Novel betaines of the hexaalkylguanidinio-carboxylate type

Article abstract of DOI:10.1515/znb-2009-11-1248

Betaines 7a, b and 8a, b have been prepared from 3- and 4-piperidinecarboxylic acid and N,N,N′N′-tetraalkyl- chloroformamidinium chlorides via the corresponding methyl esters. These betaines are highly hygroscopic, thermally very stable, and, with the exception of 7b, have rather low melting points. They undergo a surprisingly facile alkaline cleavage of the hexaalkylguanidinium moiety. They react with dichloromethane by a twofold nucleophilic substitution to form methylene dicarboxylates such as 11. The NMR (¹H, ¹³C) data of betaines 7 and 8 are discussed.

Full text of DOI:10.1515/znb-2009-11-1248

Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
Matthias Walter and Gerhard Maas
Institute for Organic Chemistry I, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm,
Germany
Reprint requests to Prof. Dr. Gerhard Maas. Fax: 49 (0)731-5022803.
E-mail: gerhard.maas@uni-ulm.de
Z. Naturforsch. 2009, 64b, 1617 – 1624; received September 29, 2009
Dedicated to Professor Hubert Schmidbaur on the occasion of his 75th birthday
Betaines 7a, b and 8a, b have been prepared from 3- and 4-piperidinecarboxylic acid and
N,N,Nꢀ,Nꢀ-tetraalkyl-chloroformamidinium chlorides via the corresponding methyl esters. These
betaines are highly hygroscopic, thermally very stable, and, with the exception of 7b, have rather low
melting points. They undergo a surprisingly facile alkaline cleavage of the hexaalkylguanidinium
moiety. They react with dichloromethane by a twofold nucleophilic substitution to form methylene
dicarboxylates such as 11. The NMR (1H, 13C) data of betaines 7 and 8 are discussed.
Key words: Betaines, Guanidinium, Nipecotic Acid, Isonipecotic Acid, Piperidinecarboxylic Acids
Introduction
Given our interest in the properties of hexaalkyl-
guanidinium salts, in particular those which are
ionic liquids [7], we became attracted to the so
far unknown betaines of the hexaalkylguanidinio-
carboxylate type. When designed appropriately, such
compounds could have properties similar to those
of hexaalkylguanidinium-based ionic liquids, such as
low melting point, high thermal stability and low
vapor pressure. In addition, the zwitterionic charac-
ter of the molecule and the presence of the car-
boxylate function in particular could endow these
compounds with a reactivity which is reminescent
of task-specific ionic liquids. A number of betaines,
mainly with imidazolium, tetraalkylammonium and
pyridinium as the cationic group and sulfonate or car-
boxylate as the anionic site, have recently been stud-
ied as a new class of ion-conductive matrices for
electrochemical devices [8, 9]. As target molecules,
we chose the hexaalkylguanidinio-carboxylates C and
D, which represent guanylated derivatives of the
pharmaceutically relevant amino acids 3- and 4-
piperidinecarboxylic acid (nipecotic and isonipecotic
acid), respectively. Sha and Liebscher [10] have re-
cently prepared a range of hexaalkylguanidinium salts,
which have the nitrogen atom of α-aminoacid es-
ters incorporated into the guanidinium group; how-
ever, they did not proceed further to generate betaines
by converting the carboxylic ester into a carboxylate
function.
Betaines are zwitterionic compounds containing a
positively charged onium group, which does not bear
a hydrogen atom, and a negatively charged functional
group not adjacent to the cationic function. They have
been named after (trimethylammonio)acetate (“be-
taine”, nowadays called glycine betaine) (Fig. 1, A),
a common naturally occurring compound which is
found in significant amounts in, e. g., sugar beet, sugar
beet molasses, and in shellfish [1]. Glycine betaine
and related betaines have various functions in biologi-
cal systems; for example, they are organic osmolytes,
which protect cells against osmotic stress and dehy-
dration [2], and act as methyl donors. Glycine betaine
and other N-peralkylated glycinates are among the so-
called compatible solutes, which can enhance the effi-
ciency of the polymerase chain reaction by destabiliza-
tion of the DNA duplex and facilitation of the initial
strand dissociation process [2, 3].
Due to their ampholytic character and the resulting
physico-chemical properties, the low toxicity, mild-on-
skin properties and biodegradability, natural betaine
A and synthetic betaines such as cocamidopropyl be-
taine (B) find wide application in shampoos, hand
soaps, hair conditioners, and cosmetic formulations
[4, 5]. Synthetic betaines, such as B and analogous sul-
fobetaines, are amphotenside ingredients in washing
powders [6].
c
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
Fig. 1. Glycine betaine (A), cocamido-
propyl betaine (B, n = 11), and novel be-
taines C and D.
Results and Discussion
Synthesis of guanidinio-carboxylates 7 and 8
The synthesis of betaines 7 and 8 (Scheme 1) em-
ploys an established method for the preparation of
hexasubstituted guanidinium salts, namely the reaction
of a sec-amine with an N,N,Nꢀ,Nꢀ-tetrasubstituted
chloroamidinium salt, readily prepared from the cor-
responding urea and phosgene or oxalyl chloride and
used without purification [11, 12]. Commercially avail-
able ( )-nipecotic acid (1a) and isonipecotic acid (1b)
were first converted into the corresponding methyl es-
ters 2a, b by treatment with SOCl2/methanol, as de-
scribed in the literature [13, 14]. These piperidinecar-
boxylic esters were then guanylated with chloroform-
amidinium salts 3 and 4 in the presence of triethy-
lamine to give the guanidinium salts 5a, b and 6a, b,
respectively. The guanidinium salts could not be iso-
lated in pure form, because the separation from also
formed triethylammonium chloride was incomplete.
While this separation in other cases succeeds by neu-
tralization of the ammonium salt with aqueous NaOH,
we found that guanidinium salts 5 and 6 suffer rapid
ester cleavage when exposed to 2 M aqueous NaOH to
provide the desired betaines 7a, b and 8a, b, respec-
tively.
Hexaalkylguanidinium salts are normally rather sta-
ble to hydroxide ions in dilute solution at r. t. [15, 16].
If at all, alkaline hydrolysis occurs at a significant rate
only at elevated temperature: while the kinetics were
studied for hexamethylguanidinium perchlorate at
60 ◦C [17], hexaalkylguanidinium salts bearing longer
alkyl chains were r◦eported to be stable to equimo-
lar KOH at 60 – 80 C [16]. Therefore, we were sur-
prised to observe that betaines 7 and 8 underwent slow
cleavage of the guanidinium function when exposed
to 2 M aqueous NaOH at r. t. The scenario is shown
exemplarily for betaine 7b in Scheme 2. In agree-
ment with the unsymmetrical constitution of the guani-
dinium group, hydrolytic cleavage proceeded in two
Scheme 1. Synthesis of betaines 7 and 8.
directions, one leading to N-dimethylaminocarbonyl-
4-piperidinecarboxylic acid (9) and dimethylamine,
the other to tetramethylurea and aminoacid 1b. The
two urea derivatives were formed in a 77 : 23 ratio
1
according to H NMR spectroscopy. Fortunately, the
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
1619
Scheme 2. Alkaline cleavage of betaine 7b.
alkaline cleavage of betaines 7 and 8 is slow under the
conditions for the generation of the betaines from es-
ters 5 and 6, so that the betaines can be obtained selec-
tively under controlled reaction conditions.
In contrast to betaines 7 and 8, the related guani-
dinium chloride 10 (Fig. 2), prepared by analogy to a
literature method [12b], shows the typical behavior of
simple hexaalkylguanidinium salts toward bases: it ap-
pears to be stable to an excess of dilute aqueous NaOH
at r. t., but is decomposed slowly in concentrated aque-
ous NaOH.
Scheme 3. Reaction of betaine 7b with dichloromethane.
water during 10 d.
In contrast to the solubility in water and acetoni-
trile, betaines 7 and 8 are almost insoluble in dichloro-
methane, but surprisingly they undergo a chemical re-
action with this solvent. For example, when a suspen-
sion of betaine 7b in CH2Cl2 was stirred for several
hours, a part of the solid had disappeared. Analysis of
the dichloromethane phase indicated the formation of
a new product, which was identified as the dicationic
salt 11 (Scheme 3) by its NMR data and an ESI-MS
([cation]2+Cl− as the base peak). This reaction appears
to be an equilibrium reaction which proceeded only to
a conversion of 85 % of 7b after 72 h (60 % conver-
sion after 3 h). Obviously, the methylene dicarboxy-
late 11 results from a twofold nucleophilic substitu-
tion reaction at the CH2Cl2 molecule. The remarkably
smooth formation of 11 may be attributed to an excep-
tionally high nucleophilicity of the carboxylate group
in betaine 7b due to the absence of ion pairing with a
cationic counterion. Kinetic investigations have shown
that CH2Cl2 is much more reluctant to an SN2 reaction
than dibromo- and diiodomethane [19]. Furthermore,
the synthesis of methylene diacetate [20] and methy-
lene dicarboxylates [21] usually requires much harsher
reactions than in our case, e. g. by heating of CH2X2
(X = Br, I) with an excess of KOAc in refluxing acetic
acid containing acetic anhydride [19].
Fig. 2.
Notably, betaines 7 and 8 cannot be obtained by di-
rect reaction of piperidinecarboxylic acids 1 with the
chloroformamidinium salts 3 and 4. The reaction of
1b with 3 or 4 in the presence of two equivalents of
triethylamine gave rise to the formation of the cor-
responding tetraalkylurea besides triethylammonium
chloride. Very likely, aminoacid 1b adds to the chlo-
roformamidinium salts through the carboxylate func-
tion, and the resulting addition product is then cleaved
to yield the tetraalkylurea and the acid chloride of 1b,
which probably forms oligomers under the reaction
conditions. The ability of chloroamidinium salts to ac-
tivate carboxylic acids [12, 18] and to undergo chlori-
nation reactions [12] is known.
Properties of betaines 7 and 8
Betaines 7 and 8 are water-soluble and water-stable
solids which are extremely hygroscopic and deliquesce
within hours or days if not kept in a rigorously dry
environment. For example, we observed that 7a, b
picked up one equivalent of water within 3 – 6 h of
Thermal behavior
Because of partial hydrolysis at elevated tempera-
exposure to laboratory air and 5 – 6 equivalents of tures (see Experimental Section), an exact description
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
Table 1. 13C chemical shifts (δ values in ppm, D2O as solvent) for guanidinium betaines 7b and 8b, compared with their
precursors.
1b
2b
5b
7b
6b
8b
C-2
C-3
C-4
43.47 43.02
25.64 24.37
41.42 38.05
182.15
47.35, 47.60 47.98, 48.30 48.09, 48.14, 48.20, 48.24
26.49, 27.50 27.71, 28.90 26.29, 26.40, 27.25, 27.40
48.70, 48.76, 48.82, 48.85
27.46, 27.59, 28.62, 28.72
43.62, 43.64
40.02
43.42
183.19
40.10
COO−
COOCH3
guanidinium-CN3
NCH3
183.23, 183.27
176.21, 52.65 177.32, 52.43
177.18/177.21, 52.59
163.07, 163.09
162.79
39.13,
162.90
39.10,
163.01, 163.07
39.43 (2 C), 39.41 (2 C),
39.78 39.92
NCH2CH3
CH3: 11.96, 12.24 (3 C);
CH3: 11.91, 12.21 (3 C);
CH2: 43.06, 43.79 (2 C), 44.12 CH2: 43.06, 43.79 (2 C), 44.12
C-1: 48.66, 49.12, 49.58, 49.76; C-1: 48.55, 49.11, 49.38, 49.72;
C-2: 28.81, 29.04, 29.08, 29.12; C-2: 28.80, 29.06, 29.10 (2 C);
N-butyl
C-3: 19.52, 19.59;
CH3: 13.02, 13.05 (3 C)
C-3: 19.50, 19.58;
CH3: 12.97, 13.06 (3 C)
of the thermally induced phase changes of betaines 7 trolled, stepwise thermal degradation of the betaines.
and 8 by differential scanning calorimetry could not be
obtained. Qualitative data could be obtained, however,
by heating the betaines under vacuum (0.01 mbar).
The powdery solid of 7a becomes sticky at about
NMR spectra
For steric reasons, hexa-substituted guanidinium
ions exist in a propeller-like configuration both in so-
lution [22] and in the solid state [23]. Charge delocal-
ization gives rise to a partial double bond character at
the three C–N bonds, with rotation barriers that prevent
free rotation at r. t. As a consequence, the NMR spec-
tra usually become more complex [9, 22, 23f]. This is
also the case for betaines 7 and 8 and their precur-
sors, methyl esters 5 and 6. An illustration is given
in Table 1, where the 13C chemical shifts of the 4-
substituted betaines 7b and 8b and methyl esters 5b
and 6b are compared with those of the piperidine-4-
carboxylates 1b and 2b. It can be seen that all four N-
methyl groups in the guanidinium systems 5b and 7b
are magnetically non-equivalent, and that the ring car-
bon atoms C-2/6 as well as C-3/5 are diastereotopic.
The suggested structures of 5 and 7 contain a piperi-
dine ring in chair conformation (which is confirmed
◦
80 C, is transformed into a yellow-orange glass at
100 ◦C and into a very viscous oil at about 120 ◦C. On
cooling, a glass is formed again around 100 ◦C and is
◦
stable on further cooling back to 20 C. Dissolution
of the glass in acetonitrile and evaporation of the
solvent reconstitutes the powdery solid of 7a. The
symmetrical betaine 7b, on the other hand, remains
unchanged when heated to 160 ◦C. As expected,
betaines 8a, b, featuring longer alkyl chains and
an unsymmetrical substitution at the guanidinium
moiety, have lower melting points than betaines 7a, b.
Betaine 8a forms◦a highly viscous orange-brownish
oil already at 40 C and a glass on cooling back to
20 ◦C. Betaine 8b forms a glass at 60 ◦C and a highly
viscous yellowish oil at about 80 ◦C; a glass is formed
again when the temperature is lowered to 60 ◦C. In the
first two heating cycles of a DSC measurement, a glass
transition temperature (Tg) was registered at 23 – 30 ◦C
for 8b. In summary, all betaines except 7b have lower
melting points than reported for a wide range of other
carboxylate and sulfonate betaines [9b].
1
by analysis of the H,H coupling constants in the H
NMR spectra, see Experimental Section) and an at-
tached tetraalkylamidinium moiety the N–C–N plane
The thermal stability of the betaines was determined
by thermogravimetric analyses (TGA). Decomposition
temperatures (Tdec), defined as the temperature of max-
imum decomposition rate, were registered at 283 (7a),
331 (7b), 269 (8a), and 300 ◦C (8b). However, notice-
able mass loss occurred already at temperatures lower
by 60 – 80 ◦C. The TGA curves gave no hints to a con-
Fig. 3. Suggested structure of guani-
dinium systems 5 and 7 (New-
man projection along C-2(6)–C-3(5)
bonds).
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
1621
of which is permanently twisted against the C–N–C chloroamidinium chloride (3) in acetonitrile (0.91 mol/kg,
5.83 g, 5.3 mmol of 3) were placed in a round-bottom
flask equipped with a gas inlet and flushed with argon. Dry
triethylamine, dried over KOH (1.5 mL, 1.09 g, 10.8 mmol),
was slowly added while cooling the flask in a water bath.
The reaction mixture was allowed to stir for 72 h, and
the precipitated triethylammonium chloride was filtered
off under an argon atmosphere. Besides small amounts of
3 and tetramethylurea, the solution still contained some
triethylammonium chloride, which could not be separated
from product 5a, and was therefore used without further
purification in the next step.
plane of the piperidine ring (Fig. 3). For the unsym-
metrically substituted guanidinium systems 6b and 8b,
two orientations of the amidinium moiety R1 N–C–
2
NR2 relative to the 4-substituted piperidine ring are
2
possible. The additional isomer gives rise to a second
set of signals in the NMR spectra. While the two sig-
nal sets can be distinguished in the 13C spectra (e. g.,
C-2, C-3, and most N-ethyl and N-butyl carbon atoms
give rise to four signals), the 1H NMR spectra can no
longer be analyzed in detail due to extensive overlap
of the multiplet signals. Analogous considerations ap-
ply for the derivatives of piperidine-3-carboxylicacids,
5a – 8a.
Guanidinium salts 5b, 6a, and 6b were prepared analo-
gously.
NMR data of salt 5a: 1H NMR (D2O): δ = 1.61 – 2.31
(several m, 4 H, 4-H2, 5-H2), 2.67 – 3.69 (several m, 17 H, 2-
H2, 3-H, 6-H2, N(CH3)2), 3.78 (s, 3 H, OCH3). – 13C NMR
(D2O): δ = 22.91 (C-5), 25.70, 26.44 (C-4); 39.23, 39.53,
39.70, 39.89 (4 NCH3); 41.80, 43.63 (C-3); 48.46, 48.62
(C-6); 49.43, 49.78 (C-2); 52.59 (OCH3), 163.02 (CN3),
175.80 (COOCH3).
Conclusion
Hexaalkylguanidinio-carboxylates7 and 8 represent
a new type of betaines. Three of them (7a, 8a, 8b)
show markedly lower melting points than many known
betaines with imidazolium, ammonium or pyridinium
as the cationic moiety and carboxylate or sulfonate
as the anionic part. With a solid→liquid phase transi-
tion below 100 ◦C, betaines 8a, b fullfill the definition
of ionic liquids (“zwitterionic ionic liquids” [9b, d]).
Two remarkable chemical properties of the new be-
taines have been observed. One is the unexpectedly
facile alkaline cleavage of the guanidinium moiety, the
other one is the high nucleophilicity of the carboxylate
function which allows the formation of a methylene
dicarboxylate by twofold nucleophilic substitution of
dichloromethane.
1-[Bis(dimethylamino)methylene]-4-(methoxycarbonyl)-
piperidinium chloride (5b)
Prepared from methyl piperidine-4-carboxylate hy-
drochloride (2b, 0.90 g, 5.0 mmol), salt 3 dissolved in ace-
tonitrile (0.91 mol/kg, 7.50 g, 6.8 mmol) and triethylamine
(1.6 mL, 1.16 g, 11.5 mmol). – 1H NMR (D2O): δ = 1.66
(dddd, 2J = 13 Hz, 3J = 11, 10 and 4 Hz, 1 H, NCH2CHax),
1.85 (dddd, 2J = 13 Hz, 3J = 11, 10 and 4 Hz, 1 H,
NCH2CHax), 2.00 (dddd, 2J = 13 Hz, 3J = 4, 4 and 3 Hz,
1 H, NCH2CHeq), 2.03 (dddd, 2J = 13 Hz, 3J = 4, 4 and
3 Hz, 1 H, NCH2CHeq), 2.73 (tt, 3J = 10 and 4 Hz, 1 H,
ring-4-H); 2.88, 2.89, 2.90, 2.97 (4 s, each 3 H, NCH3); 3.15
(ddd, 2J = 13 Hz, 3J = 11 and 3 Hz, 1 H, NCHax), 3.21 (ddd,
2J = 13 Hz, 3J = 11 and 3 Hz, 1 H, NCHax), 3.42 (ddd, 2J =
13 Hz, 3J = 4 and 4 Hz, 1 H, NCHeq), 3.52 (ddd, 2J = 13 Hz,
3J = 4 and 4 Hz, 1 H, NCHeq), 3.70 (s, 3 H, OCH3). – 13C
NMR: Table 1.
Experimental Section
General information
NMR spectra were recorded using a Bruker DRX 400
spectrometer (1H: 400.13 MHz, 13C: 100.61 MHz). 1H NMR
spectra were referenced to the residual proton signal of the
solvent [δH(D2O) = 4.79 ppm]; mc = centered multiplet.
Signal assignments were based on H,H (COSY, TOCSY)
and C,H correlation spectra (HSQC, HMBC). Mass spectra
(ESI): Micromass UK, ZMD.
Piperidinecarboxylic esters ( )-2a [13] and 2b [14] were
prepared by published procedures. Acetonitrile solutions of
chloroformamidinium chlorides 3 and 4 were supplied by
Prof. W. Kantlehner (Hochschule Aalen).
1-[(Dibutylamino)(diethylamino)methylene]-3-(methoxy-
carbonyl)piperidinium chloride (6a)
Prepared from 2b (0.90 g, 5.0 mmol), salt 4 dissolved
in acetonitrile (2.60 mol/kg, 2.69 g, 7.0 mmol) and tri-
ethylamine (1.6 mL, 1.16 g, 11.5 mmol) in dry acetonitrile
(10 mL). – 1H NMR (D2O): δ = 0.91 – 1.00 (m, 6 H, butyl-
CH3), 1.18 – 1.28 (m, 6 H, NCH2CH3), 1.32 – 1.42 (m, 4 H,
butyl-3-H2), 1.46 – 2.32 (several m, 8 H, ring-4- and 5-H2,
butyl-2-H2), 2.68 – 3.76 (several m, 13 H, ring-NCH2CH,
ring-6-H2, butyl-1-H2, NCH2CH3), 3.79 (s, 3 H, OCH3).
1-[Bis(dimethylamino)methylene]-3-(methoxycarbonyl)-
piperidinium chloride (5a); typical procedure
Methyl piperidine-3-carboxylate hydrochloride (2a, 1-[(Dibutylamino)(diethylamino)methylene]-4-(methoxy-
0.83 g, 4.6 mmol) and a solution of N,N,Nꢀ,Nꢀ-tetramethyl- carbonyl)piperidinium chloride (6b)
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
2
3
Prepared from 2b (0.90 g, 5.0 mmol), salt 4 dissolved (dddd, J = 13.5 Hz, J = 4, 4 and 3 Hz, 1 H, 3-Heq), 2.50
in acetonitrile (2.60 mol/kg, 2.85 g, 7.4 mmol) and tri- (tt, 3J = 10 and 4 Hz, 1 H, 4-H), 2.94 (s, 3 H, NCH3), 2.96
ethylamine (1.6 mL, 1.16 g, 11.5 mmol) in dry acetonitrile (s, 3 H, NCH3), 2.97 (s, 3 H, NCH3), 3.05 (s, 3 H, NCH3),
(10 mL). – 1H NMR (D2O): δ = 0.93 – 1.00 (2 t, 6 H, butyl- 3.18 (ddd, 2J = 13 Hz, 3J = 11 and 3 Hz, 1 H, NCHax), 3.25
CH3), 1.20 – 1.25 (2 q, 6 H, ethyl-CH3), 1.28 – 1.42 (m, 4 H, (ddd, 2J = 13 Hz, 3J = 11 and 3 Hz, 1 H, NCHax), 3.48 (ddd,
2
butyl-3-H2), 1.46 – 1.81 (m, 5 H, butyl-2-H2, NCH2CHax), 2J = 13 Hz, 3J = 4 and 4 Hz, 1 H, NCHeq), 3.58 (ddd, J =
1.97 (mc, 1 H, NCH2CHax), 2.12 (mc, 2 H, NCH2CHeq), 13 Hz, 3J = 4 and 4 Hz, 1 H, NCHeq). – 13C NMR: Table 1.
2.81 (mc, 1 H, ring-4-H), 3.09 – 3.52 (m, 11 H, butyl-NCH2,
ethyl-NCH2, 3 ring-NCH2), 3.62 (mc, 1 H, ring-NCHeq),
1-[(Dibutylamino)(diethylamino)methylene]piperidinium
3-carboxylate (8a)
3.79 (s, 3 H, OCH3). – 13C NMR: Table 1.
Prepared from the crude solution of 6a in acetontrile as
1-[Bis(dimethylamino)methylene]piperidinium 3-carboxyl-
described for 7a. Very hygroscopic, beige powdery solid
ate (7a); typical procedure
(1.35 g, 80 % yield based on 2a). – 1H NMR (D2O): two
The crude solution of ester 5a in acetonitrile (see above)
species, A:B = 6:4, δ = 0.94 – 0.99 (m, 6 H, butyl-CH3
(A, B)), 1.18 – 1.25 (m, 6 H, ethyl-CH3 (A, B)), 1.26 – 1.42
(m, 4 H, butyl-3-H2 (A, B)), 1.44 – 1.82 (several m, 5.4 H,
ring-4-Hax (A), ring-4-Hax, -5-Hax (B), butyl-2-H2 (A, B)),
1.82 – 1.97 (several m, 1.6 H, ring-5-H2 (A), ring-5-Heq (B)),
2.08 (d, 0.6 H, ring-4-Heq (A)), 2.21 (d, 0.4 H, ring-4-Heq
(B)), 2.41 (m, 0.4 H, ring-NCH2CH (B)), 2.65 (m, 0.6 H,
ring-NCH2CH (A)), 3.08 – 3.64 (several m, 12 H, ring-2-
H2, 6-H2 (A, B), butyl-NCH2 (A, B), NCH2CH3 (A, B)). –
13C NMR (D2O): two species A and B, δ = 11.84, 11.95,
12.08, 12.14, 12.17, 12.22 (ethyl-CH3 (A, B)); 12.97, 13.03,
13.07 (butyl-CH3 (A, B)); 19.48, 19.54, 19.57 (butyl-C-3
(A, B)); 23.14, 23.27 (ring-C-5 (B)); 23.77, 23.85 (ring-
C-5 (A)); 27.08, 27.17 (ring-C-4 (A)); 27.85, 27.94 (ring-
C-4 (B)); 28.75, 28.85, 28.95, 28.99, 29.01, 29.10, 29.18
(butyl-C-2 (A, B)); 42.76, 42.88 (ring-C-3 (A)); 43.04, 43.09,
43.63, 43.73, 43.83, 43.86, 43.91, 44.15 (NCH2CH3 (A,
B)); 44.86, 44.90 (ring-C-3 (B)); 48.56, 48.70, 49.00, 49.15,
49.30, 49.41, 49.47, 49.58, 49.69 (ring-C-6 (A, B); butyl-
NCH2 (A, B)); 51.52, 51.72, 51.78, 51.80 (ring-C-2 (A, B));
163.11, 163.16 (CN3 (A, B)); 180.77, 180.87, 181.24 (COO
(A, B)).
◦
was used. The solvent was evaporated at 0.01 mbar/35 C,
and the solid residue was dissolved in demineralized wa-
ter (10 mL). Aqueous NaOH (2 M) was added drop by
drop until 5a was consumed completely (3.9 mL, reaction
monitoring by 1H NMR, disappearance of the ester signal
at δ = 3.78 ppm). Water and triethylamine were evapo-
◦
rated at 0.01 mbar/40 C, and the solid residue was dried
at 0.01 mbar/60 ◦C during 5 h. Betaine 7a was extracted
with dry acetonitrile (10 mL), the solvent was evaporated at
◦
0.01 mbar/20 C, and the solid betaine was triturated with
dry ether (10 mL) and dried (0.01 mbar /60 ◦C, 4 h): highly
hygroscopic, beige powdery solid (0.81 g, 78 % yield based
on 2a). – 1H NMR (D2O): two species, A:B = 6:4, δ =
1.55 – 1.69 (several m, 1.0 H, ring-5-Hax (A), ring-4-Hax
(B)), 1.76 – 1.95 (several m, 2.0 H, ring-5-Heq, ring-4-Hax
(A), ring-5-H2 (B)), 2.03 – 2.11 (m, 0.6 H, ring-4-Heq (A)),
2.16 – 2.24 (m, 0.4 H, ring-4-Heq (B)), 2.42 (m, 0.4 H, ring-
3-H (B)), 2.66 (m, 0.6 H, ring-3-H (A)), 2.93 – 3.10 (sev-
eral s, 12.0 H, NCH3 (A, B)), 3.10 – 3.24 (several m, 0.8 H,
ring-2-Hax and -6-Hax (B)), 3.24 – 3.40 (several m, 1.8 H,
ring 2-Hax, 6-H2 (A)), 3.51 – 3.60 (several m, 1.4 H, ring-2-
Heq (A), ring-2-Heq, -6-Heq (B)). – 13C NMR (D2O): two
species A and B, δ = 23.45 (ring-C-5 (B)); 23.98 (ring-C-
5 (A)); 27.16 (ring-C-4 (A)); 27.87 (ring-C-4 (B)); 39.12,
39.25, 39.49, 39.69, 40.00 (NCH3 (A, B)); 43.18 (ring-C-3
(A)), 45.28 (ring-C-3 (B)), 48.64 (ring-C-6 (B)), 48.89 (ring-
C-6 (A)), 51.06 (ring-C-2 (A)), 51.41 (ring-C-2 (B)), 162.94
(CN3 (A, B)), 181.41 (COO (A, B)). – MS (ESI): m/z (%) =
228.08 (100) [M+H]+.
1-[(Dibutylamino)(diethylamino)methylene]piperidinium
4-carboxylate (8b)
Prepared from the crude solution of 6b in acetonitrile
as described for 7a. Very hygroscopic, beige powdery solid
(1.39 g, 82 % based on 2b). – 1H NMR (D2O): δ = 0.94 –
0.99 (m, 6 H, butyl-CH3), 1.18 – 1.25 (m, 6 H, ethyl-CH3),
1.30 – 1.42 (m, 4 H, butyl-3-H2), 1.45 – 1.78 (m, 5 H, butyl-
2-H2, NCH2CHax), 1.86 – 1.95 (m, 1 H, NCH2CHax), 1.98 –
2.09 (m, 2 H, NCH2CHeq), 2.47 – 2.53 (m, 1 H, ring-4-
H), 3.11 – 3.52 (m, 11 H, butyl-NCH2, ethyl-NCH2, 3 ring-
NCH), 3.60 – 3.66 (m, 1 H, ring-NCH). – 13C NMR: Table 1.
1-[Bis(dimethylamino)methylene]piperidinium 4-carboxyl-
ate (7b)
Prepared from the crude solution of 5b in acetonitrile as
described for 7a. Very hygroscopic, colorless powdery solid
(0.87 g, 76 % yield based on 2b). – 1H NMR (D2O): δ = 1.63
(dddd, 2J = 13.5 Hz, 3J = 11, 10 and 4 Hz, 1 H, 3-Hax), 1.85
(dddd, 2J = 13.5 Hz, 3J = 11, 10 and 4 Hz, 1 H, 5-Hax), 1.98
Alkaline hydrolysis of betaine 7b
Aqueous NaOH (2 M, 2 mL) was added to a solution
(dddd, J = 13.5 Hz, J = 4, 4 and 3 Hz, 1 H, 3-Heq), 2.02 of betaine 7b (0.253 g, 1.11 mmol) in demineralized water
2
3
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M. Walter – G. Maas · Novel Betaines of the Hexaalkylguanidinio-carboxylate Type
1623
◦
(5 mL). After ◦stirring for 1 h, the solvent was evaporated at evaporated to dryness at 0.01 mbar/20 C to leave a very
0.01 mbar/40 C. The solid residue was triturated with dry hygroscopic, colorless powdery solid (0.398 g), which con-
ether (10 mL) to remove residual tetramethylurea and dis- sisted of dicationic salt 11 contaminated with about 8 – 10 %
solved in water. After neutralization with dilute aqueous H◦Cl, of betaine 7b. Due to similar solubilities, complete separa-
the solution was evaporated to dryness (0.01 mbar/80 C, tion of the two components was not possible, but a small
3 h). According to the 1H NMR spectra, the solid contained sample enriched in 11 could be obtained by repeated tritura-
1-(dimethylcarbamoyl)piperidine-4-carboxylic acid (9) [24] tion with CH2Cl2. Spectroscopic data of 11: 1H NMR (D2O):
and piperidine-4-carboxylic acid (1b) in a 77:23 ratio. – δ = 1.74 (mc, 2 H, NCH2CHax), 1.93 (mc, 2 H, NCH2CHax),
NMR data of 9: 1H NMR (D2O): δ = 1.51 – 1.61 and 1.83 – 2.12 (mc, 4 H, NCH2CHeq), 2.87 (mc, 2 H, ring-4-H); 2.96,
1.92 (2 mc, each 2 H, 3,5-H2), 2.52 – 2.57 (mc, 1 H, 4-CH), 2.97, 2.98 and 3.04 (4 s, each 6 H, NCH3); 3.27 (mc, 4 H,
2.78 (s, 3H, NCH3), 2.79 (s, 3 H, NCH3), 2.89 (ddd, 2 H, NCHax), 3.50 (mc, 2 H, NCHeq), 3.60 (mc, 2 H, NCHeq),
NCHax), 3.68 (dt, 2 H, NCHeq). – 13C NMR (D2O): δ = 5.90 (s, 2 H, OCH2O). – 13C NMR (D2O): δ = 26.36, 27.33
28.90 (C-3,5), 38.09 (N(CH3)2), 44.57 (C-4), 46.44 (C-2,6), (C-3,5); 39.18, 39.51 (N(CH3)2); 39.85 (C-4); 47.33, 47.52
166.02 (CN3), 184.48 (COO).
(C-2,6); 80.42 (OCH2O), 162.92 (CN3), 175.05 (COO). –
MS (ESI): m/z (%) = 505.36 (33) [cation]2+ 37Cl−, 503.33
(100) [cation]2+ 35Cl−, 453.36 (13), 423.36 (5).
+
+
1-[Bis(dimethylamino)methylene]piperidinium chloride (10)
Under an argon atmosphere, dry piperidine (0.8 mL,
0.69 g, 8.1 mmol) was added to a solution of salt 3 in ace-
tonitrile (6.6 mL, 0.91 mol/kg, 5.50 g, 5.0 mmol). After
stirring for 20 h, the solvent was evaporated at 0.01 mbar/
30 ◦C, and the residue was dissolved in demineralized water
(5 mL). After neutralization of piperidinium chloride with
2 M aqeous NaOH (4 m◦L), water and piperidine were evap-
orated at 0.01 mbar/40 C. The solid residue was triturated
with 2×5 mL pentane and dried (0.01 mbar/80 ◦C, 5 h). Very
hygroscopic, colorless powdery solid (0.79 g, 89 % yield
based on piperidine), m. p. 173 – 175 ◦C. – 1H NMR (D2O):
δ = 1.52 – 1.76 (several m, 6 H, 3-, 4-, 5-H2), 2.87 (s, 6 H,
N(CH3)2), 2.91 (s, 6 H, N(CH3)2), 3.14 – 3.32 (mc, 2-, 6-
H2). – 13C NMR (D2O): δ = 23.19 (C-4), 24.83 (C-3,5);
39.24, 39.38 (N(CH3)2); 49.28 (C-2,6), 162.80 (CN3).
Thermal analysis
Efforts to characterize the thermal behavior of betaines
7 and 8 by differential scanning calorimetry (DSC) were
hampered by a partial hydrolysis at elevated temperatures.
For example, be◦taine 7b was submitted to three heating cy-
cles up to 250 C with a heating rate of 10 C min−1. A
◦
1H NMR spectrum of the sample then indicated the pres-
ence of betaine 7b (75 %), acid 9 (22 %) and tetramethylurea
(3 %). Therefore, qualitative observations were made on be-
taine samples which were kept in a Schlenk flask under vac-
uum (0.01 mbar) and heated with an external oil bath. The
thermal stability of the salts was determined by thermogravi-
metric analysis using a Mettler-Toledo TGA/SDTA 851 in-
◦
strument. The temperature was increased linearly at 10 C
min−1 unter nitrogen from 25 to 800 ◦C.
4,4ꢀ-[Methylenebis(oxycarbonyl)]-bis{1-[bis(dimethyl-
amino)methylene]piperidinium} dichloride (11)
Acknowledgements
A suspension of betaine 7b (0.455 g, 2.0 mmol) in dry di-
chloromethane (20 mL) was stirred for 72 h. At this point,
most of the betaine was consumed, and further reaction ap-
peared not to take place. The residual betaine was removed
by filtration under an argon atmosphere, and the solution was
This work was supported by a grant from the Bundesmin-
isterium fu¨r Bildung und Forschung (BMBF). We thank Prof.
Willi Kantlehner (Hochschule Aalen) for samples of chloro-
formamidinium salts.
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