Ji et al.
JOCArticle
For solvolysis reactions, the solvent, in addition to its role
as a nucleophile and possibly acting as a general base in a SN3
type process,3 can influence the mechanism of substitution
by its effects on the stability of the intermediate carbocation
and on its solvation of the leaving group. These solvent
effects are also present for substitutions by other nucleo-
philes, especially by solvation of the nucleophile and leaving
group in determining the extent of “push and pull”.
There is much concern about the solvents used for indus-
trial purposes, both from an efficiency and environmental
point of view and when solvents are used in large quantities,
such as in the fine-chemical and pharmaceutical production,
their selection is a major part of the environmental perfor-
mance of a process and its impact on cost and safety issues.
Some previously used common solvents, for example chloro-
form, are now proscribed, while others, although still com-
monly used in research syntheses, are generally avoided on
the manufacturing scale. It is estimated that dipolar aprotic
solvents (e.g., DMSO and DMF) are used in around 10%
of chemical manufacturing processes but they are expen-
sive, have toxicity concerns and are difficult to recycle due
to their water miscibility and are frequently disposed by
incineration.4
Although liquid ammonia is among the least expensive
bulk chemicals and is a promising candidate to replace
dipolar aprotic solvents in a number of industrial processes,
its application as a common solvent is relatively unusual.
Ammonia has only one lone pair for three potential N-H
hydrogen bonds leading to relatively weak association in
the liquid state. The internal energy of liquid ammonia is
about -21 kJ mol-1, around half the value for water,5 and it
has a boiling point of -33 °C and a vapor pressure of 10 bar at
25 °C.6 Although it is similar in many ways to conventional
dipolar aprotic solvents, it is much easier to recover and can
be handled with care in small scale laboratory glassware over
a useful temperature range. Despite the low dielectric con-
stant of liquid ammonia (16.9 at 25 °C),7 many synthetically
useful salts are highly soluble, for example, NH4N3, 67.3
g/100 g at -36 °C.8 Moreover many organic compounds have
appreciable solubility in liquid ammonia, e.g. biphenyl has a
moderate solubility, while anisole is totally miscible with
liquid ammonia.9 The nitrogen lone pair makes ammonia a
good H-bond acceptor and liquid ammonia strongly solvates
cations, as evidenced, for example, by 23Na chemical shifts.10
However, unlike water, it is not a good hydrogen bond
donor11 and does not significantly solvate anions, as shown
by the high single ion transfer energies from water.12 This
poor solvation of anions in liquid ammonia is therefore
expected to make anionic nucleophiles more reactive but
anionic nucleofuges poorer leaving groups compared with
similar reactions in water. The normalized donor number
(DNN) of liquid ammonia is 1.52, greater than that of
HMPTA (1.0),13 while its autoprotolysis constant gives a
pKa of 27.6 (25 °C), compared with 14 for water (25 °C).14
There is an extensive literature on the physical and chem-
ical properties of liquid ammonia15 and also on the reduction
of organic compounds in alkali metal/ammonia solu-
tion16 and the application of alkali metal amides in liquid
ammonia as strong bases in synthesis.17 However, there is
little about the kinetics and mechanisms of aromatic and
aliphatic18 nucleophilic substitution in liquid ammonia.
Herein, we report on the latter using substituted benzyl
chlorides as the substrate.
Results and Discussion
(i). Ionization of Phenols and Aminium Ions. Liquid ammo-
nia is a basic solvent with a very low self-ionization constant
(pKa = 27.6 at 25 °C)14 and the ionization of acids in this
solvent generates equivalent amounts of the conjugate base
and ammonium ion (eq 1).
Ki
Kd
-
HA þ NH3 h ½A- NH4 ꢀip h A þ NH4
ð1Þ
þ
þ
The low dielectric constant of liquid ammonia indicates that
most ionic species will be strongly associated in this solvent
and conductivity data shows that ion-pairing occurs even at
low concentrations and probably larger aggregates form at
higher concentrations.19 There have been several methods
used to determine ionization and dissociation constants
including spectroscopic, conductivity and NMR,20 however,
to our knowledge, there has been no systematic evaluation
of substituent effects on any one class of acids. We are
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(13) Rydberg, J.; Cox, M.; Musikas, C. Solvent Extraction Principles and
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(14) Coulter, L. V.; Sinclair, J. R.; Cole, A. G.; Rope, G. C. J. Am. Chem.
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Keoshin, C. J.; Leforestier, C.; Saykally, R. J. J. Chem. Phys. 2002, 116,
10148–10163.
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Ed.; Topic in Inorganic and General Chemistry, Monograph 17; Elsevier
Scientific Publishing Company: Amsterdam, 1979.
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Chem. Rev. 1942, 31, 525–536. (b) Watt, G. W.; Leslie, W. B.; Moore, T. E.
Chem. Rev. 1943, 32, 219–229. (c) Jorgensen, W. L.; Ibrahim, M. J. Am.
Chem. Soc. 1980, 102, 3309–3315. (d) Kraus, C. A. Chem. Rev. 1940, 26, 95–
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58, 2509–2510. (e) Fernelius, W. C.; Bowman, G. B. Chem. Rev. 1940, 26, 3–
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556. (b) Schon, I. Chem. Rev. 1984, 84, 287–297. (c) Fernelius, W. C.; Watt,
G. W. Chem. Rev. 1937, 20, 195–258.
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1966, 31, 1032–1035. (b) Flahaut, J.; Miginiac, P. Helv. Chim. Acta 1978, 61,
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1426 J. Org. Chem. Vol. 76, No. 5, 2011