Basicity of guanidines with heteroalkyl side chains in acetonitrile

Article abstract of DOI:10.1002/ejoc.200800673

The pK_a values of seven novel guanidine derivatives, six of them possessing heteroalkyl substituents capable of forming intramolecular hydrogen bonds, were determined in acetonitrile (MeCN) by using the UV/Vis spectrophotometric titration metho

Full text of DOI:10.1002/ejoc.200800673

FULL PAPER
DOI: 10.1002/ejoc.200800673
Basicity of Guanidines with Heteroalkyl Side Chains in Acetonitrile
[a]
[a]
[a]
[b]
´
ˇ
Mirjana Eckert-Maksic,* Zoran Glasovac, Pavle Troselj, Agnes Kütt,
Toomas Rodima,[b] Ivar Koppel,[b] and Ilmar A. Koppel*[b]
Keywords: Guanidines / Hydrogen bonds / UV/Vis spectroscopy / Basicity / Density functional calculations
The pKa values of seven novel guanidine derivatives, six of
them possessing heteroalkyl substituents capable of forming
intramolecular hydrogen bonds, were determined in acetoni-
trile (MeCN) by using the UV/Vis spectrophotometric ti-
tration method. The obtained pKa values range from 24.7 to
27.2. The most basic among the studied guanidines was
found to be by ca. 4 pKa units more basic than the
well-known superbase N1,N1,N3,N3-tetramethylguanidine
(TMG). The trends in the changes in the measured pKa val-
ues were compared with the experimental (determined by
the extended kinetic method) and theoretical [B3LYP/6-
311+G(2df,p)//B3LYP/6-31G(d)] gas-phase proton affinities.
It was shown that basicity ordering of the bases with dimeth-
ylaminopropyl substituents in acetonitrile follows the trend
encountered in the gas phase. However, this is not the case
for the methoxypropyl-substituted guanidines indicating that
in these molecules formation of the intramolecular hydrogen
bonds is to large extent hindered due to solvation by aceto-
nitrile.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
For all these compounds an enhancement in the gas-phase
basicity was found, in full analogy with compounds of the
general formula Y(CH2)nX (Y,X = NR2, OR; R = H,
alkyl).[12]
Introduction
Guanidine derivatives continue to attract the interest of
organic chemists due to their versatile chemistry and inter-
esting biochemical properties.[1] The guanidine moiety is an
important substructure in many molecules of biological im-
portance such as arginine, creatine phosphates, and pu-
rines.[2] On the other hand, guanidinium and substituted
guanidinium salts exhibit a variety of interesting properties
such as denaturation of proteins by the guanidinium ion
and inhibition of the DNA synthesis by, for example, hy-
droxyguanidine, which has led to their classification as pro-
spective antitumor drugs.[3] The guanidine motif is also em-
ployed in the design of new materials based on supramolec-
ular association by means of hydrogen bonding.[4] Further-
more, owing to their strong basic properties, guanidines
also serve as useful catalysts in a wide range of base-cata-
lyzed organic reactions.[5,6] More recently, the guanidine
fragment was employed as an essential building block in
computational tailoring and synthesis of strong organic su-
perbases.[7–11] Particularly interesting in this regard are gua-
nidines substituted by flexible heteroalkyl chains capable of
forming multiple intramolecular hydrogen bonds (IMHBs),
In a recent paper, we reported the synthesis and struc-
tural features of N,NЈ,NЈЈ-tris[3-(dimethylamino)propyl]-
guanidine,[13] which in its protonated form possesses three
intramolecular hydrogen bonds. Its gas-phase basicity was
predicted to be comparable to that of P2 phosphazene.[7a]
This compound was also found to exert catalytic activity
in some organic reactions, like Knoevenagel and nitroaldol
condensations, as well as transesterification of vegetable
oils.[14,15] The experimental and calculated intrinsic gas-
phase proton affinities (PAs) of its structural analogues 1–
3 and 5 and 6 (Scheme 1) indicate that replacement of the
propyl groups in 1 with dimethylaminopropyl or meth-
oxypropyl chains leads to a considerable increase in the gas-
phase basicity as a result of the formation of intramolecular
hydrogen bonds, which are absent in alkyl fragments.[16] The
aim of the present work is to determine the basicity of these
interesting guanidine derivatives in acetonitrile (MeCN) by
experimental measurements and computational methods.
This is of considerable importance from a practical point
of view, as acetonitrile is a frequently used solvent in pre-
parative organic chemistry. The standard reference bases
used in the present study are shown in Scheme 1, along with
studied guanidines 1–7.
[a] Division of Organic Chemistry and Biochemistry, Rudjer Bosˇ-
kovic´ Institute,
10002 Zagreb, Croatia
Fax: +385-1-4680-195
E-mail: mmaksic@emma.irb.hr
The basicity of a base B in solvent S is defined by using
Equation (1) and is expressed as the dissociation constant
Ka of the conjugate acid HB+ of the base B or more com-
monly by its negative logarithm pKa [Equation (2)].
[b] Institute of Chemistry, University of Tartu,
Jakobi 2, 51014 Tartu, Estonia
E-mail: ilmar.koppel@ut.ee
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Basicity of Guanidines with Heteroalkyl Side Chains in Acetonitrile
of the mixture of bases, the ∆pKa was determined as the
mean of 10–20 values. The substituted guanidine bases
measured in this work have spectral properties in the wave-
length range from 215 to 235 nm, which are suitable for our
measurements. All the phosphazene bases used as reference
bases had an isosbestic point (the absorbance of protonated
and deprotonated forms is the same) in the range 220–
230 nm in MeCN solution. Therefore, the wavelength of the
reference base isosbestic point can be used for measuring
the protonation level of the guanidine bases in the solu-
tions. The ∆pKa values were calculated as described in the
previous papers by Koppel and coworkers.[17]
The uncertainty in the measured pKa values was esti-
mated according to the approach described in ref.[18] Speci-
fically, the standard uncertainties of the obtained pKa val-
ues if interpreted “in the framework” of the MeCN basicity
scale (that is, uncertainties to be used when comparing the
different pKa values from the scale to each other) were esti-
mated to be 0.06 pKa units. In the same vein, the standard
uncertainties of the absolute pKa values “detached from the
scale” (that is, by treating them as negative logarithms of
equilibrium constants) were found to be 0.2 pKa units.
Scheme 1. Guanidine derivatives 1–7 studied in this work and phos-
phazenes P1–P7 used as the reference bases in UV/Vis measure-
ments.
Computational Details
Structures of all considered guanidine derivatives were
optimized at the HF/6-31G(d) and B3LYP/6-31G(d) level
of theory, and the minima of all structures were verified by
vibrational analysis. Several conformations of the studied
species (both neutral and protonated) were examined, in-
volving structures with intramolecular hydrogen bonds
(hereafter called “cyclic”) and those with unfolded chains
(hereafter called “open-chain”) conformers. The latter con-
formers will be abbreviated as X(oc), where X stands for
the number specifying the guanidine derivative in question.
Following a previous study of the aminopropyl-substituted
guanidines[7] in calculating structures of the protonated spe-
cies two possibilities were considered: (1) the first one where
the proton linked to the imino nitrogen atom of the guani-
dine moiety and the heteroatom within the heteroalkyl
chain with the heteroatom participating in the hydrogen
bond are attached to the same nitrogen atom form a
pseudo-six-membered ring and (2) the second, which occurs
when the heteroalkyl chain and proton participating in the
hydrogen bond are bound to different nitrogen atoms of the
guanidine fragment, forms a pseudo-eight-membered cycle.
In each of the studied species the structure of the latter type
was found to be more stable. It is important to mention
that formation of the pseudo-eight-membered ring struc-
tures was also found in a recent X-ray structural analysis of
N,NЈ,NЈЈ-tris[3-(dimethylamino)propyl]guanidinium hexa-
fluorophosphate.[13] Computational optimization of the
open-chain structures was carried out by assuming antiperi-
planar orientation of all methylene groups in the chains.
Characteristic examples of the structure involving intramo-
(1)
(2)
To exclude the necessity for measuring the solvated hy-
drogen ion (HS+) activity (its measurement is problematic
in nonaqueous solvents), we studied the equilibrium be-
tween two bases B1 and B2 [Equation (3)].
(3)
This equilibrium refers to the relative basicity of the two
bases B1 and B2, which is denoted as ∆pKa and is defined
in Equation (4).
(4)
As can be seen, the activity of HS+ is excluded from the
equation. Assuming that the ratio f(HB+)/f(B) is the same
for both bases (see ref.[18]), then the activity of species can
be replaced by equilibrium concentrations in Equation (4).
Results and Discussion
Determination of pKa values
The ∆pKa values for the pairs of bases were obtained lecular hydrogen bonding (“cyclic” isomer) and the corre-
from the UV/Vis spectra. From each titration experiment sponding open-chain isomer calculated with the HF/6-
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M. Eckert-Maksic´, I. A. Koppel et al.
FULL PAPER
31G(d) method are shown in Figures 1 and 2, respectively.
Finally, in calculating the gas-phase proton affinities, ener-
gies of the B3LYP/6-31G(d) optimized structures were re-
fined by B3LYP/6-311+G(2df,p) single-point calculations
(Table SI1 in the Supporting Information) in order to ob-
tain a very flexible basis set, which is required for a good
description of the lone pairs on the heteroatoms. The Car-
tesian coordinates of all studied species calculated with the
B3LYP/6-31G(d) method are given in the Supporting Infor-
mation. Structures of bases 4, 4H+, 7, and 7H+ and their
open forms were also optimized by using the IEFPCM/HF/
6-31G(d) method[19] by employing UAHF atomic radii
(Tables SI2 and SI3 in the Supporting Information). Key
geometrical parameters of the gas-phase geometries and
geometries of the pseudopolycyclic and unfolded forms of
cation 7H+ are also compared in Figures 1 and 2.
Figure 2. Schematic presentation of the geometry of the “open
chain” structure of guanidinium ion 7H+ optimized in acetonitrile
and the gas phase (values in parentheses).
formed by using the Gaussian03 program package.[22] The
Cartesian coordinates of the calculated species are given in
the Supporting Information.
Basicity in Acetonitrile
The results of the basicity measurements in acetonitrile
with the use of the UV/Vis spectrophotometric method are
presented in Table 1. It is instructive to start discussion with
the result obtained for 1. This compound possesses a propyl
group at each of the guanidine nitrogen atoms and does not
form hydrogen bonds either in the neutral or the protonated
form. Hence, its basicity is mainly governed by the reso-
nance effect in the guanidine moiety predominantly in the
protonated form[7b] coupled with a contribution associated
with polarizability of the alkyl groups. Thus, it is expected
Figure 1. Schematic presentation of the geometry of the “cyclic”
structure of guanidinium ion 7H+ optimized in acetonitrile and the
gas phase (values in parentheses).
Total energies and energies of solvation of the considered that its basicity should be similar to that of previously
molecules in acetonitrile were calculated by using a polar- studied polyalkyl-substituted guanidine derivatives. This is
ized continuum model[20] by employing the isodensity mo- indeed the case. The measured pKa value of 24.92 units is
lecular surfaces of the solute molecules possessing a charge very close to the pKa values of, for example, 1,5,7-triazabi-
of 0.0004 eB–3 (IPCM). The dielectric constant ε for aceto- cyclo[4.4.0]dec-5-ene (TBD) and TMG, which in acetoni-
nitrile is 36.64. The solvent effect was estimated at a lower trile possess pKa values of 26.0[17,23] and 23.4 units,[24]
level of theory [B3LYP/6-311+G(d,p)//HF/6-31G(d)], be- respectively. Replacement of the propyl groups with dimeth-
cause the computations required by the IPCM model are ylaminopropyl or methoxypropyl chains opens the possibil-
much more demanding.[21] The number of grid points for ity of forming intramolecular hydrogen bonds, which
evaluation of isodensity surface was varied in order to should additionally stabilize the protonated forms, thus
achieve convergence for all calculated molecules. Full con- raising the basicity of the parent base. Comparison of the
vergence was achieved by using 100 and 20 points for the pKa of 1 with those of its heteroalkyl analogues shows that
w(φ) and w(θ) parameters, respectively, which represent replacement of the propyl group at the imino nitrogen atom
angular integration weights over the corresponding polar in 1 by a dimethylaminopropyl chain leading to 2 increases
coordinates.[21b] The PA(acetonitrile) values were calculated the pKa value by 0.93 pKa units. Similarly, double replace-
as the difference between the total energy of the neutral ment of the propyl groups at the amino nitrogen atoms with
molecule and its conjugate acid in acetonitrile corrected for dimethylaminopropyl groups leading to 3 results in an in-
zero-point vibrational energies (ZPVEs) taken from the HF/ crease in the pKa by 1.71 pKa units. Hence, the increase in
6-31G(d) gas-phase calculations. All calculations were per- the pKa is 0.78 units or 0.85 units per single amino nitrogen
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Basicity of Guanidines with Heteroalkyl Side Chains in Acetonitrile
atom, which is slightly less than that in the case of the imino open-chain antiperiplanar conformations. The same holds
nitrogen atom in 2 (0.93 units). Finally, compound 4 con- for their protonated forms 5H+–7H+. It appears that an
taining three dimethylaminopropyl groups is found to be acetonitrile molecule is a better hydrogen-bond acceptor
more basic than 1 by 2.23 pKa units. This is less than than the ether group. Consequently, the H-bonding demand
2.64 units predicted by simple additivity indicating the pres- of the protonated imino nitrogen atom in methoxypropyl-
ence of the saturation effect. Nevertheless, this makes com- substituted guanidines is saturated by a molecule of the sol-
pound 4 the most basic guanidine derivative in acetonitrile vent (MeCN) rather than by the oxygen atom of the side
measured so far. On the other hand, the pKa values of the chain.
methoxypropyl-substituted guanidines 5–7 appear to be
In order to check this assumption, we measured the IR
slightly lower than the pKa value of 1. This is a surprising spectra of the hexafluorophosphate salts of 4 and 7 in ace-
result, as formation of intramolecular hydrogen bonds tonitrile. Their comparison with the IR spectrum of 1·HPF6
should amplify basicity. Specifically, on passing from 1 to 7 (Figure 3) reveals that the intensity of the N–H stretching
a decrease in total basicity of 0.2 units is observed. In some vibration (at 3360 cm–1) is reduced in both heteroalkyl-sub-
more detail, replacement of the propyl groups at the amino stituted compounds, and the effect is more pronounced for
nitrogen atoms by the three methoxypropyl chains in 1 lead- the salt of 4. In addition, on passing from 1·HPF6 to
ing to system 6 results in a decrease in the pKa value of 4·HPF6 the C=N stretching band undergoes a redshift by
0.1 units, which is 0.05 units per amino N atom. This 20 cm–1, whereas no change is observed upon going from
change is practically the same as the single substitution at 1·HPF6 to 7·HPF6. These findings imply that the intramo-
the imino nitrogen atom in 1 yielding derivative 5 lecular hydrogen bond in 7·HPF6 in acetonitrile should be
(0.1 units). The trend in changes in a series 1, 5, 6, and 7 indeed significantly weaker than that in 4·HPF6, thus sup-
leading to descending basicity (Table 1) roughly indicates porting the above conjecture. An additional piece of evi-
that the intramolecular hydrogen bond(s) are nonexistent in dence is given in the forthcoming section.
acetonitrile, both in neutral bases and the corresponding
conjugate acids. In other words, compounds 5–7 assume
Table 1. Results of self-consistent basicity measurements of the
substituted guanidine bases and some phosphazene bases in aceto-
nitrile.
Figure 3. Section of the IR spectra of the hexafluorophosphate
salts of 1, 4, and 7 (c = 0.05 molL–1) in acetonitrile with the charac-
teristic NH band.
Comparison with Gas-Phase Proton Affinities
In view of the above-described difference in behavior of
the dimethylaminopropyl- and the methoxypropyl-substi-
tuted guanidines in acetonitrile, it is instructive to compare
the present results with the recently measured PAs of the
same bases (with the exception of 4) in the gas phase.[16]
They are summarized in Table SI1, together with the rel-
evant energetic parameters. The analysis of the data in
Table SI1 shows that replacement of the propyl groups in
1 by the dimethylaminopropyl chains, as well as with the
methoxypropyl groups, leads to an increase in the gas phase
PA, and the effect of the methoxypropyl groups is less pro-
nounced. Specifically, replacement of the propyl group at
the imino nitrogen atom in 1 by a 3-(dimethylamino)propyl
group increases the PA by 8 kcalmol–1, which is by
6.5 kcalmol–1 higher than that on going from NЈ,NЈЈ,NЈЈЈ-
tripropylguanidine to NЈ,NЈЈЈ-dipropyl-NЈЈ-(3-methoxypro-
[a] Absolute pKa values. [b] The numbers on the arrows are the ex-
perimental ∆pKa values.[17]
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M. Eckert-Maksic´, I. A. Koppel et al.
FULL PAPER
Table 2. Total (Etot) and hydrogen-bond-interaction energies (EHB
)
[a] of the cyclic and open chain conformers of guanidines 1–7 and their
protonated forms in the gas phase and acetonitrile (MeCN) as calculated at the (IPCM)B3LYP/6-311+G(d,p)//HF/6-31G(d) level of
theory.
Base/acid
(B/BH+)
“Cyclic” forms
“Open-chain” forms
Etot(gas)
Etot(MeCN)
Etot(gas)
Etot(MeCN)
EHB(gas)[a]
EHB(MeCN)[a]
1
–559.02084
–559.42874
–692.94860
–693.36295
–826.87445
–827.29726
–960.79796
–961.23129
–673.53941
–673.95130
–788.05578
–788.47443
–902.57215
–902.99774
–559.02725
–559.49039
–692.95446
–693.42216
–826.88016
–827.35200
–960.80465
–961.28221
–673.54542
–674.01082
–788.06238
–788.53115
–902.58047
–903.05134
–559.02084
–559.42874
–692.94605
–693.35250
–826.86941
–827.27621
–960.79316
–961.20000
–673.53839
–673.94355
–788.05395
–788.45838
–902.57023
–902.97324
–559.02725
–559.49039
–692.95303
–693.41454
–826.87704
–827.33777
–960.80124
–961.25969
–673.54690
–674.00813
–788.06516
–788.52378
–902.58304
–903.04076
0.00
0.00
0.00
0.00
1H+
2
–1.60
–6.55
–3.16
–13.21
–3.02
–19.64
–0.64
–4.86
–1.15
–10.07
–1.20
–15.37
–0.90
–4.78
–1.95
–8.93
–2.14
–14.13
0.93
–1.69
1.74
–4.63
1.61
2H+
3
3H+
4
4H+
5
5H+
6
6H+
7
7H+
–6.64
[a] EHB = Etot(“cyclic”) – Etot(“open-chain”).
pyl)guanidine.[16] The same holds true for the replacement that contribution of IMHB strength to the gas phase of 7
of the propyl chains attached to the amino nitrogen atom. is 14.1 kcalmol–1, which is by 2.5 kcalmol–1 less than that
For instance, by comparing the PAs of bases 3 and 6 one in base 4. By carrying out the same analysis in acetonitrile
observes that the latter base is less basic by 3.4 kcalmol–1. solution we find that contributions of the IMHBs to the
It follows that in the gas phase IMHBs contribute to the stability of 4 and 4H+ are 2.1 and 14.1 kcalmol–1, respec-
stability of methoxypropyl derivatives 5–7 and their conju- tively, which is by ca. 30% lesser than that in the gas phase.
gate acids 5H+–7H+ as intuitively expected. However, the On the other hand, open-chain isomer 7 is predicted to be
difference in the strengths of the IMHBs in the conjugate slightly more stable in acetonitrile (by 1.6 kcalmol–1),
acids and the corresponding bases is smaller than that in whereas the stability of 7H+ is 6.6 kcalmol–1 higher than
their dimethylaminopropyl counterparts. Concomitantly, that in the open-chain isomer. Geometry optimization of
the increase in basicity is small. This experimental evidence the considered structures in MeCN by using the IEFPCM/
was corroborated by results obtained by the MP2/6- HF/6-31G(d) method (Table SI3) leads to similar results
311+G(d,p)//HF/6-31G(d) and B3LYP/6-311+G(2df,p)// with only one exception. Namely, for 4H+ the latter model
B3LYP/6-31G(d) methods[25] and should be considered as predicts significantly smaller contribution of the IMHBs to
reliable.
stability of the protonated form (7.4 kcalmol–1) than in the
In view of the importance of the intramolecular H-bond- single-point calculations (14.3 kcalmol–1). It is also note-
ing motif in designing organic superbases, we shall present worthy that the open-chain form of 7 is found to be more
here detailed analysis of their cumulative effects. For this stabilized (by 1.7 kcalmol–1) than in the single-point IPCM
purpose it is useful to compare the calculated energies of calculations. In spite of that, both methods lead to the same
the cyclic (Figure 1) and open-chain (Figure 2) conformers. qualitative conclusion. These results convincingly show that
As we are interested in the basicity in the gas phase and in interaction of 7 in solution with MeCN molecules prevents
acetonitrile, we shall use energies of the considered struc- formation of the IMHBs, whereas the interaction is dimin-
tures calculated at the B3LYP/6-311+G(d,p)//HF/6-31G(d) ished for 7H+ by 40%. This is in qualitative agreement with
level, which are summarized in Table 2.
results of the above-mentioned IR measurements of the
Taking substituted guanidine 4 as an example, we find hexaphosphofluorate salts of 7. An important corollary of
that its open-chain conformer is less stable than the pseudo- the present analysis is that structures of bases and their con-
polycyclic structure by 3.0 kcalmol–1. The pseudopolycyclic jugate acids possessing IMHBs in the gas phase could be
form of its conjugate acid, 4H+, is more stable than its fully distinctly different in solutions. Caution should be exercised
unfolded open-chain counterpart 4H+(oc) by 19.6 kcal particularly if the intermolecular hydrogen bonds between
mol–1 as expected due to the increased Coulombic character solute and solvent molecules are stronger than the IMHBs
of the hydrogen bonds upon protonation. The difference in solution.
between these two values of 16.6 kcalmol–1 can be taken as
a rough estimate of the contribution of the IMHBs to the
PA of 4 in the gas phase. In a similar vein, a comparison
Comparison of the Measured and Calculated pKa Values of
between energies of cyclic conformers 7 and 7H+ and their
Bases 1–7 in Acetonitrile
analogues with the unfolded heteroalkyl groups 7(oc) and
7H+(oc) suggests that cooperative intramolecular hydrogen
Owing to wide interest for use of strong nitrogen and
bonds participate to 1.2 and 15.3 kcalmol–1, respectively, in phosphorus bases in synthetic work, considerable efforts
the stabilization of the cyclic conformers. Thus, it follows have been devoted in the past decades to develop practical
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Basicity of Guanidines with Heteroalkyl Side Chains in Acetonitrile
theoretical methods capable of predicting pKa values in or- degrees of freedom for the internal rotations of heteropro-
ganic solvents.[26,27] The a priori estimates of the pKa values pyl chains upon protonation can be expected, thus leading
from first principles[28] are unfortunately not practical in a to the entropy loss.[29] The next point of interest is that the
large number of sizeable molecules. Therefore, one has to trend of calculated pKa values on passing from 1 to meth-
resort to simpler models of the polarized continuum oxypropyl derivatives 5–7 does not follow the ordering of
(PCM)[20] and its isodensity (IPCM) variant form.[18] The the measured pKa values. This is not surprising, as the
latter approach was used in conjunction with the B3LYP/ PA(MeCN) values used in Equation (5) are calculated for
6-311+G(d,p)//HF/6-31G(d) method[7a,7b] for
a
large the gas-phase geometries, implying that structural features
number of strong neutral nitrogen bases yielding a good of the considered species (including the geometry of the in-
correlation with the experimental pKa values (derived for tramolecular hydrogen bonds in the pseudopolycyclic struc-
the set of 16 different nitrogen bases with correlation coeffi- tures) in the gas phase and acetonitrile are the same. There-
cient of 0.997) [Equation (5)].[27]
fore, in the case of methoxypropyl guanidine derivatives,
where this assumption apparently does not hold, larger de-
viations between the calculated and measured pKa values
can be expected. It is very important to note that the
pKa(MeCN) values of bases 5–7, when calculated for open-
chain isomers, reproduce qualitatively the experimentally
obtained ordering of pKa values, but in this case, larger
∆pKa deviations from experiment are encountered. Taking
into account that these deviations are systematic in nature
and between –1 and –2 kcalmol–1 and that Equation (5) is
not very accurate for systems exhibiting intramolecular hy-
drogen bonding, it is safe to conclude that the basicities
of the open-chain forms are in better accordance with the
experimental values than the pseudopolycyclic ones. This is
in harmony with other evidence discussed earlier (vide su-
pra). It is fair to say that Equation (5) should be used in
compounds with IMHBs only with utmost care.
pKa(MeCN) = 0.4953PA(MeCN) – 119.7
(5)
Because we measured the pKa values of guanidines 1–7,
we decided to check the applicability of this correlation for
calculating pKa values of these types of strong bases. It
should be mentioned that for systems 5–7 calculations were
carried out for the cyclic, as well as for the open-chain
structures. The calculated PA(MeCN) and pKa(MeCN) val-
ues of compounds 1–7 are summarized in Table 3.
Table 3. Solvation free energies, proton affinities, and calculated
and experimental pKa values in acetonitrile (MeCN).
[b]
Measured
acids
∆Gsolv.
PA[a]
pKa
pKa
∆pKa
[kcalmol–1] [kcalmol–1] (calcd.) (exp.)
1H+
–34.7
–33.5
–30.8
–27.8
–33.5
–31.5
–28.4
–35.2
–34.0
–34.3
290.6
293.5
296.1
299.7
292.0
294.2
295.5
289.4
287.7
287.2
24.3
25.7
27.0
28.7
25.0
26.0
26.7
23.7
22.8
22.6
24.92
25.85
26.63
27.15
24.81
24.84
24.74
24.81
24.84
24.74
–0.7
–0.2
0.4
1.6
0.2
1.2
2.0
–1.1
–2.0
–2.1
2H+
3H+
Conclusions
4H+
5H+
The synthesis and spectral properties of a series of novel
guanidine derivatives containing one, two, or three heteroal-
kyl chains, capable of forming intramolecular hydrogen
bond(s) in the gas phase, was described and their pKa values
were determined in acetonitrile by using UV/Vis spectro-
photometric titration. It was found that the replacement of
the propyl group at the imino nitrogen atom in 1 by a 3-
(dimethylamino)propyl chain leading to 2 increases the pKa
6H+
7H+
5H+(oc)
6H+(oc)
7H+(oc)
[a] PA of conjugate bases 1–7 and 5(oc)–7(oc). [b] Calculated by
using Equation (5).
Analysis of the results in Table 3 reveals that the calcu- value by 0.93 pKa units. In contrast, replacement of the pro-
lated pKa values are in fair accordance with the experimen- pyl groups at the amino nitrogen atoms with 3-(dimeth-
tal ones. However, there are some larger deviations, which ylamino)propyl groups leading to 3 results in an increase in
call for rationalization, like, for example, those in molecules the pKa by 1.71 pKa units. Finally, compound 4 having
4 and 7, where the number of intramolecular hydrogen three dimethylaminopropyl substituents, was found to be
bonds increases upon protonation. This indicates that a more basic than 1 by 2.23 pKa units. This makes compound
part of disagreement might have its origin in neglecting the 4 one of the most basic guanidine derivatives in acetonitrile
entropy contribution. More precisely, the relationship given measured so far, and it is of comparable basicity to P2-
in Equation (5) is derived for the series of amidine and gua- phosphazenes, which increases the number of strong neutral
nidine derivatives lacking specific intramolecular interac- organic bases available. In contrast, the basicity of all inves-
tions like IMHB.[17] In contrast, the structures in which the tigated 3-methoxypropyl-substituted guanidines was found
heteroalkyl chains are considered are stabilized by one or to be slightly lower than that of guanidine 1. It is also worth
more intramolecular hydrogen bonds. This holds true in pointing out that basicity ordering of the bases with the
particular for the protonated forms, which in some cases dimethylaminopropyl substituents in acetonitrile follows
possess an additional IMHB and exhibit stronger hydrogen the trend encountered in the gas phase, whereas this is not
bonds than those in their parent bases as a result of an the case for the methoxypropyl-substituted guanidines, indi-
excess amount of positive charge and an increase in Cou- cating that in these molecules formation of the IMHBs is
lomb interaction. Concomitantly, reduction of a number of to large extent hindered due to solvation in acetonitrile.
Eur. J. Org. Chem. 2008, 5176–5184
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5181

M. Eckert-Maksic´, I. A. Koppel et al.
FULL PAPER
below). Purity of all guanidine derivatives was checked by gas chro-
matographic analysis, which showed the presence of only one signal
corresponding to the guanidine in question (see Experimental Sec-
tion in the Supporting Information).
NЈ,NЈЈ,NЈЈЈ-Tripropylguanidine (1): Starting from N1,N3-dipro-
pylcarbodiimide (3.52 g, 0.026) and propylamine (4.2 mL, 3.01 g,
Experimental Section
General: All solvents and reagents were purchased from commer-
cial sources and used without further purification unless stated
otherwise. THF was dried by heating at reflux and distilling over
LiAlH4. Dichloromethane was dried with CaH2 and stored over
3 Å molecular sieves. Preparation of thioureas was carried out by a
reaction of selected amines and CS2 by using a previously described
general procedure.[30] N1,N3-dipropylcarbodiimide[31] was prepared
according to a slightly modified literature procedure[32] (see below).
Synthesis of NЈ,NЈЈ,NЈЈЈ-tris[3-(dimethylamino)propyl]guanidine
was carried out following a procedure described in the literature.[13]
The same procedure was also used to prepare all other guanidine
derivatives studied in this work. Gas chromatographic analyses
were carried out with a Varian 3300 gas chromatograph fitted with
a DB-1701 capillary column (0.32 mmϫ15 m with film thickness
of 0.15 µm) by using nitrogen as the gas carrier. The standard 1D
1H and proton-decoupled 13C NMR spectra of phosphazenes were
recorded with a Bruker AC-200 NMR spectrometer at 200.13 and
50.32 MHz, respectively, whereas the NMR spectra of all other
compounds were measured with a Bruker Avance 300 NMR spec-
trometer at 300 (1D 1H) and 75.5 MHz (proton-decoupled 13C),
respectively. Chemical shifts were determined relative to TMS as an
internal standard. IR spectra were recorded with an ABB Bomem
MB102 FTIR spectrometer equipped with CsI optics and a DTGS
detector.
0.051 mol), guanidine
1 was isolated in 73% yield (3.51 g,
1
0.019 mol) as a colorless oil. H NMR (300 MHz, CDCl3, 25 °C,
TMS) δ = 0.94 (t, JH,H = 7.3 Hz, 9 H), 1.56 (q, JH,H = 7.3 Hz, 6
H), 3.02 (t, JH,H = 7.2 Hz, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C, TMS) δ = 11.7, 23.7, 45.3, 152.5 ppm. HRMS:
calcd. for C10H23N3 [M + H]+ 186.196473; found 186.193103.
NЈ,NЈЈЈ-Dipropyl-NЈЈ-[3-(dimethylamino)propyl]guanidine (2): The
same procedure as described above starting from N1,N3-dipropylca-
rbodiimide (3.28 g, 0.026 mol) and 3-(dimethylamino)propyl-1-
amine (6.30 mL, 5.11 g, 0.050 mol) in dry THF (30.0 mL) afforded
crude guanidine 2 as a colorless viscous oil. Distillation of the
crude product at 0.01 Pa (10–4 mbar) yielded 81% (4.80 g,
0.021 mol, b.p. 87–92 °C/2ϫ10–4 mbar) of pure 2. 1H NMR
(300 MHz, CDCl3, 25 °C, TMS) δ = 0.95 (t, JH,H = 7.3 Hz, 6 H),
1.57 (q, JH,H = 7.3 Hz, 4 H), 1.70 (m, 2 H), 2.21 (s, 6 H), 2.34 (t,
JH,H = 6.2 Hz, 2 H), 3.03 (t, JH,H = 7.3 Hz, 4 H), 3.19 (t, JH,H
=
6.2 Hz, 2 H) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C, TMS) δ =
11.7, 23.4, 27.4, 41.9, 45.1, 45.3, 57.1, 153.8 ppm. HRMS: calcd.
for C12H28N4 [M + H]+ 229.238672; found 229.238921.
NЈ,NЈЈЈ-Bis[3-(dimethylamino)propyl]-NЈЈ-propylguanidine (3): The
same procedure as described above starting from N1,N3-bis[3-(di-
methylamino)propyl]carbodiimide (3.24 g, 0.015 mol) and propyl-
amine (1.77 g, 0.03 mol) in dry THF (30.0 mL) afforded crude guan-
idine 3 as a colorless viscous oil in quantitative yield. Product was
further purified by fractional distillation at 0.001 Pa (10–5 mbar,
b.p. 103–108 °C/2ϫ10–5 mbar) resulting in 3.18 g. (0.012 mol,
78%) of pure 3. 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ =
0.94 (t, JH,H = 7.3 Hz, 3 H), 1.56 (q, JH,H = 7.3 Hz, 2 H), 1.76 (m,
General Procedure for the Preparation of Carbodiimides: Crude
thioureas, prepared by the reaction of the desired amine and CS2
in a 2:1 molar ratio, were dissolved in dry CH2Cl2. The solution
was vigorously stirred and slight excess of yellow HgO was added
in one portion. Stirring was continued for 2 h at room temperature.
Subsequently, the solid material was filtered off with suction by
means of a sintered funnel and thoroughly washed with CH2Cl2.
The filtrate was evaporated under vacuum resulting in a colorless
oil. Crude carbodiimide was purified by distillation under reduced
pressure.
4 H), 2.19 (s, 12 H), 2.34 (t, JH,H = 6.0 Hz, 4 H), 3.12 (t, JH,H
=
7.3 Hz, 2 H), 3.32 (t, JH,H = 6.0 Hz, 4 H) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C, TMS): δ = 11.4, 22.7, 26.4, 40.9, 44.2,
44.9, 56.0, 155.8 ppm. HRMS: calcd. for C14H33N5 [M + H]+
272.280871; found 272.283503.
N1,N3-Bis[3-(dimethylamino)propyl]carbodiimide: Desulfurization
of N1,N3-bis[3-(dimethylamino)propyl]thiourea (19.20 g, 0.077 mol)
with yellow HgO (17.00 g, 0.078 mol) in CH2Cl2 (150 mL) followed
by distillation under reduced pressure (3ϫ10–5 mbar) afforded
pure carbodiimide (13.14 g, 0.062 mol, 79%). 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 1.70 (m, 4 H), 2.20 (s, 12 H), 2.31 (t,
JH,H = 7.3 Hz, 4 H), 3.25 (t, JH,H = 6.6 Hz, 4 H) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C, TMS): δ = 29.34, 45.23, 45.52, 56.89,
NЈ,NЈЈЈ-Dipropyl-NЈЈ-(3-methoxypropyl)guanidine (5): The same
procedure as described above starting from N1,N3-dipropylcarbodi-
imide (3.28 g, 0.026 mol) and 3-methoxypropyl-1-amine (6.00 mL,
5.24 g, 0.059 mol) in dry THF (23 mL) afforded quantitative con-
version to guanidine 5. After distillation under reduced pressure
140.14 (N=C=N) ppm. IR (KBr): ν = 2130 (N=C=N stretching)
˜
1
(6ϫ10–5 mbar) pure 5 (4.14 g, 0.019 mol, 74%) was obtained. H
cm–1.
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 0.93 (t, JH,H = 7.5 Hz,
6 H), 1.54–1.62 (m, 4 H), 1.81–1.85 (m, 2 H), 3.01 (t, JH,H = 7.3 Hz,
N1,N3-Bis(3-methoxypropyl)carbodiimide: Reaction of N1,N3-bis(3-
methoxypropyl)thiourea (14.92 g, 0.076 mol) and yellow HgO
(19.74 g, 0.091 mol) in CH2Cl2 (150 mL) followed by vacuum distil-
lation gave pure carbodiimide (8.06 g, 0.043 mol, 0.57%). 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 1.81 (m, 4 H), 3.28 (m, 4 H),
3.34 (s, 6 H), 3.45 (t, JH,H = 6.2 Hz, 4 H) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C, TMS) δ = 31.25, 43.56, 58.69, 69.62,
4 H), 3.25 (t, JH,H = 4.1 Hz, 2 H), 3.33 (s, 3 H), 3.45 (t, JH,H
=
5.6 Hz, 2 H) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C, TMS): δ =
11.53, 23.23, 29.70, 41.00, 44.75, 58.60, 71.02, 153.78 ppm. HRMS:
calcd. for C11H25N3O [M + H]+ 216.207038; found 216.207379.
NЈ,NЈЈЈ-Bis(3-methoxypropyl)-NЈЈ-propylguanidine (6): The same
procedure as described above starting from N1,N3-bis(3-meth-
oxypropyl)carbodiimide (3.30 g, 17.6 mmol) and propylamine
(3.00 mL, 2.10 g, 35 mmol) dissolved in dry THF (23 mL) afforded
pure guanidine 6 (3.33 g, 14 mmol, 77%). 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 0.95 (t, JH,H = 7.3 Hz, 3 H), 1.55 (m, 2
140.16 (N=C=N) ppm. IR (KBr): ν = 2128 (N=C=N stretching)
˜
cm–1.
General Procedure for the Synthesis of Guanidine Derivatives 1–7:
Carbodiimide and the corresponding amine in a 1:2 molar ratio
were dissolved in dry THF and stirred under reflux for 24 h. After
cooling to room temperature, the solvent and the excess amount of
amine were evaporated under vacuum (1332 Pa, 13 mbar), and the
raw product was purified by distillation under reduced pressure af-
fording the desired guanidine derivative in a very good yield (see
H), 1.80 (m, 4 H), 3.00 (t, JH,H = 7.3 Hz, 2 H), 3.16 (t, JH,H
=
6.5 Hz, 4 H), 3.33 (s, 6 H), 3.47 (t, JH,H = 5.9 Hz, 4 H) ppm. 13C
NMR (75.5 MHz, CDCl3, 25 °C, TMS): δ = 11.67, 23.62, 30.29,
41.13, 44.97, 58.56, 71.25, 153.00 ppm. HRMS: calcd. for
C12H27N3O2 [M + H]+ 246.217603; found 246.218816.
5182
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5176–5184

Basicity of Guanidines with Heteroalkyl Side Chains in Acetonitrile
NЈ,NЈЈ,NЈЈЈ-Tris(3-methoxypropyl)guanidine (7): The same pro-
cedure as described above starting from N1,N3-bis(3-methoxypro-
pyl)carbodiimide (3.28 g, 17.5 mmol) and 3-methoxypropyl-1-
amine (3.60 mL, 3.14 g, 35 mmol) in dry THF (23 mL) afforded
pure 7 (4.44 g, 16 mmol, 91%). 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 1.80 (m, 6 H), 3.15 (t, JH,H = 6.6 Hz, 6 H), 3.34 (s, 9
H), 3.46 (t, JH,H = 5.9 Hz, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3, 25 °C, TMS): δ = 30.21, 40.87, 58.57, 71.17, 153.12 ppm.
HRMS: calcd. for C13H29N3O3 [M + H]+ 276.228168; found
276.225512.
tion, where both of the bases are present, with an optically trans-
parent acid or base. In all experiments the simultaneous titration
of two free bases of comparable basicity with an acid was carried
out, and the UV/Vis spectrum was recorded after each addition of
acidic titrant. Also, both bases were titrated separately. A profes-
sional glove box was used to ensure that the environment was free
from humidity and oxygen. Concentrations of measured bases were
in the 5ϫ10–5 molL–1 range during the titration experiments, con-
centration of acidic and basic titrants were usually around
5ϫ10–4 molL–1. For a more detailed description of the experimen-
tal set up the reader is referred to ref.[17] Acetonitrile (MeCN)
[Romil, Ͼ99.9%, Super purity Solvent (Far UV), water content
Ͻ0.005%] was the same as that used in previous works[17,36] and
was used without further purification. The water content was deter-
mined by coulometric Karl Fischer titration to be about 0.004%.
A solution of methanesulfonic acid (MeSO3H) (Ͼ99%) was used
as acidic titrant. A solution of phosphazene base EtP2(dma)
(Ͼ98%) was used[17] as basic titrant.
Synthesis of Reference Compounds: The synthesis and purifications
of reference compounds P1, P2, P3 and P5 are described in ref.[33]
,
and the synthesis of compounds P4 and P7 in ref.[7f] In this work
the Staudinger reaction was used to synthesize new compound P6
as well as for a new synthesis of known compounds P4 and P5
according to the scheme:
Supporting Information (see footnote on the first page of this arti-
cle): Procedure for the synthesis of phosphazenes P4 and P5 and
their tetraphenylborate salts; copy of the 1H and 13C NMR spectra
of all new guanidine derivatives and phosphazenes; description of
the procedure for determination of the pKa values; Cartesian coor-
dinates of the studied neutral and protonated guanidine derivatives;
summary of the measured and calculated gas-phase PAs.
where pyrr denotes the pyrrolidino group.
The reaction conditions are not optimized. The compounds were
isolated as their HBPh4 salts, and the free bases were liberated by
means of MeOK as described in ref.[19] (a mixture of THF/MeOH
was used as solvent).
Acknowledgments
4-CF3-C6H4P2(pyrr)·HBPh4: To the solution of 4-trifluoromethyl-
phenylazide[34] (6.9 mmol, 1.30 g) in benzene (8 mL) was added a
solution of (pyrr)2PCl[34] (6.9 mmol, 1.31 g) in benzene (4 mL) by
syringe at room temperature under flow of argon. The mixture was
stirred and heated at reflux for 1 h. To the warm mixture of
HN=P(pyrr)3 (4.24 g, 16.6 mmol) was added the free base[35] in
benzene (3 mL), and the mixture was heated at reflux for another
4 h. The solvent was distilled off, and to the residue was added dry
THF (10 mL). Precipitated HN=P(pyrr)3·HCl was filtered off and
THF was removed. The rest, dark brown viscous oil, was dissolved
in MeOH (11 mL), and a solution of NaBPh4 (3.4 g) in MeOH
was added to precipitate the title compound. The raw product was
recrystallized (2ϫ; EtOH/MeCN, 3:1) to give colorless crystals
(yield 24%). M.p. 209.7–210.7 °C. 1H NMR (200.13 MHz, CDCl3)
Financial support of this work by the Ministry of Science, Educa-
tion and Sport of Croatia (M.E.M., Z.G., and P.T. through project
No. 098-0982933-2920) and grants from the Estonian Science
Foundation (5508 and 6701) are gratefully acknowledged. Dr. Va-
hur Mäemets is gratefully acknowledged for recording the NMR
spectra of some reference bases and their derivatives. Dipl. eng.
Nikola Biliskov is gratefully acknowledged for recording the FTIR
ˇ
spectra of the hexafluorophosphate salts of 1, 4, and 7.
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δ = 1.72 (m, 12 H), 1.77 (m, JP,H = 6.8 Hz, 8 H), 2.92 (dt, JH,H
=
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6.6 Hz, JP,H = 3.5 Hz, 12 H), 3.00 (m, 8 H), 4.73 (d, JP,H = 10.8 Hz,
1 H), 6.61 (d, JH,H = 8.5 Hz, 2 H), 6.87 (t, JH,H = 7.0 Hz, 4 H),
7.01 [t, JH,H(av) = 7.5 Hz, 8 H], 7.33–7.46 (m, 10 H) ppm. 13C NMR
(50.32 MHz, CDCl3): δ = 26.2 (d, JP,C = 8.7 Hz), 26.4 (d, JP,C
=
9.5 Hz), 46.8 (d, JP,C = 5.2 Hz), 47.0 (d, JP,C = 5.8 Hz), 118.1 (d,
JP,C = 7.1 Hz), 121.6, 124.3 (q, JF,C = 33.0 Hz), 125.4 (q, JB,C
2.8 Hz), 126.4 (q, JF,C = 2.8 Hz), 136.3, 142.4, 164.3 (q, JB,C
=
=
49.5 Hz) ppm.C51H65BF3N7P2 (905.87): calcd. C 67.62, H 7.23, N
10.82; found C 67.53, H 7.26, N 10.81.
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= 4.3 Hz, 12 H), 3.16 (m, 8 H), 6.64 (d, JH,H = 8.7 Hz, 2 H), 7.07
(d, JH,H = 8.7 Hz, 2 H) ppm. 13C NMR (50.32 MHz, [D8]THF): δ
= 27.0 (d, JP,C = 8.2 Hz), 27.3 (d, JP,C = 8.5 Hz), 47.4 (d, JP,C
=
4.0 Hz), 47.8 (d, JP,C = 4.7 Hz), 114.4 (q, JF,C = 31.5 Hz), 121.9 (d,
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Measurements of pKa in Acetonitrile: The measurements were car-
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groups,[36] that is, by UV/Vis spectrophotometric titration of a solu-
Eur. J. Org. Chem. 2008, 5176–5184
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[24] The pKa value of TMG was also measured in this work. TMG
was found to be a stronger base by 0.24 units than the phos-
phazene base 4-MeO-C6H4P1(pyrr) and a weaker base by
0.50 units than 4-NMe2-C6H4P1(pyrr);[17] the pKa value of
TMG is therefore 23.4 units.
[9]
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Received: July 8, 2008
Published Online: September 11, 2008
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