Degradation of dichloromethane by bispidine

Article abstract of DOI:10.1002/poc.2909

An effective degradation reaction of CH₂Cl₂ by bispidine (3,7-diazabicyclo[3.3.1]nonane, C₇H₁₂(NH) ₂, 1) is reported. The reaction starts as low as -20 °C and is quantitative with respect to 1. The overall reaction implies nucleophilic substitution of chloride, followed by a series of cascading acid-base reactions, ending with the formation of two easily separable products, one being soluble and the other insoluble. The starting 1, the intermediates, and the products show a variety of interesting solid-state structures, associated with plasticity, N-H...N and N-H...Cl...H-N hydrogen bonding, and polymorphism. Copyright

Full text of DOI:10.1002/poc.2909

Research Article
Received: 20 September 2011,
Revised: 25 November 2011,
Accepted: 5 December 2011,
Published online in Wiley Online Library: 2012
(wileyonlinelibrary.com) DOI: 10.1002/poc.2909
Degradation of dichloromethane by bispidine
Huiling Cuia, Richard Goddarda and Klaus-Richard Pörschkea*
An effective degradation reaction of CH2Cl2 by bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H12(NH)2, 1) is reported.
The reaction starts as low as ꢀ20 ꢁC and is quantitative with respect to 1. The overall reaction implies nucleophilic
substitution of chloride, followed by a series of cascading acid–base reactions, ending with the formation of two
easily separable products, one being soluble and the other insoluble. The starting 1, the intermediates, and the
products show a variety of interesting solid-state structures, associated with plasticity, N–H⋯N and N–H⋯Cl⋯H–N
hydrogen bonding, and polymorphism. Copyright © 2012 John Wiley & Sons, Ltd.
Keywords: alkaloids; amines; hydrogen bonds; mesophases; polymorphism; solid-state structures
bispidine skeleton and many more synthetic bispidines have
INTRODUCTION
become known.[18–22] Frequently encountered examples from
nature include, besides (ꢀ)-sparteine and its isomers, cytisine, lupa-
Although methylene dichloride is widely used as solvent in
nine, albine, anagyrine, aphylline, angustifoline, and others.[23–26]
These compounds, being contained in various parts of common
garden plants such as broom, golden chain (laburnum), and some
forms of lupine, are highly toxic when swallowed, leading to
cardiac circulatory collapse. In turn, the pharmacological activity
of bispidines is being studied, partly inspired by folk medicine.
Pachycarpine is known for its oxytocic properties, and synthetic
tedisamil has been clinically tested as a cardiac antiarrthymic
agent.[27–29] 18F-labeled bispidines are studied as radioactive trac-
ers for positron emission tomography.[30] As to the mechanism of
action of bispidines, both complex formation with magnesium
and adduct formation with nicotinic receptors are discussed.
Some time ago, we studied the coordination of N,N′-dimethyl-
bispidine at nickel(0).[31] The isolated complexes such as
(C7H12N2Me2)Ni(C2H4) and (C7H12N2Me2)Ni(C2H2) represent limit-
ing cases of the Pearson hard–soft acid–base concept,[32–34]
which assesses the combination of a tertiary amine as a hard
Lewis base and nickel(0) as a soft Lewis acid as being unfavor-
able. Thus, the existence of the products demonstrates the out-
standing coordination properties that multidentate ligands[35]
can attain by following the principles of “preposition of donor
atoms” and “preorganization of ligand conformation” as traits
of the macrocyclic effect.[36–39]
organic and inorganic chemistry, it does react with strong bases[1]
and nucleophiles.[2–4] As applied in the Menshutkin reaction,[5]
secondary (Eqn (1a)) and tertiary amines (Eqn (1b))[6] react with
CH2Cl2 by nucleophilic attack at the
carbon to give the chloromethyl ammonium chloride [R3ꢀnHnNCH2Cl]
Cl or geminal ammonium salts [(R3ꢀnHnN)2CH2]Cl2 (n = 0, 1)
and possibly secondary products, such as aminals. Low steric
requirements of the amine are important for a relatively rapid
reaction. Among the most reactive amines is quinuclidine,[7]
but some tertiary and secondary amines containing methyl groups
(trimethylamine, dimethylamine) and certain cyclic secondary
amines (pyrrolidine, piperidine) are also fairly reactive.[3] Particu-
larly noteworthy in the context of this work is the seminal finding
that the parent bispidine (3,7-diazabicyclo[3.3.1]nonane) reacts
with CH2I2 in refluxing methanol to afford, after base treatment,
1,3-diazaadamantane.[8] Similarly, the isomeric (ꢀ)-sparteine,[10]
a-isosparteine,[10] and pachycarpine[11] (C15H26N2), all bearing the
bispidine skeleton, react with CH2X2 (X= Cl, I) under still more
forcing conditions (autoclave, 80–180 ꢁC) to afford diazanium salts
[C16H28N2]X2. The reaction of N,N′-dimethyl-bispidine with
CH2I2 yields at room temperature the bispidine diazanium salt
[C7H12N2Me2(CH2I)2]I2 and in refluxing ethanol the 1,3-diaza-
adamantane diazanium salt [C8H14N2Me2]I2.[12] Recently, the very
slow reaction of CH2Cl2 with pyridine derivatives has been
studied.[13] Rapid decomposition of bispidines in CH2Cl2 has
been noted.[15] A sometimes invoked deprotonation of CH2Cl2
by amines to generate chlorocarbene appears insignificant, unlike
the situation for CHCl3.[4,15]
In an attempt to characterize the ligand properties of parent
bispidine (C7H12(NH)2, 1)[8,9,14,40–44] toward transition metals,[43]
we noticed the formation of a colorless byproduct when CH2Cl2
was used as a solvent. This prompted us to investigate the reac-
tion of 1 with CH2Cl2 in its own right. We report here a detailed
study of this seemingly simple but actually quite complex and
instructive reaction, involving (i) fast and clean degradation of
CH2Cl2 by bispidine in the initial reaction step, (ii) a subsequent
* Correspondence to: K.-R. Pörschke, Max-Planck-Institut für Kohlenforschung,
D-45466 Mülheim an der Ruhr, Germany. E-mail: poerschke@mpi-muelheim.
mpg.de
Since the first synthesis of a bispidine by Mannich and Mohs [17]
in 1930, hundreds of naturally occurring alkaloids having the
a H. Cui, R. Goddard, K.-R. Pörschke
Max-Planck-Institut für Kohlenforschung, D-45466 Mülheim an der Ruhr, Germany
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
series of cascading acid–base reactions resulting in two easily
separable products, and (iii) a variety of interesting structural
features of intermediates and products.
the one at higher field displays a marked doublet splitting due
to vicinal coupling with the bridgehead CH (3J = 2.6 Hz). The
different coupling behavior of the NCHeHa protons suggests
different time-averaged dihedral angles between these protons
and bridgehead CH. This would seem in agreement with a
time-averaged flattened chair conformation of the two rings
and/or rapid chair–boat conformational exchange between the
rings (cf. discussions of the 1H NMR spectra of N,N′-dimethyl-
bispidine[12] and sparteine[46]). Nevertheless, we assume that the
pronounced chair–chair conformation with an intramolecular
N–H⋯N bridge bonding as it exists in the solid state (see below)
persists also in the solution.[47,48] The NH signal (d(H) 2.10,
RESULTS AND DISCUSSION
When a solution of bispidine (1) in CH2Cl2 is kept at ambient
temperature for 1–3 days, large colorless crystals of bispidine
di(hydrochloride), either solute-free [C7H12(NH2)2Cl]Cl (6) or as
the CH2Cl2 solute [C7H12(NH2)2Cl]ClꢂCH2Cl2 (6(CH2Cl2)), separate
in 33% yield. Evaporating the solvent from the mother
liquor leaves colorless crystals of pure 1,3-diazaadamantane
hydrochloride, C8H14N2(HCl) (5), as the main product in 65%
yield (Eqn (2)). The reaction between 1 and CH2Cl2 starts as low
as about ꢀ20 ꢁC.
w = 16Hz) is broad at low temperature, which is attributed to
½
relatively slow exchange of the bonding situation of the two NH
groups. Between ꢀ80 and ꢀ20 ꢁC, all signals of 1 (Table 1)
uniformly and reversibly shift downfield by about 0.07 p.p.m.,
and the NH signal sharpens (w = 5 Hz).
½
When the temperature is successively increased from ꢀ20 to
22 ꢁC, all signals of 1 start irreversibly moving downfield to
approach the chemical shifts attributed to bispidine hydrochlo-
ride, C7H12(NH)(NH2)Cl (4, Table 1). These shifts are reached
within about 90 min at 22 ꢁC. Note that the signals of C2H
and C3H2 switch their order in the spectrum. The NH signal
moves most rapidly downfield and intermediately broadens
Which of 6 or 6(CH2Cl2) precipitates from the reaction solution
appears to have its origin in polymorphism, and is likely due to
the different crystallization dynamics of the two solids. In a
series of experiments, 6 usually crystallized out admixed with
6(CH2Cl2), the latter even representing the major component,
but in several cases, 6 exclusively crystallized out from CH2Cl2
solution. More details on 6 and 6(CH2Cl2) are given below. For sim-
plicity, in the synthetic part of this paper, we usually refer to 6, but
with the understanding that 6(CH2Cl2) may be formed as well.
The formation of products 5 and 6 in Eqn (2) can be rational-
ized as nucleophilic attack of both secondary amine functions in
1 on the carbon atom in CH2Cl2. This results in substitution of the
two chloride ions and formation of 1,3-diazaadamantane di-
(hydrochloride), C8H14N2(HCl)2 (2), as the addition compound
of 1 and CH2Cl2 and principal intermediate of the reaction
(Scheme 1). In the overall reaction, two of the three molecules
of 1 become stepwise converted into intermediate 2, whereas
one molecule of 1 serves as a base to accept one HCl from each
2 to afford—via 3 and 4 as further intermediates—products 5
and 6 in a 2 : 1 ratio.
to an unsymmetrical signal of w = 24 Hz, suggesting the pres-
ence of two partially overlapping signals for different NH
groups in slow exchange, to end up as an again symmetrical
½
signal at d(H) 7.0 (w = 12 Hz). In addition, signals of the neutral
½
1,3-diazaadamantane, C8H12D2N2 (3-d2), arise for the present at
constant chemical shifts. In this first stage of the reaction, all 1
is converted into a 1 : 2 mixture of 3-d2 and 4 (Scheme 1). The
reaction is quite rapid at the beginning but then markedly
slows down.
In stage 2 of the reaction, which lasts for about 30 h, the new
signals of 3-d2 (with the exception of C3H2) move downfield,
approaching the chemical shifts expected for C8H12D2N2(HCl)
(5-d2). The signals of the bispidine skeleton in 4 retain their
chemical shifts but diminish in intensity. The NH signal reaches
about d(H) 8.2 and has markedly broadened (w = 70 Hz). No
½
precipitate is observed at this stage.
In the third and final stage, the signals attributed to 5-d2 and 4
both retain their chemical shifts. However, the signals of 5-d2
increase in intensity and those of 4 vanish, and after a total
reaction time of 2–3 days, only the signals of 5-d2 are left in the
spectrum. The NH signal moves to still lower field (d(H) 9.0 after
48 h) and becomes very broad. It is during this stage that crystal-
line 6 precipitates.
In a separate experiment, a solution of bispidine in CH2Cl2
was kept in a refrigerator at –8 ꢁC for 6 days. As identified by
NMR, we note complete conversion of 1 into crystalline 6
and a mixture of dissolved 5 and some residual 4 (as a
precursor to 6).
To gain more insight into the reaction mechanism, we
monitored the reaction of 1 with CD2Cl2 by 1H nuclear magnetic
resonance (NMR). The 1H NMR spectrum[14,44] of 1 at ꢀ80 ꢁC
shows for the bispidine skeleton four signals, namely, for
NCHeHa, an apparent AB-type signal[45] for He (d(H) 3.02) and a
higher field ABX-type signal for Ha (d(H) 2.91) (geminal coupling
2J = 12 Hz) and one signal each for the bridging CH2 (d(H) 1.70)
and bridgehead CH (d(H) 1.43). Of the two NCHeHa signals, only
2
N
N
H
H
CH2Cl2
1
CH2Cl2
+
2
2
+
+
N
H
N
H
N
H
N
H
H
H
N
N
N
ClH
N
N
N
N
N
H
Cl
(a)
(b)
(c)
H
H
HCl
HCl
n
Cl
Cl
1
2
3
4
5
6
Scheme 1. Reaction sequence of 1 to generate intermediates 2-4 and end-up in the formation of products 5 and 6
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
These observations allow us to shed some light on the mecha-
nism of the reaction (Eqn (2) and Scheme 1). In the first stage, 1/3
of total bispidine (1) reacts with CH2Cl2 (respectively CD2Cl2) to
give the adduct 2 (2-d2). This can be viewed as a dibasic acid,
which becomes fully deprotonated by previously unreacted 1
to form parent 3 (3-d2). The chelating diamine 1 itself acts as a
relatively strong twofold base. As long as an excess of 1 is present
(accounting for 2/3 of total 1), it accepts just one HCl to become
monoprotonated 4 and so far retains high solubility in CH2Cl2.
Thus, during the initial reaction and as much 2 is generated, the
1H NMR signals of 3 increase in intensity at constant chemical
shifts, whereas the signals of 1 shift downfield toward the
expected signals of the HCl adduct 4, because of equilibration
of 1 and the emerging 4 by HCl exchange. With the increasing
consumption of 1, the partial reactions a and b in Scheme 1 slow
down, as do proton exchange reactions between different
species, and after 90 min at 22 ꢁC, all 1 is converted into a mixture
of 1/3 3 (3-d2) and 2/3 4.
reactions, governed by the diminishing basicity of the various
amines (Eqn (5a)). Bispidine (1) is the strongest base because it
preferably installs the full HCl molecule by intramolecular
N–H⋯Cl⋯H–N hydrogen bridge bonding to become 4 having
a tricyclic structure
In the following stages of the reaction, compound 4 presents
itself as an intermediate with the ability to react with CH2Cl2
(CD2Cl2), albeit distinctly slower than the starting 1. All in all,
half of 4 becomes methylated to generate 2 (2-d2). In the
second stage, as 1 is used up and 3 (3-d2) has become the
strongest base, the first portion of 4 (1/6 of the original 1)
becomes methylated, whereas all released HCl is absorbed by
the existing 3 (3-d2). Thus, both this portion of 4 (via 2 (2-d2))
and all 3 (3-d2) uniformly end up in 5 (5-d2) (1/2 of 1) (Eqn
(3)). It is during this process that the 1H NMR signals of 3
(3-d2) shift downfield, because of its increasing protonation to
give 5 (5-d2) and their equilibration by proton exchange.
Concurrently, the 1H NMR signals of 4 retain their chemical
shifts but decline in intensity.
(see crystal structure). The tertiary diamine 1,3-diazaadamantane
(3), featuring two independent normal pyramidal nitrogen
atoms in a rigid structure, merely binds HCl in a monodentate
fashion giving 5; it is consequently less basic than 1 but more
basic than 4. In bispidine hydrochloride (4), HCl bonding at
the almost planar secondary amine N atom appears a priori
unfavorable, but nevertheless appears to be driven by the
possibility of forming intermolecular N–H⋯Cl⋯H–N hydrogen
bridges and the insolubility of the resulting 6 (see crystal structure).
1,3-Diazaadamantane hydrochloride (5) is the weakest base of the
series in CH2Cl2, because protonation of the remaining tertiary
amine to yield 2 occurs in b-position to an already existing azanium
center. By the same arguments, a reverse sequence of decreasing
acidity (Eqn (5b)) can be established.
In the third and last stage of the reaction, a further portion
of 4 (1/6 of 1) becomes methylated to generate 2 (2-d2), and
with bases 1 and 3 being both depleted, ultimately 4 itself
(corresponding to the remaining 1/3 of 1) serves as base to
bind another HCl. Besides more of 5 (5-d2) (1/6 of 1), all of 6
(1/3 of 1) is formed now (Eqn (4)).
General properties of 1–6
We give here a brief characterization of the properties of starting
1, intermediates 2–4, and the products 5 and 6.
Bispidine (1), which has first been prepared and studied by
Bohlmann et al.,[40,41] Galinovsky et al.,[8,9] and Stetter et al.[42,43]
,
is presently accessible in an overall yield of 37%.[14] As we found,
1 sublimes readily under vacuum at ambient temperature, and
slow sublimation already takes place when the compound is
stored in an air-tight flask at ambient temperature and normal
pressure for several weeks. Because of its stickiness at ambient
temperature, 1 is best handled cold. It is very soluble in most
solvents but crystallizes well from dry pentane between ꢀ20
and ꢀ40 ꢁC. As is obvious from this article, halocarbons as
solvents must be avoided. Vacuum sublimation at ambient
temperature (to withhold any hydrolyzed material) and recrystal-
lization from pentane appear best for purification of 1. There
has been some uncertainty in the literature as to the correct
melting point of 1, and temperatures around 134 ꢁC,[9,43]
Thus, over all three stages, 5 (5-d2) accumulates to a total yield
of 2/3 of the starting 1, and 1/3 of 1 precipitates as insoluble 6.
Carrying out the reaction in CD2Cl2, the CD2 entity exclusively
becomes part of the 1,3-diazaadamantane skeleton, which is
generated as C8H12D2N2(HCl)2 (2-d2), and in the stages of the
reaction is present as either 3-d2 or 5-d2.
It follows from that given previously that intermediate 2 has
been the starting point of a series of cascading acid–base
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
160 ꢁC,[14] and 204 ꢁC[44] have been reported, the discrepancy
being attributed to hygroscopic deliquescence in the air.[14]
We found the melting point of sublimed 1, stored under argon,
to be 190–192 ꢁC. When studied by Differential Scanning
Calorimetry (DSC), 1 undergoes an endothermic transition at
5 ꢁC (278 K), associated with a moderate transition enthalpy of
ΔH278 K = 10 kJ molꢀ1, corresponding to a transition entropy
of ΔS278 K = 36 J Kꢀ1 molꢀ1. When recooled, this solid–solid
phase transition is reversed at ꢀ23 ꢁC (250 K). Melting gives
rise to a sharp and smaller endothermic effect at 198 ꢁC
(471 K; ΔH471 K =6kJmolꢀ1 and ΔS471 K =12.5JKꢀ1 molꢀ1), which is
followed just 20 ꢁC higher at 218ꢁC by a much stronger effect for
boiling (491 K; ΔH491 K = 44 kJ molꢀ1 and ΔS491 K = 90 J Kꢀ1 molꢀ1).
These thermal effects, including the short liquid phase, as well as
ready sublimation and stickiness of 1 appear as typical properties
of plastic crystals.[49] We conclude that 1 crystallizes from cold
pentane in the ordered crystalline phase 1-II which at 278 K
undergoes a phase transition into the plastically crystalline phase
1-I. The Electron Ionization (EI) mass spectrum (MS) of 1 is
described in detail in Ref.[50]. The Electrospray Ionization-Mass
Spectrum (ESI-MS) (MeOH) furnishes [1 + H]+ as sole ion. In the
IR spectrum, 1 triturated in Nujol shows two strong ν(NH) bands
at 3400 and 3298 cmꢀ1, which are attributed to the terminal
and the bridging NH groups, respectively. Despite its tendency
to transform into the plastic phase, we have been able to deter-
mine the crystal structure of ordered 1-II by single-crystal X-ray
diffraction (described below).
two equivalents of 5 (Scheme 2). Compound 2 protonates
1 Eq of 1 to give a mixture of 4 and 5 (Eqn (6a)), and it also
protonates 1 Eq of 4 (or 1/2 Eq of 1) to afford 6 and likewise
5 (Eqn (6b)). Hence, 2 is more acidic than any of 4–6. Al-
though reactions involving bispidine (1) and its HCl adduct 4
with CH2Cl2 need to be performed at low temperature (eqs
6–8) to prevent side reactions with the solvent, for reactions
of the HCl adducts 2 and 4–6, CH2Cl2 is the preferred solvent.
The parent 1,3-diazaadamantane (1,3-diazatricyclo[3.3.1.13,7]
decane, 3)[8,42,51–53] is obtained from 5 by treating an aqueous so-
lution with K2CO3 (Scheme 2). 3 sublimes under vacuum at 40 ꢁC.
At normal pressure, we found 3 to sublime below the melting point
given in literature (260ꢁC,[42] 265 ꢁC[8]). In agreement with this, a
DSC scan of 3 showed—besides two minor endothermic effects
at ꢀ50 and ꢀ30ꢁC—a single strong endothermic effect around
240 ꢁC, associated with substantial enthalpy and entropy changes
(ΔH513 K = 52 kJ molꢀ1, ΔS513 K = 101 J Kꢀ1 molꢀ1), which are too
large to be explained solely by melting. In addition, the transition
leaves an empty crucible. We conclude that at normal pressure
solid 3 remains unchanged up to 240ꢁC, and it then sublimes from
this phase. Compound 3 does not appear to form a plastic phase,
in contrast to the parent adamantane.[49] Compound 3 is very
soluble in pentane and other solvents, rendering recrystalliza-
tion difficult. When a solution of 3 in CH2Cl2 is kept at ambient
temperature for several hours, the high nucleophilicity of the
N atoms in 3 brings about replacement of one chloride atom
in CH2Cl2 and colorless [C8H14N2(CH2Cl)]Cl precipitates (a re-
lated reaction occurs between 1,4-diazabicyclo[2.2.2]octane
and CH2Cl2).[54,55] In the EI-MS of 3 (25 ꢁC), M+ is the base ion,
and in the ESI-MS (MeOH), [M + H]+ is almost the exclusively
observed ion.
1,3-Diazaadamantane di(hydrochloride) (2)[8,42] represents
the principal intermediate of the reaction (Scheme 1). We
prepared 2 in form of a colorless precipitate by treating the
solution of 5 (as obtained in Eqn (2)) or parent 3 with gaseous
HCl (Scheme 2). When solid 2 is heated, it changes color to
yellow at 126 ꢁC and fuses at 253–255 ꢁC due to exothermic
decomposition, as revealed by DSC. Under vacuum, solid 2 is
stable at ambient temperature but dissociates both HCl
molecules when heated. The EI-MS of 2 (115 ꢁC) agrees with
that of 3, with the addition of an HCl peak.
Compound 2 is insoluble in CH2Cl2, tetrahydrofurane (THF),
dimethyl formamide (DMF), and other nonprotonating organic
solvents. It dissolves well in hot dimethyl sulfoxide (DMSO),
from which it can be recrystallized, and very well in MeOH
and water. The ESI-MS (MeOH) of 2 reveals, besides the base
peak [2 ꢀ Cl2H]+ (identical to [3 + H]+), an additional intense
signal for [(C8H14N2H)2(m-Cl)]+ (m/e = 313, 30%). Clearly, in the
sample solution of 2, after partial HCl and Clꢀ dissociation, a
relatively firm N–H⋯Cl⋯H–N bridge bond is formed, in which
two azanium centers are bridged by chloride. Compound 2
acts as a dibasic acid. Comproportionation of 2 and 3 affords
In order to isolate bispidine hydrochloride (4), a suspension of
6 in cold CH2Cl2 (ꢀ20 ꢁC) was equilibrated with an equal amount
of 1. Evaporation of the solvent from the resulting clear solution
leaves crystalline 4 in quantitative yield (Eqn (7)). Compound 4 is
insoluble in THF but
N
N
3
K2CO3
NHCl
K2CO3
ClHN
2
2 HCl
dissolves well in MeOH and H2O, and this is also true for 6.
Compound 4 differs from 6 in that it is highly soluble in CH2Cl2,
DMSO, and acetonitrile, so association of the molecular entities
appears to be weaker for 4. Compound 4 can be recrystallized
from hot DMF. When heated under normal pressure, 4 fuses at
264 ꢁC, concomitant with gas evolution (presumably HCl). In
HCl
N
NHCl
3
5
2
Scheme 2. Interconversion of 1,3-diaza-adamantane (2) and its HCl
adducts 5 and 2
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
DSC, two reversible, broad endothermic effects appear at about
100 and 156 ꢁC, each is associated with a moderate enthalpy
change of ΔH ꢃ 5 kJ molꢀ1. They are presumably due to as yet
unidentified reorganizations of the solid-state structure. As
evidenced by the EI-MS, in a vacuum above 30 ꢁC, 4 dissociates
into 1 and HCl. The base peak in the ESI spectrum (MeOH,
CH2Cl2, DMSO) of 4 is [4 ꢀ Cl]+, identical to [1 + H]+ (m/e = 127).
Further prominent ions in MeOH and CH2Cl2 solution are
[2ꢂ1 + H]+ (253, 20%) and [4 + 1 + H]+ (289, 40%), as fragments
of the chain structure of solid 4.
Eqn (8) that the secondary diamine 1 is a stronger base than
the tertiary amine 3. The molecular structure of the ordered 5
is described below.
Finally, we come to a discussion of bispidine di(hydrochloride)
(6). As we have shown, 6 is only formed from 4 in the last stage
of the reaction cascade (Eqn (4)). Nevertheless, it is the most
obvious product because, due to its insolubility, it separates
directly and quantitatively from the solution. The fact that well-
formed crystals of 6 grow despite the insolubility of the
compound suggests that the formation of 6 is rather slow in the
reaction solution. A measure of the relative acidity of 6 (Eqn (5b))
can be obtained by noting that 6 protonates the parent 1 affording
4 (Eqn (7)), and that it also protonates the parent 3 to give a
mixture of 4 and 5 (Eqn (9); the same mixture is obtained from 2
and 1, see Eqn (6a)).
In DMSO, these ions are also found; moreover, the se-
quence of [1 + H]+ (100%) and [4 + 1 + H]+ (90%) is continued
by [2ꢂ4 + 1 + H]+ (451, 30%) and [3ꢂ4 + 1 + H]+ (613, 5%),
corresponding to [n4 + 1 + H]+, n = 0–3.
Cl
The results are in agreement with association of the molecular
entities in solution through (relatively weak) intermolecular
N–H⋯N bridge bonds (two azane centers bridged by a proton)
and more stable N–H⋯Cl⋯H–N bridge bonds (azane and
azanium bridged by chloride). The latter bonds are particularly
stable in DMSO because of weaker solvation of chloride by the
solvent. For the crystal structure of 4, see below. Similar to 1
but much slower (2 days), 4 reacts with CH2Cl2 at 20 ꢁC by nucle-
ophilic substitution of both chloride ions to give 5 and 6,
corresponding to the last stage of the reaction cascade
(Scheme 1 and Eqn (4)).
1,3-Diazaadamantane hydrochloride (5) is the main product of
bispidine methylation (Eqn (2)). It dissolves very well in CH2Cl2,
DMF, and acetonitrile but is insoluble in THF. Single crystals of
5 have been obtained by slow evaporation of CH2Cl2. When
heated, colorless 5 turns yellow-orange at 140 ꢁC and fuses
above 270 ꢁC to give a brown oil. In a vacuum, the solid eva-
porates at 140 ꢁC, liberating the HCl moiety. According to
DSC, 5 undergoes a reversible phase transition at 160 ꢁC
(433 K), associated with an enthalpy and entropy of transition
of ΔH433 K = 2.7 kJ molꢀ1 and ΔS433 K = 6.2 J Kꢀ1 molꢀ1. We as-
sume that the transition comprises the onset of rotation of the
molecules about the N–H⋯Cl axis and thus the formation of a
plastic phase, similar to those observed for 1-haloadamantanes
and 1-cyanoadamantane.[56] The EI (125 ꢁC) and ESI-MSs of 5
are indistinguishable from those of 2. Thus, the ESI spectrum
(MeOH) of 5 displays, as for 2, [3 + H]+ as base ion and an addi-
tional prominent peak for [(C8H14N2H)2(m-Cl)]+ (m/e = 313, 20%),
showing that in solution, after partial Clꢀ dissociation from 5, a
cationic dimeric species is formed, involving N–H⋯Cl⋯H–N
bridge bonding between two azanium centers and chloride.
Compound 5 is a weak acid and protonates 1 (but not 4) to
become 3 and 4 (but not 6) (Eqn (8)); it is also obvious from
As mentioned, the solid that separates from reaction solution
occurs in two crystalline forms, either solvent-free 6 or the
CH2Cl2 solute 6(CH2Cl2). When a mixture of 6(CH2Cl2) and 6,
both of which are crystalline, is subjected to a vacuum at ambi-
ent temperature for 2 h, 6(CH2Cl2) irreversibly loses CH2Cl2 (but
not the strongly held HCl) and converts to amorphous 6. The
original crystals of the solute-free 6 remain crystalline and can
be detected under a polarizing microscope. Amorphous 6 sus-
pended in CH2Cl2 does not reconvert into 6(CH2Cl2). Hence,
we conclude that solvent-free 6 is thermodynamically stable
and the formation of 6(CH2Cl2) is due to kinetic reasons.
In a sealed capillary, 6 appears to melt only at 276–278 ꢁC with
decomposition. In DSC, minor endothermic effects are found
between 40 and 90 ꢁC, which, however, are difficult to interpret
because of the variable fractions of 6 and 6(CH2Cl2). The EI-MS,
observed at 160 ꢁC evaporation temperature, is identical to that
of 1 except for an additional HCl peak. Compounds 6 and
6(CH2Cl2) are insoluble in CH2Cl2, THF, and DMF, suggesting
strong aggregation. The solubility of both is high in MeOH and
water. The solids dissolve well also in hot DMSO, from which 6
1
recrystallizes. The H and 13C NMR spectra of 6 and 6(CH2Cl2)
have been recorded in DMSO-d6 (Table 1) and D2O and are iden-
tical, aside from the CH2Cl2 signals. The ESI-MS for the MeOH so-
lution of 6 displays exclusively the ion [1 + H]+, and for the DMSO
solution, the sequence of ions [nꢂ4 + 1 + H]+, n = 0
(m/e = 127,
100%), 1 (289, 22), 2 (451, 7), and 3 (613, 1), declines more rapidly
in intensity than for 4 (see the previous part of this article). This
observation is puzzling at first glance, because it suggests a di-
minished stability of the N–H⋯Cl⋯H–N bridge bonds in 6, al-
though its content of chloride ions is twice that of 4. A possible
explanation is that in solution, the higher HCl content of 6 causes
competitive HClꢀ2 ion formation, thus withholding chloride from
N–H⋯Cl⋯H–N bridge bonding. Below, we shall describe the
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
polymeric structures of 6 and 6(CH2Cl2) in the solid state, as de-
termined by single-crystal structure analysis.
rather than NH, is observed (these signals are given in brackets in
Table 1).
Background to the structure and basicity of bispidines
1H and 13C nuclear magnetic resonance spectra of 1–6
1H and 13C NMR data of bispidine (1), together with the HCl
adducts 4 and 6, and of 1,3-diazaadamantane (3) and its HCl
adducts 5 and 2 in various solvents are given in Table 1. Within
each series 1 ! 4 ! 6 and 3 ! 5 ! 2, there appears with an
increasing HCl load a steady shift of the 1H signals to lower field
and of the 13C signals to higher field.
Before we describe the molecular and crystal structures of 1-II, 4,
5, and 6, it is appropriate to recap some of the structural and
base features of bispidines. Although the precise structure of
parent 1 was hitherto unknown, it appears that most substituted
bispidines favor chair–chair conformation of the piperidine
rings,[57,58] unless additional structural effects stabilize a chair–
boat conformation, such as is the case inter alia for sparteine[46]
and 9-ol derivatives.[59] In bispidines of chair–chair conformation,
the two nitrogen atoms are cisoid and assume a nonbonding
N⋯N distance of about 3 Å (see examples A–C in Table 2), which
compares well with twice the van der Waals radius of nitrogen
(1.55 Å). A closer positioning of the two nitrogen atoms is
probably unfavorable because of the mutual repulsion of the
lone-pair electrons.
1
The H NMR spectra of 1 and 4 have already been described.
As to the NMR spectra of 3 and its congeners, in the rigid tricyclic
1,3-diazaadamantane skeleton, all six-membered rings have
the chair conformation. Because the dihedral angles are
fixed at 60ꢁ, vicinal coupling of NCHeHa with the bridgehead
CH is small, and only the geminal couplings of 12–13 Hz are
visible. The spectra of 3 are unspectacular.[51–53] The spectra of
the mono(hydrochloride) 5 in DMSO-d6 correspond to time-
averaged C2v symmetry, indicating rapid exchange of HCl bond-
ing at the two N atoms. In contrast, in CD2Cl2 solution 5 furnishes
It was already noted by Mannich and Mohs[17] in the very first
report on bispidines that these may bind one or two equivalents
of HCl, with the second entity less strongly held than the first.
Since then, a series of bispidine adducts with mostly one acid
equivalent have been isolated, as shown by examples D–M,
which have been characterized by X-ray diffraction. For these,
an unsymmetrical and angled N–H⋯N hydrogen bridge is
given, connecting azanium and tertiary amine nitrogen atoms.
The N–H⋯N hydrogen bridge bond generally results in a
reduction of the N⋯N distance to 2.65–2.68 Å if no additional
steric effects are present.
1
at 22 ꢁC for NCHeHa one broad signal in both H and 13C NMR
and at ꢀ30 ꢁC four signals for inequivalent NCHeHa and N′CHeHa
groups, so HCl exchange between the two N atoms is slow here.
Although the di(hydrochloride) 2 dissolves scarcely in DMSO-d6,
it has been possible to acquire the 1H and 13C NMR spectra with
high data accumulation. Although solubility of 2 in MeOD is
much higher, here, the NH protons exchange with the solvent.
Thus, for NC1H2, a second (minor) signal is found, attributed to
the deuterium effect resulting from ND, and the signal of MeOH,
Table 2. Some structurally characterized bispidine derivatives
Bispidine derivative
d(N⋯N) (Å)
Ref.
[57]
3,7-Diphenylbispidine (A)
3,7-Dibenzhydrylbispidine (B)
a-Isosparteine hydrate (C)
3.072
2.854
3.01(2)
2.670
[58]
[72]
[75]
3,7-Dimethyl-1,5-diphenylbispidin-9-one dihydrosulfate hemihydrate (D)
3,7-Dibenzhydrylbispidine hydrotrifluoromethylsulfonate (E)
3,7-Dibenzyl-9,9-dimethoxybispidine hydroperchlorate (F)
3-Isopropyl-7-benzyl-9,9-dihydroxybispidine hydrobromide (G)
3-Isopropyl-7-(3,4-dimethoxybenzyl)-9,9-dihydroxybispidine hydrobromide (H)
Tedisamil sesquifumarate (I)
3,7-Dimethyl-9-(3-indoylcarbonyloxy)-bispidine hydrochloride (J)
(ꢀ)-Sparteine hydrobromide (K)
[58]
2.727
[66]
2.667a
[67]
2.675(4)
2.677(4)
2.645(2)
2.683(7)
2.741
2.714(8)
2.755(5)
2.736
3.150, 3.125
3.203
3.161
3.147(7)
2.436
2.478
[67]
[27,28]
[76]
[77]
[73]
[79]
(ꢀ)-Sparteine hydroperchlorate (L)
[15,16]
[80]
Bis(3,7-di(methylene)bispidine) di(deuterochloride) (M)
3,7-Dimethyl-bispidine-9-amino-9-carboxamide di(hydrochloride)(two independent molecules) (N)
3,7-Diisopropyl-9,9-dihydroxybispidine di(hydrochloride) dihydrate (O)
Tedisamil di(hydrochloride) (P)
[67]
[27,29]
[73]
a-Isosparteine di(hydroperchlorate) (Q)
2,2-Dimethyl-5,7-diphenyl-1,3-diazaadamantane (R)
4,8,9,10-Tetraphenyl-1,3-diazaadamantane (S)
5,7-Diphenyl-1,3-diazaadamantan-9-one dihydrosulfate (T)
1,16-Endomethylene-a-isosparteine diiodide (U)
1,16-Endomethylene-sparteine diiodide (V)
[81]
[82]
[83]
2.418
2.478, 2.451
2.327, 2.498
[74]
[74]
aDetermined by trigonometry.
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
Bispidines are very strong bases, in particular, when the N
atoms bear aliphatic substituents, as is the case for sparte-
ine.[58,60–62] The basicity of bispidines may well surpass that of
“proton sponge” compounds,[63–65] that are given by sterically
congested and thus strained diamino-substituted ortho-annelated
arenes, which exclusively undergo monoprotonation to experi-
ence relief of strain. In the “proton sponge” monocations, the
N⋯N distance of the N–H⋯N hydrogen bridges are as short as
2.55–2.65 Å.
Monoprotonation of bispidines is observed with weak acids
and usually also with typical strong acids (HClO4) even though
an excess of acid is given. Diprotonation of bispidines, affording
cleavage of the initial N-H⋯N hydrogen bridges, requires partic-
ularly strong acids (e.g., neat CF3COOH),[12] hydrohalides (N-P), or
steric assistance (Q) (see also Ref. [66]). The fact that hydrohalides
such as HCl and HBr, which are of only intermediate acidic
strength, usually bring about diprotonation rather than mono-
protonation of bispidines may appear surprising at first glance.
However, in the di(hydrohalides) N-P (X = Cl), the two azane N
atoms may be viewed as being protonated by a bridging H2Xꢀ
entity including one halide anion. The proper geometrical
and base features of Xꢀ allow for the formation of a rather stable
N–H⋯X⋯H–N twofold hydrogen bridge (for X = Br, see Ref. [67]).
The second halide ion is left to be stabilized outside of this
structural element. This keeps the resulting two azanium NH
functions in N-P at an N⋯N distance of 3.12–3.20 Å. A distance
of the same magnitude is also found for Q (X = O; 3.15 Å), in
which both NH functions share one of the O atoms of the two
ClO4 anions.
(a)
N1
C1
Cl1
H1
C5
N2
(b)
C4*
C3*
C5
C2*
N1
N2
C1
Cl1
C4
C3
C2
Figure 1. Crystal (a) and molecular structure (b) of (C8H14N2)(HCl) (5).
Selected distances (Å) and angles (ꢁ): N1-C1 = 1.510(5), N1-C2 = 1.489(4),
N2-C1 = 1.472(6), N2-C4 = 1.470(4), N1⋯N2 = 2.446(5), N1⋯Cl1 = 3.028
(2), N1-C1-N2 = 110.2(3), C3-C5-C3* = 109.6(3), N1-H1⋯Cl1 = 174.2(6)
Finally, we view the structures of a series of substituted 1,3-
diazaadamantanes.[68,69] Compounds
R (N⋯N distance at
2.436 Å) and S (2.478 Å) represent neutral 1,3-diazaadamantane
derivatives in which two azane N atoms are linked by methylene.
In the ketone T (2.418 Å), one of the N atoms is protonated,
leaving HSO4 as the anion, whereas protonation of the
second N atom of the 1-aza-3-azanium-adamantane skeleton
appears more difficult. In the dicationic U and V (2.44(8) Å,
average of four values), two azanium centers are bridged by
methylene. As the data show, the N⋯N distance in all these
1,3-diazaadamantanes remains approximately constant around
2.44 Å despite an increasing charge. These data will be helpful
in the discussion of the following solid-state structures.
As expected, the three six-membered rings of the
1,3-diazaadamantane skeleton have nearly perfect chair confor-
mation with the torsional angles in the 57–62ꢁ range. The C-N
bonds at the azanium N1 atom (1.49–1.51 Å) are somewhat lon-
ger than those at the azane N2 atom (1.47 Å) and thus of about
similar length as the C-C bonds (1.50–1.53 Å, note that distances
are not corrected for the effects of libration). The N1-C1-N2
bridge between the azane and azanium N atoms is therefore
unsymmetrical; nevertheless, the angle N1-C1-N2 = 110.2(3)ꢁ is
close to ideal tetrahedral. As a consequence, the N1⋯N2
distance at about 2.45 Å is short; it compares well with that in
compounds R (2.436 Å) and S (2.478 Å), but it is not as short as
that in T (2.418 Å) (Table 2).
The H atom attached to N was located from a difference Four-
ier synthesis and refined using a riding model (N-H bond
distance, 0.92 Å). Clearly, the diazaadamantane has been proton-
ated by hydrochloride (H⋯Cl 2.10 Å, cf. H-Cl in HCl 1.275 Å[70]).
The N1-H1⋯Cl1 group is almost linear (174.2ꢁ), showing that
the major interaction between the cation and anion is via the
N1-H1 bond. The N⋯Cl distance at 3.028(2) Å to the terminal
chloride is relatively short compared with the other strong
N-H⋯Cl hydrogen bonds to bridging chloride in this study
(average, 3.08(1) Å).
Crystal and molecular structure determinations
We start here with a description of the structure of 1,3-diazaada-
mantane (mono)hydrochloride (5), followed by the structures of
the parent bispidine (1), its hydrochloride 4, and the di(hydro-
chlorides) 6 and 6(CH2Cl2).
Structure of (C8H14N2)(HCl) (5)
Crystals of the very soluble 1,3-diazaadamantane hydrochloride
(5) were obtained from CH2Cl2 solution by slow evaporation of
solvent. The compound crystallizes in the monoclinic crystal
system in the space group P21/m (no. 11) with two identical
molecules in the unit cell (Table 3). The solid consists of separate
molecules in which only one of the two tertiary amine N atoms is
protonated by HCl. There is no hydrogen bonding between
contiguous molecules (Fig. 1(a)). The molecules of 5 (Fig. 1(b)) re-
side on a mirror plane passing through the 1,3-diazaadamantane
atoms N1, N2, C1, and C5, and also through the H1–Cl1 moiety.
Structure of C7H12(NH)2 (1-II)
Single crystals of the prototypical bispidine in its ordered crystal-
line phase 1-II were obtained from a dilute pentane solution
at ꢀ40 ꢁC. The crystal under study was mounted on the
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
diffractometer while keeping below this temperature. Diffraction
data were collected at 200 K (Table 3).
H2*⋯N1 interaction at 2.295(2) Å is significantly shorter than the
sum of the corresponding van der Waals radii of 2.64 Å, and the
angle N2*-H2*-N1 is 160.9(4)ꢁ. However, the intermolecular
N1⋯N2* distance of 3.114(2) Å is significantly longer than the in-
tramolecular N1⋯N2 distance of 2.849(2) Å. The N2*-H2*⋯N1
bonds between neutral azane functionalities appear weak, allow-
ing for easy dissolution of the compound in hydrocarbons.
Interestingly, they also appear to cleave thermally when the
compound is heated to 5 ꢁC, as the ordered crystalline 1-II
transforms into the plastically crystalline phase 1-I, in which
the molecules presumably spin around on their respective sites
in the lattice.
Compound 1-II (Fig. 2) belongs to the orthorhombic crystal
system (space group P212121, no. 19) with four identical mole-
cules in the unit cell. The bispidine molecule exhibits chair–chair
conformation of the two piperidine rings in the solid, with the
N1-H1 proton in an endo and the N2-H2 proton in an exo orien-
tation with respect to the concave face of the molecule. Interest-
ingly, although the chair conformation of the piperidine ring
involving N2 is close to ideal (dihedral angles, 56–62ꢁ), the ring
involving N1 is flattened at N1 (dihedral angles, 48–62ꢁ). The flat-
tening at N1 appears to result from a steric effect caused by the
intramolecular N1-H1⋯N2 hydrogen bridge. The N-C bond
lengths at both N1 and N2 are relatively uniform at 1.47 Å
(mean), as typical for azane N-C bonds (cf. 5, at N2), and thus
markedly shorter than the likewise relative uniform C-C bond
lengths at 1.53 Å (mean). The quality of the diffraction data
allowed the positions of the H atoms attached to N1 and N2 to
be refined. Although the length of the exo N2-H2 bond at 0.85
(2) Å appears typical for a nonbridging azane N-H bond, that of
the N1-H1 bond at 0.96(2) Å is significantly longer and indicates
that the endo H1 is part of a strongly asymmetrical intramolecu-
lar N1-H1⋯N2 hydrogen bridge bond, with an elongated and
presumably weak N2-H1 bond of 2.23(2) Å. Nevertheless, the
N1⋯N2 distance at 2.849(2) Å is substantially shorter than for
the reference bispidines A and C (3.01–3.07 Å) and is of same
magnitude as for B (2.854 Å). The intramolecular N1-H1⋯N2
hydrogen bridge directs H2 at N2 into an exo position. The ob-
served molecular structure of 1 agrees well with the gas phase
structure calculated by the ab initio MP2 formalism and density
functional theory, both of which predict a preferred chair–chair
conformation of the two piperidine rings with one N-H proton
in an endo and the other proton in an exo orientation, and an
N⋯N distance of 2.91 Å.[16]
Structure of C7H12(NH)2(HCl) (4)
Bispidine hydrochloride (4) crystallizes from DMF in the triclinic
space group Pꢀ1 (no. 2). Details of the crystal structure analysis
are given in Table 3, and a drawing of a section of the chain
structure of 4 is shown in Figure 3. There are two independent
azane/azanium C7H12(NH)(NH2)+ monocations in the asymmetric
unit, which differ in the conformation of the amine and are thus
conformational epimers. In one cation (i), the azane hydrogen
atom H2 is exo to the concave surface of the cation, and the
N2 atom to which it is bonded is able to accept an intramolecular
N-H⋯N hydrogen bond from the neighboring azanium center;
in the other, (ii) the amine hydrogen atom H3 is endo and such
an interaction is blocked. The cations and chloride anions
form infinite and parallel hydrogen bonded chains, linked by
N-H⋯Cl and N-H⋯N hydrogen bonds, which lie approximately
in a plane.
Superficially, the geometry of cation i is quite similar to that of
the neutral parent 1-II. However, closer inspection reveals that
the N1⋯N2 distance at 2.753(2) Å in cation i is significantly
shorter than that in 1-II (2.849(2) Å). This can be explained in
terms of a stronger N-H⋯N interaction resulting from a higher
positive charge on the endo H1A of the azanium center. Inside
the piperidine rings, for the ring involving the azane N2, the
N-C bond lengths are at 1.46 Å (mean) and the torsional angles
about the N-C bonds amount to 57–59ꢁ, and for the ring
Although the N2-H2 distance is as expected, it nevertheless
takes part in an intermolecular, likewise asymmetrical,
N2*-H2*⋯N1 hydrogen bridge to a neighboring molecule, form-
ing an infinite zigzag chain in the crystal.[71] The distance of the
C7*
C14
C2*
C3*
C11
C12
Cl2
H4B
C1*
C5*
C13
H2*
C9
C4*
C10
N4
H1
C1
C8
N2*
N1
C6*
N3**
H4A
H1B
N1
H3**
N3
N1*
H2
N2
C6
H1*
H3
H1A*
H1A
C4
C6
C5
Cl1
H1C
C3
C1
C2
C5
N2*
N2
H2
H2*
C4
C2
C3
C7
C7
Figure 2. Two molecules of C8H14N2 in the crystal, showing the intermo-
lecular and intramolecular hydrogen bonding interactions (1-II). Selected
distances (Å) and angles (ꢁ) (the positions of the H atoms on N1 and N2
were refined using isotropic atomic displacement parameters): N1-
H1 = 0.96(2), N2-H1 = 2.23(2), N2-H2 = 0.85(2), N1-H2* = 2.30(2), N1⋯N2
(intramolecular) = 2.849(2), N1⋯N2* (intermolecular) = 3.114(2), N1-
H1⋯N2 = 121.8(4), N2*-H2*⋯N1 = 160.9(4)
Figure 3. Crystal structure of 4; part of the infinite chain of C7H12(NH)
(NH2)+ cations and Clꢀ anions showing the intramolecular and
intermolecular interactions. Selected distances (Å) and angles (ꢁ):
N1⋯N2 = 2.753(2), N3⋯N4 = 3.058(2), N1⋯N3** = 2.899(2), N1⋯Cl2 =
3.146(1), N2*⋯Cl1 = 3.520(1), N3⋯Cl1 = 3.379(1), N4⋯Cl1 = 3.097(1),
N4⋯Cl2 = 3.077(1), N3⋯Cl1⋯N4 = 56.14(1), N1⋯Cl2⋯N4 = 100.10(1),
N2*⋯Cl1⋯N3 = 54.81(1)
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
involving the azanium N1, the N-C bond lengths are elongated
to 1.50 Å (mean) with the torsional angles at 50–52ꢁ, the latter
indicating some flattening of this ring. As in the case of 1-II,
we attribute the flattening of the protonated ring to a steric
effect from the N1-H1A⋯N2 hydrogen bridge.
a)
In cation ii, the endo H atom prevents the formation of an
N-H⋯N bond. As a result, there is a long nonbonding N3⋯N4
distance of 3.058(2) Å. This feature is related to those in the
substituted bispidine di(hydrochlorides) N-P (Table 2), where
two azanium centers are bridged by an H2Cl moiety in a quite
symmetrical fashion, resulting in relatively large N⋯N distances
(3.12–3.20 Å). Similar as in cation i, inside the piperidine rings
of cation ii, the N-C bond lengths around the azane N3 are at
1.47 Å (mean) and those around the azanium N4 at 1.50 Å
(mean). However, the torsional angles around the N-C bonds
are here relatively uniform at 43–45ꢁ and much smaller than
those in cation i, indicating increased flattening of both chair
conformations. This is probably due to steric repulsion between
the endo H atoms on the two N atoms.
C1
H1B
C3
Cl1
C2
N1 H1A
H2A
H2B
C6
C7
N2
C5
Cl2*
C4
b)
Interest focuses on the interionic interactions in the solid.
Cation i undergoes two major N-H⋯X interactions. There is an
N1-H1A⋯N3** interaction between the azanium center of cation
i and the N3** atom containing the endo H3** on cation ii. The
N1⋯N3** distance at 2.899(2) Å is relatively short considering
that the interaction is between two cations. The H1B atom on
the azanium moiety forms an N1-H1B⋯Cl2 bond of 3.146(1) Å.
This compares excellently with the mean interionic N+-H⋯Clꢀ
distance for a secondary azanium group from the Cambridge
Crystallographic Database[68] (3.147(2) Å, based on 1852 observa-
tions). Although the endo H2 is directed toward Cl1**, the
N-H⋯Clꢀ distance is relatively long (3.520(1) Å) and probably
not a very strong interaction, considering that the mean inter-
ionic N-H⋯Clꢀ distance for an uncharged NH group in a cation
from the Cambridge Crystallographic Database is 3.255(3) Å
(1496 observations).
C1
C2
H1B
C3
Cl1
N1 H1A
H2A
H2B
C6
C7
N2
C4
C5
Cl2*
c)
C7
C5
C2
In contrast, all NH H atoms in cation ii appear to interact well
with the chloride anions. The shortest N-H⋯Cl distance in the
structure at 3.077(1) Å is between the azanium N4 and Cl2, which
undergoes the additional N1-H1B⋯Cl2 interaction to cation i
(see above). The other H atom attached to the azanium N4 forms
a similarly short N-H⋯Cl interaction to Cl1 (3.097(1) Å). Interest-
ingly, the endo azane H3 atom at N3 is also directed toward
Cl1, but with a significantly longer N-H⋯Cl distance (3.379(1) Å).
Considering the nature of these interactions, the structure of
crystalline 4 can be best formulated as consisting of a chain of
dimeric subunits of the epimeric cations i and ii. The cations i
and ii are paired by a presumably strong N-H⋯Cl2⋯H-N bridge;
in addition, cation ii is bonded to Cl1. The dimeric subunits are
linked via presumably weaker N1-H1A⋯N3** and N2-H2⋯Cl1**
interactions. This might explain the high solubility of 4 in CH2Cl2
and other solvents, compared with the insolubility of 6 and
6(CH2Cl2), where only N-H⋯Cl⋯H-N interactions are seen
(see below).
C6
C1
C4
C3
H1B
H2B
N1
H1A
N2
H2A
Cl2*
Cl2
Cl1
Figure 4. Crystal and molecular structure of solute-free [C7H12(NH2)2Cl]
Cl (6). (a) Crystal structure, showing the chain-linked molecules (red
and black). (b) Alignment of anions and cations in a row. (c) Ionic
structure. Selected nonbonding distances (Å) and angles (ꢁ):
N1⋯N2 = 3.094(2), N1⋯Cl1 = 3.098(1), N2⋯Cl1 = 3.076(1), N1⋯Cl2 =
3.068(1), N2⋯Cl2* = 3.055(1)
crystals of 6 unchanged, which can be detected in a polarized
microscope.
Bispidine di(hydrochloride) (6) crystallizes in the orthorhombic
crystal system, space group Pbca (no. 61), with eight equivalent
ion pairs in the unit cell (Table 3). Both amino groups of the bis-
pidine are protonated, so the dication contains two secondary
azanium groups in 3- and 7-positions (Fig. 4(c)). Compound 6
thus corresponds to the substituted bispidine di(hydrochlorides)
N-P (Table 2). The N1⋯N2 distance at 3.094(2) Å in 6 is longer
than in the azane/azanium compound 4, cation ii (3.058(2) Å),
Structure of solute-free [C7H12(NH2)2Cl]Cl (6)
Surprisingly, 6 has been obtained from CH2Cl2 both as single
crystals of exclusively pure 6 and as a mixture of single crystals
of pure 6 and single crystals of the solute 6(CH2Cl2). When the
mixture is subject to vacuum, the crystals containing the solute
become amorphous and turn from clear to white, leaving single
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
and 47ꢁ (at N1) and 40ꢁ (at N2), evidencing different degrees
of flattening of the two chair conformations.
(a)
The azanium centers in 6 form N-H⋯Cl interactions to
chloride anions, which take up two different positions: one
(Cl1) bridging a dication and one (Cl2) linking two dications.
Although all N⋯Cl distances are quite similar, the N⋯Cl
distances to Cl2 linking dications are slightly shorter at 3.055(1)
and 3.068(1) Å than those for Cl1 bridging one dication (3.076
(1) and 3.098(1) Å). The cations and anions thus appear to be
arranged in infinite and parallel chains along the c axis, in
what can be formally considered as alternating asymmetric
[C7H12(NH2)2Cl]+ cations and chloride anions, linked via
N1⋯Cl2⋯N2* bridges (Fig. 4(a, b)).
C9
Cl5
Cl6A
N2
C3
C3
C2
Cl1
C2
C4
C1
C7
C6
C8
C1
C5
N3
C5
N1
Cl3
N3
Cl4
Cl2
C6
C7
Crystal structure of [C7H12(NH2)2Cl]ClꢂCH2Cl2 (6(CH2Cl2))
Crystals of 6(CH2Cl2) were separated from the reaction solution
of Eqn (2). The crystals belong to the orthorhombic crystal
system, and the space group is Pbcm (no. 57). There are eight
ion pairs in the unit cell with two independent ion pairs in the
asymmetric unit (Table 3). As in 6, the cations and anions can
be thought of as forming infinite and parallel chains, each of
which is made up from alternating [C7H12(NH2)2Cl]+ cations
and chloride anions, linked via N-H⋯Cl⋯H-N bridges. However,
in the case of 6(CH2Cl2), the two independent chains adopt
significantly different conformations (Fig. 5). Although the
constitution of the [C7H12(NH2)2Cl]+ cations and one type of
chain are similar to the structure of 6 (Fig. 5(b)), the second
chain is appreciably different (Fig. 5(c)).
(b)
C8
C6
C5
N3
C7
H3A
H3B
Cl4
Cl3
The N⋯Cl distances within the chains at 3.077(2) and
3.070(2) Å for chain 1 (Fig. 5(b)) and 3.054(2), 3.079(2), 3.094(2),
and 3.064(2) Å for chain 2 (Fig. 5(c)) are relatively constant
throughout the structure. The intramolecular N⋯N distances
are similarly invariable: in chain 1, this distance is 3.078(2) Å,
and in chain 2, it is 3.056(2) Å. In the solid, the individual chains
of each type are arranged parallel to each other in sheets.
The chains of different types are stacked in layers running
perpendicular to one another, forming a pile, which extends
along the crystallographic a axis. The resulting loose structure
leaves channels along this axis, which are filled with one CH2Cl2
solvent molecule per ionic unit.
Within the piperidinium rings of 6(CH2Cl2), the N-C bonds are
perhaps slightly shorter (1.49 Å, mean) than in 6, and the ring
torsional angles about the N-C bonds, found at 43–45ꢁ, appear
more balanced but still indicative of marked flattening of the
chair conformations.
(c)
Cl1
N1*
H1B*
Cl2*
H1A
N1
H2A
N2
H1B
H2B
C3*
C1*
C2*
C2
C1
C3
C4
Figure 5. Crystal structure of the solute compound [C7H12(NH2)2Cl]
ClꢂCH2Cl2 (6(CH2Cl2)). (a) View of one unit cell, showing the horizontal
(red) and vertical (black) running ionic chains. (b) View along the red
chains, showing the eclipsed arrangement of cations. (c) View onto the
plane of the black chains, showing the alternating arrangement of
cations. Selected distances (Å) and angles (ꢁ): chain 1 (red): N3⋯N3*
(intramolecular) = 3.078(2), N3⋯N3* (intermolecular) = 5.217(2), N3⋯Cl3 =
CONCLUSIONS
We have shown that the conventional solvent CH2Cl2 encounters
ready nucleophilic attack (≥ ꢀ 20 ꢁC) by the prototypical
bispidine 1, affording substitution of both chloride ions to
generate the 1,3-diazaadamantane-derived (C8H14N2)(HCl)2 (2),
as the principal intermediate, and (C8H14N2)(HCl) (5), as the main
product of the reaction. In addition, 1 acts as a base, abstracting
one or two HCl molecules from 2 to intermediately become
monoprotonated C7H12(NH)(NH2)Cl (4) and eventually precipi-
tate as the di(hydrochloride) [C7H12(NH2)2Cl]Cl (6). Ultimately,
all 1 is converted into an easily separable mixture of soluble 5
(65%) and insoluble 6 (33%) as components. Essential findings
from this study are as follows:
3.077(2), N3⋯Cl4 = 3.070(2). Chain
2
(black): N1⋯N2= 3.056(2),
N1⋯N2* = 6.138(2), N1⋯Cl1= 3.054(2), N2⋯Cl1 = 3.079(2), N2⋯Cl2* =
3.094(2), N1⋯Cl2= 3.064(2)
but not as long as in N-P (3.12–3.20 Å). All N-C bonds in 6 have
the same length as found for the azanium centers of cations i
and ii in 4 (1.50 Å, mean). Nevertheless, the N-C bond torsional
angles within the two piperidinium rings in 6 vary between 46ꢁ
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)

DEGRADATION OF DICHLOROMETHANE BY BISPIDINE
• The parent 1 crystallizes from cold pentane (ꢀ40 ꢁC) in the
ordered crystalline phase 1-II. Despite a propensity to trans-
form into a plastic phase, we have been able to determine
the single-crystal structure of 1-II. In 1-II, the molecules have
chair–chair conformation with one N-H hydrogen atom in
endo and the other in exo position, resulting in intramolecu-
lar and intermolecular N-H⋯N hydrogen bridging.
C8H14N2 (1,3-diazaadamantane, 3)
A solution of 5 (175 mg, 1.00 mmol) in 20 mL of water was stirred with 1 g
of K2CO3 for 30 min (no deprotonation occurred for CH2Cl2 as a solvent
due to the insolubility of K2CO3). The mixture was extracted with CH2Cl2
and the extract dried over Na2SO4. After removal of the solvent, the prod-
uct sublimed under vacuum at 40 ꢁC: yield, 125 mg (90%). EI-MS: (25 ꢁC)
m/e (%) = 138 (M+, 100). Anal. Calcd for C8H14N2 (138.2): C, 69.52; H,
10.21; N, 20.27. Found: C, 69.51; H, 10.17; N, 20.29.
• At 278 K, the ordered crystalline 1-II reversibly transforms
into the plastically crystalline phase 1-I. The presence of this
phase at ambient temperature explains some of the obvious
solid-state properties of 1 (stickiness, ready sublimation).
• The reactivity of the secondary diamine 1 is determined by (i)
high nucleophilicity of the nitrogen atoms due to little steric
hindrance, as opposed to the situation for 3,7-disubstituted
bispidines, and (ii) high basicity of the rigid diamine structure,
in particular, toward hydrohalides HX, resulting in intramolec-
ular and intermolecular N-H⋯X⋯H-N bridge bonding, the
latter facilitating the formation of supramolecular structures.
• For the soluble bispidine hydrochloride 4, the propensity to
act both as a nucleophile and as a base is lower than for 1,
but otherwise retained. The di(hydrochloride) 6 is no longer
nucleophilic because of its insolubility.
• The reaction of the principal intermediate 2 with further 1 to
afford a mixture of (soluble) 5 and (insoluble) 6 occurs as a
three-staged cascade of acid–base reactions, and only in
the last stage, 6 crystallizes from the solution. The insolubility
of 6 is seen as a key to the successful interpretation of the
overall reaction.
• The di(hydrochloride) [C7H12(NH2)2Cl]Cl (6) crystallizes from
CH2Cl2 either as such or, due to delicate nucleation kinetics,
as the CH2Cl2 solute [C7H12(NH2)2Cl]ClꢂCH2Cl2 (6(CH2Cl2)),
both showing a common ⋯Cl⋯[C7H12(NH2)2Cl]⋯Cl⋯[C7H12
(NH2)2Cl]⋯ polymeric motive, but distinctly different
structures.
C7H12(NH)(NH2)Cl (4)
A suspension of 6 (110 mg, 0.55 mmol) in 10 mL of CH2Cl2 was stirred
with bispidine (63 mg, 0.50 mmol) at ꢀ20 ꢁC for 30 min. Compound 6
almost completely dissolved, and the excess was removed by filtration.
Evaporation of the solvent from the solution afforded colorless micro-
crystals of 4 in quantitative yield (163 mg). Anal. Calcd for C7H15ClN2
(162.7): C, 51.69; H, 9.29; N, 17.22; Cl, 21.80. Found: C, 51.75; H, 9.28; N,
17.19; Cl, 21.76. EI-MS: At 30–140 ꢁC evaporation temperature, the spectra
correspond to a mixture of 1 (m/e = 126) and HCl (36).
[C7H12(NH2)2Cl]Cl (6) and/or [C7H12(NH2)2Cl]ClꢂCH2Cl2 (6(CH2Cl2))
A solution of bispidine (126 mg, 1.00 mmol) in 5 mL of dry CH2Cl2 was kept
without stirring at room temperature for 3 days. After about 2days, well-
formed colorless crystals formed. These were freed from the mother liquor
and washed with 1mL of CH2Cl2. Drying occurred in a stream of argon: yield
65–94 mg (33%) of an undefined mixture of 6 and 6(CH2Cl2). For X-ray
structure determinations, single crystals were picked from the wet precipi-
tate before drying. Drying of 6(CH2Cl2) (C7H16Cl2N2ꢂCH2Cl2, 284.2) in a vac-
uum at ambient temperature for 2h afforded a mixture of amorphous and
crystalline 6. Anal. Calcd for C7H16Cl2N2 (199.1): C, 42.22; H, 8.10; Cl, 35.61; N,
14.07. Found: C, 42.76; H, 8.04; N, 13.79. For MS data, see text.
C8H14N2(HCl) (5)
Slow evaporation of the mother liquor from the synthesis of 6 to dryness
afforded large crystals of 5: yield 113mg (65%). Anal. Calcd for C8H14N2
(HCl) (174.7): C, 55.01; H, 8.66; N, 16.04; Cl, 20.30. Found: C, 53.65; H, 8.94;
N, 15.48; Cl, 21.93 (corresponding to C8H14N2(HCl)1.12). For MS data, see text.
• Insight into the various forms of hydrogen bridge bonding is
obtained, from the relatively strong N-H⋯Cl⋯H-N bridge
bonding (one azane and one azanium center bridged by
chloride or two azanium centers bridged by chloride) to the
weaker N-H⋯N bridge bonding (positively charged when
two azane centers are bridged by a proton or neutral for
azane–azane association).
SUPPLEMENTARY MATERIAL
The supporting material comprises H and 13C NMR spectra of
1
complexes 1–6 and the DSC scan of compound 1.
EXPERIMENTAL SECTION
Acknowledgements
3,7-Diazabicyclo[3.3.1]nonane (bispidine, 1) was prepared according to
the literature.[14] Dichloromethane was dried over CaH2. All compounds
and solvents were kept under argon. EI-MSs were recorded at 70 eV,
and ESI-MS data were obtained with a Bruker Esquire 3-D ion-trap mass
spectrometer operated in positive mode (Bruker Daltonik, 28359 Bremen,
Germany). DSC was studied at 5 K minꢀ1 heating and cooling rates.
Microanalyses were performed at the local Mikroanalytisches Labor
Kolbe (45470 Mülheim, Germany). NMR data of all compounds were
recorded at 300 MHz (1H) and 75.5 MHz (13C) relative to tetramethylsilane
and are contained in Table 1.
This study is part of the research project IGF Nr. 15691N, admin-
istered by DECHEMA and AiF. Financial support from the German
Ministry of Economy and Technology (BMWi) is gratefully
acknowledged. We thank Mrs Angelika Dreier for collecting the
X-ray diffraction data and Mr Udo Blumenthal for the DSC
measurements. KRP wishes to dedicate this paper to Professor
Uwe Rosenthal, Rostock, in appreciation of a long friendship.
REFERENCES
[1] G. L. Closs, L. E. Closs, J. Am. Chem. Soc. 1960, 82, 5723.
[2] S. Bekkevoll, I. Svorstøl, H. Høiland, J. Songstad, Acta Chem. Scand. B
1983, 37, 935.
[3] G. O. Nevstad, J. Songstad, Acta Chem. Scand. B 1984, 38, 469.
[4] J. E. Mills, C. A. Maryanoff, R. M. Cosgrove, L. Scott, D. F. McComsey,
Org. Prep. Proc. Int. 1984, 16, 97 and references cited therein.
[5] N. Menshutkin, Z. Phys. Chem.-Leipzig 1890, 5, 589; 1890, 6, 41.
[6] W. C. Davies, E. B. Evans, F. L. Hulbert, J. Chem. Soc. 1939, 412.
[7] C. G. Swain, N. D. Hershey, J. Am. Chem. Soc. 1972, 94, 1901.
[8] F. Galinovsky, H. Langer, Monatsh. Chem. 1955, 86, 449.
C8H14N2(HCl)2 (2)
A solution of 5 (175 mg, 1.00 mmol) in 20 mL of CH2Cl2 (using either
isolated 5 or the mother liquor from the reaction of Eqn (2)) was
treated with gaseous HCl to afford a colorless precipitate, which was
separated by filtration and dried under vacuum: yield, 205 mg (97%).
Anal. Calcd for C8H16Cl2N2 (211.1): C, 45.51; H, 7.64; N, 13.27; Cl,
33.58. Found: C, 45.21; H, 7.79; N, 13.17; Cl, 33.68. For MS data,
see text.
J. Phys. Org. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

H. CUI, R. GODDARD AND K.-R. PÖRSCHKE
[9] F. Galinovsky, F. Sparatore, H. Langer, Monatsh. Chem. 1956, 87, 100.
[10] F. Galinovsky, P. Knoth, W. Fischer, Monatsh. Chem. 1955, 86, 1014.
[11] A. I. Ishbaev, A. N. Nizamkhodzhaeva, K. T. Ilyasova, Khim. Prir.
Soedin. 1979, 532; Chem. Nat. Compd. 1979, 15, 462.
[12] J. E. Douglass, T. B. Ratliff, J. Org. Chem. 1968, 33, 355.
[13] A. B. Rudine, M. G. Walter, C. C. Wamser, J. Org. Chem. 2010, 75,
4292.
[49] (Ed.: J. N. Sherwood), The Plastically Crystalline State, Wiley,
Chichester, UK, 1979.
[50] H. Cui, R. Goddard, K.-R. Pörschke, Organometallics 2011, 30, 6241.
[51] L. Meurling, Chem. Scripta 1975, 7, 23.
[52] A. Hussénius, O. Matsson, G. Bergson, J. Chem. Soc. Perkin Trans. 2
1989, 851.
[53] There appears to be a misprint of the 13C NMR data of 3 given in ref. [52]
.
[14] Y. Miyahara, K. Goto, T. Inazu, Synthesis 2001, 364.
[15] Y. Miyahara, K. Goto, T. Inazu, Tetrahedron Lett. 2001, 42, 3097 and
9097 (corrigendum).
[54] L. M. Vallarino, V. L. Goedken, J. V. Quagliano, Inorg. Chem. 1973, 12, 102.
[55] B. Almarzoqi, A. V. George, N. S. Isaacs, Tetrahedron 1986, 42, 601.
[56] N. T. Kawai, D. F. R. Gilson, I. S. Butler, Can. J. Chem. 1991, 69, 1758
and references cited therein.
[57] O. I. Levina, K. A. Potekhin, E. N. Kurkutova, Y. T. Struchkov, V. A. Palyulin,
N. S. Zefirov, Dokl. Akad. Nauk 1984, 277, 367.
[58] L. Toom, A. Kütt, I. Kaljurand, I. Leito, H. Ottosson, H. Grennberg,
A. Gogoll, J. Org. Chem. 2006, 71, 7155.
[59] S. G. Klepikova, V. A. Solomin, T. K. Iskakova, V. K. Yu, K. D. Praliev,
N. A. Zhumanova, K. D. Berlin, Chem. Heterocyc. Compd. 2003, 39, 504.
[60] N. J. Leonard, P. D. Thomas, V. W. Gash, J. Am. Chem. Soc. 1955, 77,
1552.
[16] V. Galasso, K. Goto, Y. Miyahara, B. Kovač, L. Klasinc, Chem. Phys.
2002, 277, 229.
[17] C. Mannich, P. Mohs, Ber. Dtsch. Chem. Ges. 1930, 63, 608.
[18] R. Jeyaraman, S. Avila, Chem. Rev. 1981, 81, 149.
[19] N. S. Zefirov, V. A. Palyulin, Top. Stereochem. 1991, 20, 171.
[20] P. Comba, M. Kerscher, W. Schiek, Prog. Inorg. Chem. 2007, 55, 613.
[21] R. D. Hancock, D. L. Melton, J. M. Harrington, F. C. McDonald,
R. T. Gephart, L. L. Boone, S. B. Jones, N. E. Dean, J. R. Whitehead,
G. M. Cockrell, Coord. Chem. Rev. 2007, 251, 1678.
[22] M. Breuning, Synthesis 2008, 18, 2841.
[61] F. Schneider, P. Fischer, T. Ebner, C. O. Meese, Bioorg. Med. Chem.
Lett. 1993, 3, 1667.
[62] W. Boczoń, B. Jasiewicz, Collect. Czech. Chem. Commun. 2003, 68, 696.
[63] R. W. Alder, P. S. Bowman, W. R. S. Steele, D. R. Winterman, Chem.
Commun. 1968, 723.
[23] N. J. Leonhard, in: The Alkaloids. Chemistry and Pharmacology (Eds: R.
H. F. Manske, H. L. Holmes), Academic Press, New York, 1953, vol. 3,
pp. 119–199.
[24] K. A. Aslanov, Y. K. Kushmuradov, A. S. Sadykov, in: The Alkaloids.
Chemistry and Pharmacology, (Ed.: A. Brossi), Academic Press, New
York, 1987, vol. 31, Chapter 5, pp. 118–193.
[25] S. Ohmiya, K. Saito, I. Murakoshi, in: The Alkaloids. Chemistry and
Pharmacology, (Ed.: G. A. Cordell), Academic Press, San Diego,
1995, vol. 47, Chapter 1, pp. 1–115.
[26] J. P. Michael, Nat. Prod. Rep. 2008, 25, 139 and preceding reviews.
[27] U. Schön, J. Antel, R. Brückner, J. Messinger, R. Franke, A. Gruska,
J. Med. Chem. 1998, 41, 318.
[64] R. W. Alder, Chem. Rev. 1989, 89, 1215.
[65] H. A. Staab, T. Saupe, Angew. Chem. Int. Ed. 1988, 27, 865.
[66] G. S. Smith, M. D. Thompson, K. D. Berlin, E. M. Holt, B. J. Scherlag,
E. Patterson, R. Lazzara, Eur. J. Med. Chem. 1990, 25, 1.
[67] S. Tyagi, K. D. Berlin, M. B. Hossain, C. Sinars, D. van der Helm,
S. Sangiah, Phosphorus Sulfur 1997, 123, 385.
[68] Cambridge Structural Database (CSD, version 5.32, update February
2011).
[28] P. G. Jones, U. Schön, E. Finner, Acta Crystallogr. E 2004, 60, o1285.
[29] U. Schön, P. G. Jones, Personal communication 1994.
[30] E. Marrière, J. Rouden, V. Tadino, M.-C. Lasne, Org. Lett. 2000, 2, 1121.
[31] K.-J. Haack, R. Goddard, K.-R. Pörschke, J. Am. Chem. Soc. 1997, 119,
7992.
[69] On submission of the manuscript, CSD lists a total of 21 structur-
ally characterized compounds having the 1,3-diazaadamantane
skeleton.
[70] K. P. Huber, G. Herzberg, Molecular Spectra and Molecular Structure,
Constants of Diatomic Molecules, Van Nostrand Reinhold, New York,
1979, Vol. IV.
[32] R. G. Pearson, J. Am. Chem. Soc. 1963, 185, 3533.
[33] R. G. Pearson, J. Chem. Educ. 1968, 45, 3533.
[71] Model compounds for the association of secondary amines by inter-
molecular N-H⋯N hydrogen bonds are piperazine (N-H = 0.88 Å,
H⋯N = 2.32 Å, N⋯N = 3.186(1) Å) and piperidine (N-H = 0.85 Å,
H⋯N=2.35Å, N⋯N = 3.185(1) Å). A. Parkin, I. D. H. Oswald, S. Parsons,
Acta Crystallogr. B 2004, 60, 219. See also: J. H. Loehlin, E. L. N. Okasako,
Acta Crystallogr. B 2007, 63, 132 and 674 (corrigendum).
[72] M. Przybylska, W. H. Barnes, Acta Crystallogr. 1953, 6, 377.
[73] M. Przybylska, Acta Crystallogr. B 1974, 30, 2455.
[74] A. E. Kozioł, J. Cryst. Spectrosc. Res. 1992, 22, 449.
[75] O. I. Levina, E. N. Kurkutova, K. A. Potekhin, Y. T. Struchkov,
V. A. Palyulin, N. S. Zefirov, Cryst. Struct. Commun. 1982, 11, 1915.
[76] M. J. Fernández, R. Huertas, E. Gálvez, J. Server-Carrió, M. Martínez
Ripoll, A. Orjales, A. Berisa, L. Labeaga, J. Mol. Struct. 1995, 351, 127.
[77] A. Farina, S. V. Meille, M. T. Messina, P. Metrangolo, G. Resnati,
G. Vecchio, Angew. Chem. Int. Ed Engl. 1999, 38, 2433.
[78] A. Farina, S. V. Meille, M. T. Messina, P. Metrangolo, G. Resnati, Acta
Crystallogr. C 1999, 55, 1710.
[79] Y.-M. Lee, Y.-B. Shim, S. J. Lee, S. K. Kang, S. N. Choi, Acta Crystallogr.
C 2002, 58, o733.
[80] M. J. Fernández, M. S. Toledano, E. Gálvez, E. Matesanz, M. Martínez-
Ripoll, J. Heterocyclic Chem. 1992, 29, 723.
[81] N. S. Zefirow, V. A. Palyulin, O. I. Levina, K. A. Potekhin, E. N. Kurkutova,
Y. T. Struchkov, Vestn. Mosk. Univ., Ser. 2: Khim. 1987, 28, 276.
[82] S. Natarajan, K. Uthayasankari, K. E. Satesh Goud, C. Gangadurai,
V. Vijayakumar, J. Suresh, Anal. Sci.: X-Ray Struct. Anal. Online 2008,
24, x249.
[34] R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 1983, 105, 7512.
[35] For a discussion of structurally reinforced macrocyclic ligands,
covering also the bispidine group, see R. D. Hancock, G. Pattrick,
P. W. Wade, G. D. Hosken, Pure Appl. Chem. 1993, 65, 473.
[36] D. K. Cabbiness, D. W. Margerum, J. Am. Chem. Soc. 1969, 91, 6540.
[37] F. P. Hinz, D. W. Margerum, J. Am. Chem. Soc. 1974, 96, 4993; Inorg.
Chem. 1974, 13, 2941.
[38] R. M. Izatt, J. S. Bradshaw, S. A. Nielsen, J. D. Lamb, J. Christensen,
J. Chem. Rev. 1985, 85, 271.
[39] R. D. Hancock, A. E. Martell, Comment. Inorg. Chem. 1988, 6, 237 and
literature cited therein.
[40] F. Bohlmann, N. Ottawa, R. Keller, Liebigs Ann. Chem. 1954, 587, 162.
[41] F. Bohlmann, N. Ottawa, Chem. Ber. 1955, 88, 1828.
[42] H. Stetter, H. Hennig, Chem. Ber. 1955, 88, 789.
[43] H. Stetter, R. Merten, Chem. Ber. 1957, 90, 868.
[44] J. Kuthan, J. Palecek, L. Musil, Collect. Czech. Chem. Commun. 1974,
39, 750.
[45] For an analysis of similar spin systems, see: A. Gogoll, H. Grennberg,
A. Axén, Magn. Reson. Chem. 1997, 35, 13.
[46] W. M. Golebiewski, Magn. Reson. Chem. 1986, 24, 105.
[47] For a recent NMR study of intra- and intermolecular hydrogen
bonds in polyamines, see: N. S. Nudelman, C. E. S. Alvaro, J. Phys.
Org. Chem. 2011, 24, 1067.
[48] An intramolecular N-H⋯N hydrogen bond in a secondary diamine
has been suggested for Me(H)NC2H4N(H)Me. J. Graton, M. Berthelot,
C. Laurence, J. Chem. Soc., Perkin Trans. 2 2001, 2130.
[83] P. H. McCabe, N. J. Milne, G. A. Sim, Acta Crystallogr. C 1989, 45, 114.
wileyonlinelibrary.com/journal/poc
Copyright © 2012 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. (2012)