Ionization of carbon acids in liquid ammonia

Article abstract of DOI:10.1021/ol2026153

The acidities of various carbon acids in liquid ammonia (LNH₃) at room temperature were determined by NMR and rates of D-exchange. There is a reasonable linear correlation of the pK_as in LNH₃ with those in water and DMSO of slope 0.7 and 0.8, respectively. Carbon acids with an aqueous pK_a of less than 12 are fully ionized in liquid ammonia. Nucleophilic substitution of benzyl chloride by carbanions in liquid ammonia generates a Bronsted β_nuc = 0.38.

Full text of DOI:10.1021/ol2026153

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6118–6121
Ionization of Carbon Acids in
Liquid Ammonia
Pengju Ji, Nicholas T. Powles, John H. Atherton, and Michael I. Page*
IPOS, The Page Laboratories, Department of Chemical and Biological Sciences,
University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom
m.i.page@hud.ac.uk
Received September 28, 2011
ABSTRACT
The acidities of various carbon acids in liquid ammonia (LNH3) at room temperature were determined by NMR and rates of D-exchange. There is a
reasonable linear correlation of the pKas in LNH3 with those in water and DMSO of slope 0.7 and 0.8, respectively. Carbon acids with an aqueous
pKa of less than 12 are fully ionized in liquid ammonia. Nucleophilic substitution of benzyl chloride by carbanions in liquid ammonia generates a
Brønsted βnuc = 0.38.
The acidity of carbon acids and their rates of deprotona-
tion and the rates of protonation of their conjugate base
carbanions have contributed to our understanding of
electronic effects1 and the “imbalance” between various
motions required in the transition states of their reactions.2
The solvent plays an important role in these phenomena
both in terms of the stability of the carbanion and solvent
reorganization that is often required for charged deloca-
lized species.3 We are interested in using liquid ammonia as
a promising solvent for organicreactionstoreplacedipolar
aprotic solvents in a number of industrial processes.4
Ammonia has only one lone pair for three potential
NꢀH hydrogen bonds leading to relatively weak associa-
tion in the liquid state and a boiling point of ꢀ33 °C and a
vapor pressure of 10 bar at 25 °C.5 The nitrogen lone pair
makes ammonia a good H-bond acceptor and liquid
ammonia strongly solvates cations;6 however, unlike water,
it is not a good hydrogen bond donor and does not
significantly solvate anions.7 Its autoprotolysis constant
corresponds to a pKa of 27.6 (25 °C).8 Although liquid
ammonia has a low dielectric constant (16.9 at 25 °C),9
many salts are highlysoluble.10 Inview of the relatively low
dielectric constant of liquid ammonia, the ionization of
carbon acids in liquid ammonia may give rise to ion-pairs
in equilibrium with the dissociated species (eq 1), where the
product KiKd corresponds to the normal ionization con-
stant Ka.
Ki
Kd
CH þ NH3 h [CꢀNH4þ ]ip h Cꢀ þ NH4þ
ð1Þ
Carbonyl activated carbon acids that have an aqueous
pKa of less than 11 (<15 in DMSO) are fully ionized in
liquid ammonia at 25 °C as shown by 1H and 13C NMR
spectra. So relativelystrongcarbonacids suchasdimedone
(5,5-dimethylcyclohexane-1,3-dione), which has an aque-
ous pKa of 5.25,11 is deprotonated to its monoanion in
liquid ammonia but, as expected, is un-ionized in CDCl3
(1) (a) March, J. Advanced Organic Chemistry, 3rd ed.; Wiley-Inter-
escience: New York, 1985; Chapter 8. (b) Cram, D. J. Fundamentals of
Carbanion Chemistry; Academic Press: New York, 1965. (c) Streitwieser,
A., Jr.; Hammons, J. H. Prog. Phys. Org. Chem. 1965, 3, 41–80.
(2) (a) Finneman, J. I.; Fishbein, J. C. J. Org. Chem. 1994, 59, 6251–
6256. (b) Bernasconi, C. F.; Fairchild, D. E.; Murray, C. J. J. Am. Chem.
Soc. 1987, 109, 3409–3415. (c) Bordwell, F. G.; Boyle, W. J., Jr. J. Am.
Chem. Soc. 1972, 94, 3907–3911.
(6) Herlem, M.; Popov, A. I. J. Am. Chem. Soc. 1972, 94, 1431–1434.
(7) Marcus, Y. Pure Appl. Chem. 1983, 55, 977–1021.
(8) Coulter, L. V.; Sinclair, J. R.; Cole, A. G.; Rope, G. C. J. Am.
Chem. Soc. 1959, 81, 2986–2989.
(3) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
3rd ed.; Wiley-VCH: Weinheim, Germany, 2003; Chapter 4.
(9) (a) Billaud, G.; Demortler, A. J. Phys. Chem. 1975, 79, 3053–
3055. (b) Grubb, H. M.; Chittum, J. F.; Hunt, H. J. Am. Chem. Soc.
1936, 58, 776–776.
(10) Howard, D. H., Jr.; Friedrich, F.; Browne, A. W. J. Am. Chem.
Soc. 1934, 56, 2332–3240.
(4) (a) Ji, P.; Atherton, J. H.; Page, M. I. J. Chem. Soc. Faraday
Discuss. 2010, 145, 15–25. (b) Ji, P.; Atherton, J. H.; Page, M. I. J. Org.
Chem. 2011, 76, 1425–1435. (c) Ji, P.; Atherton, J. H.; Page, M. I. J. Org.
Chem. 2011, 76, 3286–3295.
(5) Nicholls, D. Inorganic Chemistry in Liquid Ammonia; Clark,
R. J. H., Ed.; Topic in Inorganic and General Chemistry, Monograph 17;
Elsevier Scientific Publishing Company: Amsterdam, 1979.
(11) Cremlyn, R. J.; Osborne, A. G.; Warmsley, J. F. Spectrochim.
Acta A 1996, 52, 1423–1432.
r
10.1021/ol2026153
Published on Web 10/25/2011
2011 American Chemical Society

and DMSO-d6 (DMSO-d6 (0.1 M) shows no H-D ex-
change with liquid ammonia at room temperature after
1
1
Scheme 1
several weeks, monitored by H NMR). H NMR and
DEPT 135 spectra of dimedone in liquid ammonia show
only one proton attached to carbon 2 between the two
carbonyl groups, and the carbon shift of the carbonyl
carbons in liquid ammonia is about 10 ppm lower than
that at 200 ppm in CDCl3.11 Diethyl malonate, which has
an aqueous pKa of 12.912 and one of 15.9 in DMSO,13 is
not ionized in liquid ammonia but shows a broad single
peak of the central methylene protons, probably due to a
fast exchange of these protons with the solvent. Acetyla-
cetone and 2-acetylcyclohexanone with aqueous pKas of
9.0 and 10.1, respectively,12 (13.313and 15.514 respectively
in DMSO) react in liquid ammonia to give their corre-
sponding enamines, confirmed by GC-MS analysis.
Monocyano-activated carbon acids, such as benzyl cya-
nide with a pKa of 21.9 in DMSO,15 are not ionized in
liquid ammonia. Unlike other solvents, liquid ammonia
causes the relaxation time of the methylene protons of
benzyl cyanide to be fast compared with the aromatic
protons and, consequently, it takes 10 s relaxation time
to obtain the expected integration ratio between aromatic
protons and methylene protons in liquid ammonia.
indicating that there is less than 1% MDN with hydrogen
1
still attached. There are no H NMR signals associated
with the methylene carbon of MDN at ꢀ40 °C so if this is
due to a rapid exchangemechanism leading to a very broad
signal that is not observable, this lower temperature is
insufficient to slow the rate of exchange. Ionization of
MDN would transfer the protons to ammonia to form
ammonium ions but the addition of ammonium chloride
does not affect the 1H NMR spectrum. Of course, within
the ion-pair (eq 1) added ammonium ions would not alter
the equilibrium with the undissociated species.
The 13C NMR spectrum of MDN in liquid ammonia at
25 °C shows a high field carbon signal at ꢀ3.12 ppm,
consistent with the formation of a negatively charged
carbon, and contrasts with the methylene carbon signal
of 8.4 ppm for MDN in DMSO. These observations are
not due to a chemical reaction of MDN which is stable in
liquid ammoniaꢀafter two days at room temperature,
evaporation of the ammonia, acid neutralization and
extraction yields unreacted MDN. The carbon chemical
shifts of MDN with 2 equiv of NaH in liquid ammonia are
similar to those without the added base. Although it is not
clear whether MDN actually forms a carbon dianion in
liquid ammonia or simply forms a monoanion with un-
usual NMR properties, the signal at ꢀ3.12 ppm is signifi-
cantly further upfield compared with that of 11.5 ppm of
benzylmalonodinitrile monoanion in liquid ammonia.
The carbon shift of MDN in liquid ammonia is upfield,
but this could be due to a poorly solvated monoanion
leading to a relatively larger negative charge density on the
central carbon in liquid ammonia compared with other
solvents. Earlier work on NMR data for the ionization of
MDN is inconclusive, one17 reports the monoanion shift in
DMSO as ꢀ0.25 ppm, but another18 quotes the mono-
anion shift in HMPT as ꢀ2.1 and ꢀ2.2 ppm, but then gives
as shift of þ32 ppm for the dianion. Very highfield carbon
shifts are seen for carbon dianions or quasi-dianions in
other solvents, for example, carbon suboxide has a very
negative carbon shift of ꢀ14.6 ppm in CDCl3 at ꢀ40 °C,19
while iminopropadienones have shifts ofꢀ3.8 toꢀ6.8 ppm
in CDCl3 at room temperature.20 It has been proposed that
the resonance stabilization of R-cyano carbanions is not
Dicyano derivatives are, however, fully ionized in liquid
1
ammonia; the H NMR spectrum of benzylmalonodini-
trile does not show a proton attached to the methine
carbon and the 13C chemical shift is upfield (11.5 ppm)
for the central carbon compared with that in CDCl3, as
expected from an increased negative charge density in the
carbanion. Ionization in liquid ammonia is further sup-
ported by DEPT 135 spectra, which show no coupling
between the methine carbon and its attached proton pre-
sent in neutral benzylmalonodinitrile. The surprisingly
large downfield 13C shift of the cyano groups (145.1 ppm)
is similar to the 144.3 ppm reported for the cyano group of
the lithium salt of benzyl cyanide anion in THF.16
Malonodinitrile, MDN, with an aqueous pKa of 11.212
(11.1 in DMSO13) shows very unusual behavior in liquid
ammonia. In stark contrast to that observed in other
solvents, its 1H NMR spectrum at 25 °C shows no protons
attached to the central methylene carbon present in neutral
MDN. It would be surprising if both protons of MDN
have been removed to form a carbon dianion, but the lack
of a proton signal is not due to H-D exchange with the
deuteriated dimethyl sulfoxide used to “lock” the spectro-
meter as the same result is observed with toluene-d8 or
benzene-d6 as a lock. A similar spectrum is also seen when
one equivalent of acetonitrile is added using its three
methyl hydrogens as an internal standard, apparently
(12) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants: A Laboratory Manual, 3rd ed.; Chapman and Hall: London,
1984.
(13) Bordwell, F. G.; Harrelson, J. A., Jr.; Satish, A. V. J. Org. Chem.
1989, 54, 3101–3105.
(14) Kern, J. M.; Federlin, P. Tetrahedron 1978, 34, 661–670.
(15) Bordwell, F. G.; Bares, J. E; Bartmess, J. E.; McCollum, G. J.;
Van der Puy, M.; Vanier, N. R.; Matthews, W. S. J. Org. Chem. 1977, 42,
321–325.
(17) Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem. 1993,
58, 449–455.
(18) Vogt, H.-H.; Gompper, R. Chem. Ber. 1981, 114, 2884–2897.
(19) Williams, E. A.; Cargioli, J. D.; Ewo, A. Chem. Commun. 1975,
366–367.
(16) Crowley, P. J.; Leach, M. R.; Meth-Cohn, O.; Wakefield, B. J.
Tetrahedron Lett. 1986, 27, 2909–2912.
(20) Bibas, H.; Moloney, D. W. J.; Neumann, R.; Shtaiwi, M.;
Bernhardt, P. V.; Wentrup, C. J. Org. Chem. 2002, 67, 2619–2631.
Org. Lett., Vol. 13, No. 22, 2011
6119

Table 1. Ionization of Carbon Acids in Liquid Ammonia at 25 °C Compared with pKa Values in Water and DMSO
second order rate constant for
pKa
ionization
in LNH3
kobs for D-exchange
in LNH3 25 °C/sꢀ1
apparent
reaction with benzyl chloride
carbon acid
dimedone
pKa (aq)
(DMSO)
pKa (LNH3)
in LNH3 25 °C/Mꢀ1sꢀ1
5.3a
9.2c
9.0a
11.2b
12.9b
13.3e
15.5f
11.1e
16.4b
21.9g
22.6h
19.8
28.8j
26.5h
N.A.
29.5h
31.3g
ionized
<0
HCN
ionized
2.18 ꢁ 10ꢀ3
acetylacetone
2-acetylcyclohexanone
malonodinitrile
diethyl malonate
benzyl cyanide
fluorene
ionized
10.1d
11.2d
12.9d
N.A.
N.A.
19.1
20.0i
20.0k
24.1i
25.6l
28.9m
ionized
6.44 ꢁ 10ꢀ3
8.88 ꢁ 10ꢀ3
2.27 ꢁ 10ꢀ3
1.40
ionized
not ionized
not ionized
not ionized
not ionized
not ionized
not ionized
not ionized
not ionized
not ionized
<1
<10.5
11.3
0.23
1.13 ꢁ 10ꢀ4
14.6
acetophenone
phenyl acetylene
acetone
0.256
1.75 ꢁ 10ꢀ4
1.45 ꢁ 10ꢀ6
1.16 ꢁ 10ꢀ2
2.80 ꢁ 10ꢀ8
2.65 ꢁ 10ꢀ8
14.4
16.5
12.6
18.2
18.3
chloroform
ethyl acetate
acetonitrile
a Reference 23. b Reference 24. c Reference 25. d Reference 12. e Reference 13. f Reference 14. g Reference 15. h Reference 26. i Reference 27. j Reference
28. k Reference 29. l Reference 30. m Reference 21.
significant and the negative charge is localized at the
R-carbon, which may explain why there is such a highfield
signal for MDN anion in liquid ammonia.21
The acidity of carbon acids that do not ionize in
liquid ammonia can be estimated from the rates of pro-
ton exchange in the deuteriated derivatives. However, a
problem arises depending on whether exchange occurs
from the ion-pair or from the fully dissociated species
(Scheme 1).
If isotopic exchange occurs with the dissociated carb-
anion, then the rate of protonation can be assumed to be
diffusion-cꢀon2 trolled which, based on a viscosity of 1.35 ꢁ
10ꢀ4 N s m for liquid ammonia,22 can be estimated to be
4.9 ꢁ 1010
M
ꢀ1 sꢀ1. However, ifexchangeoccurs withinthe
ion-pair then the rate of reprotonation could be much
fasterꢀpossibly 1012
s
ꢀ1. The rates of isotopic exchange of
deuteriated carbon acids in liquid ammonia were deter-
1
mined by H NMR and GC-MS and first order rate
Figure 1. pKa of carbon acids in liquid ammonia against their
pKa in water (0) and DMSO (2).
constants are given in the Table 1. The rates of H-exchange
of ethyl d3-acetate and d3-acetonitrile are very slow and
were followed by initial rates over four weeks, during
which period only one D was exchanged giving CHD2
1
with the expected quintet in the H NMR spectrum at
2.0 ppm and 2.08 ppm, respectively. The corresponding
“pKa” values were calculated using the estimated diffu-
sion-controlled rate constant and are uncorrected for any
primary kinetic isotope effect on the rate of exchange,
which, if k1 is the rate-limiting step, would increase the
relative values. Upper and lower limits are given for those
carbon acids which undergo exchange either too quickly or
slowly to be measured accurately. Given the variety of
carbon acids examined, there is a reasonable correlation
between the apparent ionization constants in liquid am-
monia and those in DMSO and water (Figure 1) which
have slopes of about 0.7 and 0.8, respectively. This con-
trasts with the 1.68 observed for the ionization of phenols
in liquid ammonia against their aqueous pKa.4b
(21) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999,
121, 715–726.
(22) Plank, C. J.; Hunt, H. J. Am. Chem. Soc. 1939, 61, 3590–3591.
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3296.
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J. Org. Chem. 1993, 58, 3060–3066.
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Chem. Soc. 1983, 105, 5380–5386.
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A. D. J. Am. Chem. Soc. 1986, 108, 7310–7313.
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6120
Org. Lett., Vol. 13, No. 22, 2011

Liquid ammonia is a useful solvent for carbanion reac-
tions and pKa values for carbon acids are useful for
interpreting linear free-energy relationships. Nucleophilic
substitution by those carbon acids that are deprotonated in
liquid ammonia can occur without the aid of strong bases.
For example, thereaction between 0.2M 2-acetylhexanone
with 0.01 M benzyl chloride in liquid ammonia at 25 °C
forms the monobenzylated product within 5 min, whereas
say benzyl cyanide reacts with benzyl chloride only when
converted to its anion by sodamide in liquid ammonia to
give a monobenzylated product. The second order rate
constants for cyanide ion reacting with benzyl chloride
(2.18 ꢁ 10ꢀ3 Mꢀ1 sꢀ1) in liquid ammonia is similar to that
order rate constants for some carbanions reacting with
benzyl chloride in liquid ammonia (Table 1) generate a
Brønsted βnuc = 0.38 with a positive deviation of mal-
onodinitrile carbanion. This small value is similar to that
seen for amine nucleophiles,4b and suggests that the nu-
cleophilic substitution of benzyl chloride by carbanions
occurs with a transition state in which only a small amount
of charge is removed from the carbanion in liquid
ammonia.
Supporting Information Available. General experimen-
tal procedure, preparation of deuterium starting materi-
als and NMR spectra of individual carbon acid in liquid
ammonia.This material is available free of charge via the
Internet at http://pubs.acs.org.
in DMF (3.20 ꢁ 10ꢀ3
M
ꢀ1 sꢀ1) at 25 °C.31 The second
(31) Jobe, D. J.; Westaway, K. C. Can. J. Chem. 1993, 71, 1353–1361.
Org. Lett., Vol. 13, No. 22, 2011
6121