agents, see "Techniques in Carbanion Chemistry", T. Durst in Comprehensive Carbanion Chemistry, Part B.
Elsevier Science Publishers BV., Amsterdam,
The Netherlands, 1984. 4.
G. Wittig and H. Reiff. Angew. Chem. Int. Ed. 1, 7 (1968).
5.
R.A. Olofson and C.M. Daugherty, J. Amer. Chem. Sot., 2,
582 (1973).
6.
U. Wannagat and H. Niederpriim. Chem. Ber. 9&
7.
H. Normant. Angew Chem. Int. Ed. 6, 1046 (1967), see also D. Seebach and D. Enders. Angew. Chem. Int. Ed. l&
1540 (1961).
15 (1975).
a.
T. Mukhopadhyay and D. Seebach. Helv. Chim. Acta. 65, 385 (1982).
9.
The acidities reported herein involve equilibria between a lithiated amine and a weak carbon acid. It is known that both the lithiated hydrocarbons and the lithiated amines can form aggregates in solution; W. Bauer and D. Seebach. Helv. Chim. Acta., z,
10.
1972 (1984).
Recent work on butyllithium in THF has established the presence of a dimer-tetramer equilibium [D. Seebach, R. Hassig and J. Gabriel. Helv. Chim. Acta, E,
308 (1983)], and a
greater reactivity of the dimer (J.F. McGarrity, C.A. Ogle, 2. Brich and H.-R. Loosli. J. Am. Chem. Sot., 107, 1810 (1985). 11.
A. Streitwieser,Jr. and R.A. Caldwell. J. Am. Chem. Sot., 87, 5394 (1965).
12. E.A. Symons, M.F. Powell, J.B. Schnittker and M.J. Clermont., J. Am. Chem. Sot., 101, 6704 (1979). 13. B. Ranger, H. Hugel, W. Wykypiel and D. Seebach, Chem. Ber., 111, 2630 (1978). 14.
S. Raucher and G.A. Koolpe, J. Org. Chem., z,
15.
Intuitively, one could expect to alter the position of an acid-base equilibrium
3794 (1978).
significantly if the addition could selectively deaggregate and thereby stabilize one of the two lithio derivatives. 16. R.R. Fraser, M. Bresse and T.S. Mansour, J. Am. Chem. Sot., 105, 7790 (1983). 17. C.L. Liotta and T.C. Caruso, Tetrahedron Letters, 1599 (1985). 18. L.M. Jackman and T.S. Dunne, J. Am. Chem. Sot., 107, 2805 (1985). 19. R.R. Fraser and F. Akiyama and J. Banville. Tetrahedron Letters, 3929 (1979). 20. M. Eyer and D. Seebach, .I.Am. Chem. Sot., 107, 3601 (1985). 21. R.R. Fraser, M. Bresse and T.S. Mansour, J. Chem. Sot. Chem. Commun., 621 (1983). 22. R.R. Fraser, T.S. Mansour and S. Savard, Can. J. Chem., in press. 23.
R.R. Fraser, T.S. Mansour and S. Savard, J. Org. Chem., 2,
24. R.R. Fraser and T.S. Mansour, J. Org. Chem., 2, (Received
in USA
19 August
1985)
0000 (1985).
3442 (1984).