Synthesis and properties of novel guanidine bases. N,N′,N″- Tris(3-dimethylaminopropyl)-guanidine

Article abstract of DOI:10.1016/j.tetlet.2005.10.035

The synthesis of novel N,N′,N″-tris(3-dimethylaminopropyl)- guanidine 1 is described and X-ray structure of its hexafluorophosphate salt measured (1H?PF₆). The hydrogen bonding in protonated 1 and in 1H?PF₆ is also discussed.

Full text of DOI:10.1016/j.tetlet.2005.10.035

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8733–8736
Synthesis and properties of novel guanidine bases.
0
00
N,N ,N -Tris(3-dimethylaminopropyl)-guanidine
a
b
c,ꢀ
a,
*
Zoran Glasovac, Borislav Kova cˇ evi c´ , Ernest Me sˇ trovi c´ and Mirjana Eckert-Maksi c´
a
-
Laboratory for Physical-Organic Chemistry, Division of Organic Chemistry and Biochemistry, The Ruder Bo sˇ kovi c´ Institute,
PO Box 180, HR-10002 Zagreb, Croatia
b
-
Quantum Organic Chemistry Group, Division of Organic Chemistry and Biochemistry, The Ruder Bo sˇ kovi c´ Institute,
PO Box 180, HR-10002 Zagreb, Croatia
c
Laboratory of General and Inorganic Chemistry, Chemistry Department, Faculty of Science, University of Zagreb,
Ul. kralja Zvonimira 8, HR-10000 Zagreb, Croatia
Received 8 August 2005; revised 3 October 2005; accepted 12 October 2005
0
00
Abstract—The synthesis of novel N,N ,N -tris(3-dimethylaminopropyl)-guanidine 1 is described and X-ray structure of its hexa-
fluorophosphate salt measured (1HÆPF ). The hydrogen bonding in protonated 1 and in 1HÆPF is also discussed.
2005 Published by Elsevier Ltd.
6
6
ꢀ
1. Introduction
dence in favour of formation of IMHB in hexafluoro-
phosphate salt of 1 (1HÆPF ) in the solid state, as
well as in solution.
6
There has been growing interest in theoretical model-
1
,2
1c,3,4
ling and the synthesis
of strong novel organic
bases in recent years primarily due to their high catal-
ytic potential in a number of synthetically important
reactions. These studies have been mainly concerned
with acyclic and cyclic guanidines, biguanides, vinami-
The target guanidine derivative 1, the synthesis of which
has not been described in the literature so far, was pre-
pared in three steps starting from 3-dimethylaminopro-
pan-1-amine according to Scheme 1 in an overall yield
5
–8
10
dines and phosphazenes.
The present study was
of 76%.
motivated by a recent theoretical prediction that multi-
ple dimethylaminopropyl substitutions of the parent
guanidine lead to high intrinsic gas phase basicities
The structure of compound 1 was unequivocally identi-
fied by spectroscopic methods (IR, H and C NMR,
1
13
and proton affinities (PA) culminating in PA =
HRMS) and by X-ray analysis of its HPF salt. The lat-
6
À1
2
75.5 kcal mol (at the MP2/6-311+G**//HF/6-31G*
ter was prepared by reacting 1 with ammonium hexaflu-
0
00
11,12
level of theory) in N,N ,N -tris(3-dimethylaminoprop-
orophosphate in dry acetonitrile.
X-ray structure of
9
yl)-guanidine 1. The reason behind the high proton
1HÆPF is shown in Figure 1 together with selected bond
6
affinity of 1 was identified as being due to the cooper-
ative action of strong cationic resonance in the central
guanidine moiety and formation of intramolecular
multiple hydrogen bonding (IMHB), which is enhanced
upon protonation. The present study provides firm evi-
lengths and angles.
Inspection of X-ray structure revealed that the guanidi-
nium moiety lies diagonally within the unit cell with a C3
axis of symmetry passing exactly through the central
carbon atom of the guanidine fragment. Furthermore,
the mutual orientation of the dimethylaminopropyl
chains and close contacts between nitrogen atoms in
the protonated subunit (Fig. 1b) provided strong
evidence for the formation of three N–HÁ Á ÁN intramole-
cular hydrogen bridges with the distance between
Keywords: Organic synthesis; X-ray diffraction analysis; Hydrogen
bonds; Density functional calculations; AIM calculations.
*
Corresponding author. Tel.: +385 1 4680 197; fax: +385 1 4680
95; e-mail: mmaksic@emma.irb.hr
Present address: Pharmaceutical Company PLIVA d.d. Baruna
Filipovi c´ a 78, Zagreb, Croatia.
1
ꢀ
˚
9
nitrogen atoms of 2.886(4) A being in agreement with
earlier theoretical prediction.
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.035

8734
Z. Glasovac et al. / Tetrahedron Letters 46 (2005) 8733–8736
S
a
Me N
NH2
Me N
2
N
N
NMe2
2
H
H
2
b
NMe2
c
N
Me N
N
N
NMe2
2
Me N
N
N
NMe2
2
H
H
1
3
2
Scheme 1. Reagents and conditions: (a) CS , EtOH, reflux, 22 h; (b) yellow HgO, rt, 2 h; (c) 3-dimethylaminopropan-1-amine/THF, reflux, 24 h.
1
3,14
Figure 1. X-ray structure of the (a) 1HÆPF
6
unit cell
and (b) guanidinium cation substructure extracted from the X-ray data as obtained using the
14a
15
˚
Mercury 1.2program.
Discontinuation lines show the hydrogen bonding. Selected geometrical parameters: C1–N1: 1.326(3) A; N1–C2:
˚
˚
˚
˚
0
˚
0
1
.445(4) A; C2–C3: 1.508(4) A; C3–C4: 1.490(4) A; N2–C4: 1.456(4) A; N1 Á Á ÁN2: 2.885(4) A; N1 –H: 0.85(4); C1–N1–C2: 124.7(3)ꢁ; N1–C2–C3:
15.5(3)ꢁ; C2–C3–C4: 115.3(3)ꢁ; C3–C4–N2: 114.0(3)ꢁ; N1–C1–N1 –N1 : À179.3(5)ꢁ; N1 –C1–N1–C2: À20.9(5)ꢁ; C1–N1–C2–C3: 106.4(3)ꢁ;
0
00
0
1
N1–C2–C3–C4: À61.7(4)ꢁ; C2–C3–C4–N2: À50.7(4)ꢁ. Numbering of atoms is shown in Figure 2.
1
Another point of interest concerns the existence of
sponding signal in the H NMR spectrum of 4HÆPF
6
IMHB in 1HÆPF in solution. To this end we tackled this
was found to be shifted upfield by ca. 3 ppm. Further-
6
1
1
problem by comparing FT-IR and H NMR spectra of
more, from variable temperature H NMR spectra,
0
00
À1
1
HÆPF and N,N ,N -tri-n-propylguanidinium hexaflu-
Dd/DT of À0.006 and À0.004 ppm K
for 1HÆPF6
6
orophosphate (4HÆPF ), in which intramolecular hydro-
and 4HÆPF , respectively, were deduced. Both results
6
6
gen bonding is not possible. Measurements were carried
out in acetonitrile (fully deuterated in the case of NMR
analysis) as a solvent. Analysis of the IR spectra of
are consistent with the existence of weak hydrogen
bonding in 1HÆPF6.
4
HÆPF revealed the presence of a strong N–H stretching
Finally, in order to shed light on the intrinsic strength of
6
À1
vibration at 3360 cm , whereas no band in this region
hydrogen bonding in 1HÆPF (i.e., in the gas phase) we
6
was observed for 1HÆPF . Instead, a new broad vibra-
tion band (in the region of 2900–3100 cm ) appeared,
also calculated the topological properties of the electron
density distribution for the N–HÁ Á ÁN intramolecular
bridges in terms of the Bader theory of atoms in mole-
6
À1
as would be expected for systems involving intramole-
1
6
1
18
cular N–HÁ Á ÁN hydrogen bonding. The H NMR
cules (AIM) for the protonated form of 1 using the
1
9
spectra of 1HÆPF and 4HÆPF were measured in the
B3LYP/6-311+G** method. The minimum energy
structure, together with the selected bond distances
and bond angles are shown in Figure 2. Before turning
to analysis of the calculated topological parameters
it is worth noting that, likewise in the crystal state,
6
6
temperature range of 243–293 K in order to evaluate
the dependence of the chemical shift of the NH protons
on temperature (denoted hereafter as Dd/DT), which is
customarily considered as one of the tests for the exis-
1
7
tence of intramolecular hydrogen bonding. At 243 K
the optimized structure is close to C -symmetry. It is
3
1
the H NMR spectrum of 1HÆPF exhibited a signal
also interesting to observe that the proton is located
unsymmetrically in a non-linear hydrogen bridge (e.g.,
6
for the NH protons at 9.34 ppm, whereas the corre-

Z. Glasovac et al. / Tetrahedron Letters 46 (2005) 8733–8736
8735
In summary, we have prepared hithertho unknown
0
00
N,N ,N -tris-(3-dimethylaminopropyl)-guanidine deriv-
ative 1. The X-ray structural analysis of the hexafluoro-
phosphate salt of 1 provided firm evidence for the
existence of multiple intramolecular hydrogen bonding
in the solid state, in accordance with previous theoretical
9
predictions. The existence of hydrogen bonding in solu-
tion and in the gas phase is also discussed. Our further
efforts will involve investigation of the catalytic activity
of 1, as well as a measurement of its basicity.
2. Experimental
1
3
N ,N -Bis-(3-dimethylaminopropyl)-thiourea 2 was pre-
pared by reacting CS2 with 3-dimethylaminopropyl-
2
3
amine according to a previously described procedure.
1
3
N ,N -Bis-(3-dimethylaminopropyl)-carbodiimide 3 was
+
prepared by modification of the procedure for the
Figure 2. Molecular geometry of 1H calculated at the B3LYP/
1
3
15
˚
preparation of N -cyclohexyl-N -dimethylaminopropyl-
6
-311+G** level. Selected geometrical parameters: C1–N1: 1.344 A;
N1–C2: 1.467 A; C2–C3: 1.535 A; C3–C4: 1.532A ; N2–C4: 1.475 A;
2
4
˚
˚
˚
˚
carbodiimide. It involved treatment of 2 with an equi-
0
˚
0
˚
˚
N1 Á Á ÁN2: 2.941 A; N1 –H: 1.036 A, HÁ Á ÁN2: 1.917 A; C1–N1–C2:
molar amount of yellow HgO in CH Cl for 2h followed
2
2
1
25.2ꢁ; N1–C2–C3: 115.3ꢁ; C2–C3–C4: 116.1ꢁ; C3–C4–N2: 114.7ꢁ;
by high vacuum distillation, yielding pure carbodiimide
0
0
0
00
N1 –N2–C4: 96.6ꢁ; N1 –H Á Á ÁN2: 168.8ꢁ; N1–C1–N1 –N1 : À179.8;
in 80% yield. Crystals of 1HÆPF ÆCH CN suitable for
6
3
0
N1 –C1–N1–C2: À23.7ꢁ; C1–N1–C2–C3: 106.7ꢁ; N1–C2–C3–C4:
X-ray analysis are unstable at room temperature and
decompose if left in air. To prevent decomposition, a
single crystal was mounted on a goniometer head and
rapidly cooled in a stream of nitrogen to 100 K, at which
temperature full X-ray diffraction experiments were
performed. Full data sets were collected using the x scan
mode over the 2h range of 4–60ꢁ. The structures were
À59.7ꢁ; C2–C3–C4–N2: À50.9ꢁ.
0
0
N1 –HÁ Á ÁN2, where N1 and N2are the donor and
acceptor nitrogen atoms, respectively). This is indicated
0
˚
by the short N1 –H bond length of 1.036 A, a long dis-
˚
0
tance HÁ Á ÁN2of 1.917 A and an N1 –HÁ Á ÁN2angle of
1
4b
1
68.8ꢁ. It should also be noted that the distance between
solved and refined using the SHELXS package.
˚
the proton and the accepting nitrogen atom of 1.917 A is
Structure solution was accomplished using direct
methods followed by differential Fourier syntheses using
˚
shorter by ca. 0.8 A than the sum of their van der Waals
radii, implying that the strength of the hydrogen
bonds in 1H in the gas phase is substantial. In agree-
2
0
14c
the WINGX program package.
+
21a
ment with anticipated behaviour, the N–H bond is
˚
found to be longer by 0.029 A than the unperturbed
Acknowledgements
0
00
N–H bond in, for example, protonated N,N ,N -tri-
methylguanidine (calculated at the same level of theory).
The Croatian Ministry of Science, Education and Sport
is acknowledged for financial support (Grants Nos.
0098056 and 0098058).
In recent years, the topological parameters derived from
the Bader theory have often been applied in the analysis
2
1
of intramolecular hydrogen bonds. Koch and Popelier
proposed eight criteria based on AIM theory to charac-
Supplementary data
2
2
terize hydrogen bonds. Two of them are connected
2
with electron density qBCP and Laplacian ($ qBCP) of
Cartesian coordinates for the optimized structure of 1
and its protonated form are available. Supplementary
data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2005.10.035.
the electron density at the bond critical point (BCP)
of the HÁ Á ÁA (protonÁ Á Áacceptor) bond. The ranges of
2
À3
˚
q
0
and $ q
are 0.002–0.040 e A
and 0.024–
BCP
BCP
À5
˚
.139 e A , respectively, if H-bonds do exist. Both
of these criteria are found to be fulfilled for the opti-
mized geometry of the 1H cation: the q value is
References and notes
HÁ Á ÁN
À3
2
À5
˚
˚
0
.036 e A
and for $ q
a value of 0.085 e A
HÁ Á ÁN
1
2
. (a) Llamas-Saiz, A. L.; Foces-Foces, C.; Elguero, J. J.
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Chem. 2002, 15, 499–508.
is obtained. The corresponding values for the N–H bond
amount to 0.314 e A
smaller by 0.027 e A and 0.136 e A compared to
the unperturbed N–H bond in the previously men-
tioned protonated N,N ,N -trimethylguanidine. Addi-
À3
À3
À5
˚
˚
˚
and À1.568 e A , which are
À5
˚
0
00
tional support for the existence of intramolecular
+
hydrogen bridging in 1H is provided by locating a ring
critical point (RCP) in each of the eight-membered
rings.

8736
Z. Glasovac et al. / Tetrahedron Letters 46 (2005) 8733–8736
1
3
. (a) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C.
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therein; (b) Nagasava, K.; Georgieva, A.; Takahashi, H.;
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acetonitrile). H NMR (300 MHz, CD
3
CN, 25 ꢁC, TMS)
), 2.43 (s, 18H, CH ), 2.57 (t,
J(H,H) = 6 Hz, 6H, CH ), 3.46 (t, J(H,H) = 6 Hz, 6H,
d/ppm = 1.94 (m, 6H, CH
2
3
3
3
2
1
3
2 3
CH ), 9.00 (br s, 1H, NH); C NMR (75.5 MHz, CD CN,
25 ꢁC, TMS) d/ppm = 27.31, 40.44, 44.76, 55.29, 159.55.
1996, 32, 215–220.
13. Crystal data: Crystal dimensions: 0.4 mm · 0.3 mm ·
4
. For a recent review article see: Berlinck, R. G. S. Nat.
Prod. Rep. 1999, 16, 339–365; Greenhill, J. V.; Lue, P. In
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D. K., Eds.; Elsevier Science, 1993; Vol. 30, pp 206–327,
and references cited therein.
0.3 mm; crystal system: cubic; space group: P2 3; unit-
1
˚
3
cell dimensions (pm): a = 1382.5(1); volume (A ) = 2643;
calcd = 1.269; 2hmax = 30.11; radiation and wave-
length = Mo Ka/71.073, scan mode = omega scan; tem-
perature = 293 K; no. of measured and independent
reflections = 2558/1124; no. of reflections included in
refinement = all; Lorenzian polarization and absorption
correction = analytical; method of structure solution and
program = direct method in SHELXS-97;
refinement and program = SHELXL-97; no. of param-
eters = 110; the position of hydrogen atoms bound to the
N1, N1 and N1 atoms were located in the final stage of
the refinement, while H atoms bonded to the carbon
atoms were introduced at calculated positions and treated
q
5
. Raczynska, E. D.; Cyranski, M. K.; Gutowski, M.; Rak,
J.; Gal, J.-F.; Maria, P.-C.; Darowska, M.; Duczmal, K. J.
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1
4a
method of
1
4a
0
00
6
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Catal. A: Chem. 1995, 99, 65–70; (b) Gelbard, G.;
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singer, R. Angew. Chem., Int. Ed. Engl. 1987, 26, 1164–
as riding, with Uiso(H) values equal to 1.2U (C) and C–H
distances of 0.93 A. R = 0.0589 (F > 2r(F )); wR =
0.1345; refinement based on jF j; residual q (max/
eq
˚
2
2
7
2
min) = 0.251/À0.199; database: Cambridge Crystallo-
graphic Data Centre (CCDC, 12Union Road, Cambridge
CB21EZ, UK); CCDC reference number: 23 6453.
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Universit a¨ t, Tammanstrasse 4, D-3400 G o¨ ttingen, Ger-
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68, 9988–9993; (b) Koppel, I. A.; Burk, P.; Koppel, I.;
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structures in Figures 1 and 2 were erroneously drawn as a
n-butyl- instead of n-propyl-derivatives.
3
15. Since the protonated form has C -symmetry the structural
parameters of only one of the chains participating in the
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0
00
1
0. N,N ,N -Tris-(3-dimethylaminopropyl)-guanidine 1:
A
solution of carbodiimide 3 (7.33 g, 0.035 mol) and 3-
dimethylaminopropyl-1-amine (8.70 g, 0.070 mol) in
3
4
0.0 cm of dry THF was stirred under reflux for 24 h.
After cooling to room temperature, the solvent was
evaporated under vacuum (133 Pa, 1 mmHg) affording
guanidine 1 as a colourless viscous oil (10.75 g, 0.034 mol,
yield = 99%), which was used for preparation of hexaflu-
orophosphate salt without further purification. An
analytically pure sample was obtained by distillation of
À5
the crude product at 0.01 Pa (10 mmHg, bp = 132–
À4
1
36 ꢁC/2 · 10 mmHg). Selected data: IR (KBr)
À1
+
(m/cm = 1584, 1628; N@C(NH)
2
); HR-MS (MÀH )
1
exp.: m/z = 315.322185 (theor. m/z = 315.32307);
H
NMR (300 MHz, CDCl
3
m, 6H, CH ), 2.14 (s, 18H, CH ), 2.25–2.29 (t, J(H,H) =
3
3
, 2 5ꢁC, TMS) d/ppm: 1.59–1.68
3
(
2
6
2 2
Hz, 6H, CH ), 3.09–3.13 (t, J(H,H) = 6 Hz, 6H, CH ),
1
3
C NMR (75.5 MHz, CDCl , 2 5ꢁC, TMS) d/ppm: 27.5,
3
39.3, 45.2, 57.3, 159.2.
1
1. Raab, V.; Kipke, J.; Gschwind, R. M.; Sundermeyer, J.
Chem. Eur. J. 2002, 8, 1682–1693.
2. Guanidine 1 was converted to hexafluorophosphate salt
1
4 6
by mixing equimolar amounts of 1 and NH PF in dry
acetonitrile, followed by the filtration through a Celite pad
and evaporation of the filtrate. Guanidinium salt was
crystallized from acetonitrile by slow addition of diethyl
22. Koch, U.; Popelier, P. L. A. J. Phys. Chem. A 1995, 99,
9747–9754.
23. McKay, A. F.; Garmaise, D. L.; Baker, H. A.; Hawkins,
L. R.; Falta, V.; Gaudry, R.; Paris, G. Y. J. Med. Chem.
1963, 6, 587–595.
ether and cooling below 0 ꢁC yielding 75% of 1HÆPF
6
. A
crystal of 1HÆPF suitable for X-ray analysis was obtained
6
by slow diffusion of diethyl ether into a solution of
hexafluorophosphate salt in acetonitrile at room temper-
ature. The crystal incorporates one molecule of solvent in
the unit cell. Selected data: Mp = 111–112 ꢁC (from
24. Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org.
Chem. 1961, 26, 2525–2528.