Molecular structure and acid/base properties of 1,2-dihydro-1,3,5-triazine derivatives

Article abstract of DOI:10.1039/c1nj20595a

It is shown that guanidine and its N,N-dimethyl-derivative react with substituted carbodiimides, affording hitherto unknown 1,2-dihydro-1,2,3-triazine derivatives. The structures of three novel compounds of this type and their perchlorate salts were elucidated by spectroscopic (IR, ¹H and ¹³C NMR and ¹⁵N solid-state NMR) and X-ray diffraction methods. The acid/base properties were also determined experimentally and by using DFT calculations with the B3LYP functional. The most basic compound was found to be dihydrotriazine 3, the basicity of which with the pK_a value of 23.3 is of the same order of magnitude as that of tetramethylguanidine. Acidity measurements revealed that all the compounds studied are very weak acids with pK_a values in the range of 25.8-30.8 pK_a units in acetonitrile. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/c1nj20595a

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PAPER
Molecular structure and acid/base properties of 1,2-dihydro-1,3,5-triazine
derivativesw
a
b
b
c
´
´
´
Vjekoslav Strukil, Ivica Ðilovic, Dubravka Matkovic-Calogovic, Jaan Saame,
a
Ivo Leito,c Primoz Sket,de Janez Plavecdef and Mirjana Eckert-Maksic*
´
Received (in Montpellier, France) 8th July 2011, Accepted 4th October 2011
DOI: 10.1039/c1nj20595a
It is shown that guanidine and its N,N-dimethyl-derivative react with substituted carbodiimides,
affording hitherto unknown 1,2-dihydro-1,2,3-triazine derivatives. The structures of three novel
1
compounds of this type and their perchlorate salts were elucidated by spectroscopic (IR, H and
13C NMR and 15N solid-state NMR) and X-ray diffraction methods. The acid/base properties
were also determined experimentally and by using DFT calculations with the B3LYP functional.
The most basic compound was found to be dihydrotriazine 3, the basicity of which with the
pKa value of 23.3 is of the same order of magnitude as that of tetramethylguanidine. Acidity
measurements revealed that all the compounds studied are very weak acids with pKa values in the
range of 25.8–30.8 pKa units in acetonitrile.
to attract considerable attention.9 In the course of our ongoing
Introduction
project on the design and reactivity of strong guanidine
bases,10 we became interested in exploring the possibility of
preparing some specifically substituted dihydrotriazines using
guanidine derivatives and carbodiimides as reactants. This
approach, as well as the reaction of biguanide derivatives
and carbodiimides, has been extensively explored in the past.
In all the reports published so far, only the formation of
melamine or isomelamine derivatives was reported.11–13 The
reaction was proposed to proceed through the primary
addition of the reactants, followed by the cyclization of the
resulting intermediate triguanide, with the loss of amine, to the
heterocyclic end-product.11 However, although this approach
to melamine and isomelamine derivatives has been known for
a long time, no thorough study of a reaction mechanism and a
structure of the so obtained products has been published as
yet.11,12 Therefore, we considered it of interest to address some
of these questions in the present work. Furthermore, an
additional focus of our interest in the properties of dihydro-
triazines concerned their acid–base properties. Namely, due to
the presence of guanidine-type subunits in their molecular
framework, they are expected to exhibit basicity of a similar
order of magnitude as guanidine or biguanide derivatives.14
Herewith, we report on the synthesis and structural features
of three novel 1,2-dihydro-1,3,5-triazine derivatives, namely
1–3 (Scheme 2). It should be noted that they differ from
previously reported members of this family of compounds
by the presence of the exo-cyclic imino group at ring position 2.
We were particularly interested in establishing the structure of
compound 1, for which the isomelamine geometry (see Scheme 5)
from UV spectral analysis was previously proposed.11,12 Our
second aim in this work was to evaluate their basicity and acidity
Dihydrotriazine derivatives comprising a variety of substituents
have been extensively studied in the past due to their broad
biological activity. Some of these compounds have been used as
antibacterial,1 anti-inflammatory,2 antimalarial,3 anti-diabetic4
and antitumor5 agents (Scheme 1).
Other successful applications include use as herbicides,6
insecticides7 and corrosion inhibitors.8 Consequently, their
syntheses and the evaluation of their biological activity continue
Scheme 1 The structure of cycloguanil, an antimalarial 1,2-dihydro-
triazine inhibitor of dihydrofolate reductase (Ar = 4-ClC6H4).3
a
´
ˇ
Ru:er Bosˇkovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia.
E-mail: mmaksic@emma.irb.hr; Fax: +385-1-4680-195;
Tel: +385-1-4680-197
b Faculty of Science, Department of Chemistry, Horvatovac 102A,
10000 Zagreb, Croatia
c University of Tartu, Institute of Chemistry, Ravila 14a, 50411 Tartu,
Estonia
d Slovenian NMR Centre, National Institute of Chemistry,
Hajdrihova 19, SI-1000 Ljubljana, Slovenia
e EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana,
Slovenia
f Faculty of Chemistry and Chemical Technology,
University of Ljubljana, Askerceva cesta 5, SI-1000 Ljubljana, Slovenia
w Electronic supplementary information (ESI) available: Spectra, X-ray
CIF files, tables of bond length, angles and Cartesian coordinates of the
optimized structures. CCDC 830994–830998. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1nj20595a
c
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reaction was carried out using a 1 : 2 ratio of 5 and 7, and a
pure product was isolated by high-vacuum distillation in 80%
yield. Moreover, no N,N0,N0 0-triisopropylguanidine (9) was
observed, presumably due to the lower reactivity of dialkyl-
carbodiimide 7 (R2 = i-Pr) and high volatility of isopropyla-
mine (bp 32 1C) under the applied experimental conditions.
Another important observation is that an intermediate triguanide
derivative could not be identified in any of the reactions studied
in this work, which is in accordance with the available literature
studies.11,12
This confirms the previous proposition11,12 that an inter-
mediately formed triguanide derivative undergoes sponta-
neous cyclization accompanied by the elimination of amine
R2NH2 (aniline in the reaction of N,N0-diphenylcarbodiimide
(6) or isopropylamine when N,N0-diisopropylcarbodiimide (7)
is used). From a mechanistic point of view, two modes of
cyclization to 1,2-dihydrotriazines could be envisaged
(Scheme 4): one starting directly from the triguanide moiety
10 (path A) or from its ring tautomer intermediate 11, which is
formed by a nucleophilic attack of the lone pair at the imino
nitrogen N1 to the carbon atom C6 in triguanide 10, followed
by the elimination of the R2NH2 molecule (path B). This type
of tautomerism is well known from, e.g., sugar chemistry.15
More recently, chain–ring tautomerism, which, in fact, corre-
sponds to thermally allowed 6p-electrocyclization, has also
been invoked to explain the mechanism of the cyclization of
some unsaturated hetero chains of the oligonitrile type into
1,2-dihydro-1,3,5-triazine derivatives.16
Scheme 2 The 1,2-dihydro-1,3,5-triazine derivatives 1–3 studied in
this work.
experimentally by employing quantum chemical calculations.
This is of considerable importance since due to the presence of
exo-cyclic imino- and amino-type nitrogen atoms, they are
expected to have the ability either to donate or accept a
proton, i.e., to act as either an acid or a base (Scheme 2). In
addition, the results of a computational study of the effect of
p-substituents in aryl-substituted species on the protonation
energies, with the goal of designing potentially stronger acids/
bases belonging to this class of compounds, will be presented. To
the best of our knowledge, this has been the first comprehensive
study of the structural features and acid/base properties of
1,2-dihydro-1,3,5-triazine derivatives so far.
Results and discussion
Synthesis and characterization of products
Compounds 1–3 were prepared in an excellent yield by applying
a modified one-pot procedure based on a protocol reported
earlier by Kurzer and Pitchfork.11 Guanidine (4) or N,N-
dimethylguanidine (5) was first treated with two equivalents
of N,N0-diphenylcarbodiimide (6) in refluxing THF (Scheme 3),
affording the phenyl derivatives 1 and 2 in moderate yields
(60% and 51%, respectively), accompanied by the corres-
ponding biguanide derivative and N,N0,N00-triphenylguanidine
(8) (Fig. S1, ESIw; Scheme 4). This suggests that the aniline
molecule liberated during cyclization competes with the in situ
formed biguanide derivative for N,N0-diphenylcarbodiimide
(6), yielding by-product 8. To increase the yield, the reaction
was repeated using three equivalents of N,N0-diphenylcarbo-
diimide (6), which led to a complete consumption of the biguanide
intermediate and an increase in the isolated yield of the cyclic
product to 98% (1) and 94% (2), respectively (Fig. S2, ESIw).
After removing the solvent, the main product was isolated by
suspending the crude reaction mixture in diethylether followed by
filtration (1 and 2). In the case of the isopropyl derivative 3, the
However, in this work, we could not confirm the presence
of these intermediates experimentally due to their obvious
instability. Therefore, we calculated the energies of both types
of tautomers for the model compounds in which R1 and R2
groups were replaced by methyl groups, using the B3LYP/
6-311+G(d,p)//B3LYP/6-31G(d,p) method. In addition to the
gas phase, calculations were carried out in THF as the solvent.
The geometries of the fully optimized species are shown in
Fig. S3 and Table S1 (see ESIw) and the computed energies are
listed in Table 1. A glance at the calculated energies in Table 1
clearly shows that the open-chain and cyclic tautomers 10 and 11
are of similar stability, with the latter being slightly more stable in
THF (by 1.07 kcal molꢀ1). Thus, based on these data, albeit
qualitative, we presume that path B would be favored.
The 1,2-dihydrotriazine products were fully characterized
by elemental analysis and spectroscopic methods (IR, HRMS,
1
1H and 13C solution and H, 13C and 15N solid-state NMR).
Scheme 3 Synthesis of triazines 1–3.
c
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Scheme 4 Possible mechanisms of the formation of 1,2-dihydro-1,3,5-triazine derivatives 1–3 (R1 = H or Me, R2 = Ph or i-Pr).
Similar chemical shifts for carbon atoms have been observed
in the solid state as well (Fig. 1). The 1H and 13C NMR spectra
of triphenyl derivatives 1 and 2 (see the Experimental section)
in solution, as well as in the solid state (Fig. S4–S7 and
S19–S22 in ESIw), are also fully consistent with the 1,2-
dihydro-1,3,5-dihydrotriazine structures. Notably, the signals
for the NH proton in the 1H NMR spectra of 1 and 2, taken in
DMSO, appear in the same region (7.61 ppm in 1 and
7.75 ppm in 2 in DMSO), thereby confirming that the imino
proton is in the same chemical environment in both compounds
(Fig. S4 and S6 in ESIw).
Table 1 Single point B3LYP/6-311+G(d,p)//B3LYP/6-31G(d,p)
and CPCM/B3LYP/6-31G(d,p) energies in the gas phase and THF
solution for open-chain and cyclic tautomers 10 and 11, respectively
Structurea Eel/a.u.
EZPV/a.u. Etot/a.u.
Erel/kcal molꢀ1
Gas phase
10
TS
11
ꢀ739.06485 0.32223
ꢀ738.74262
0.00
ꢀ738.72442 11.42
ꢀ739.04652 0.32210
ꢀ739.06342 0.32486
DGsolv/kcal molꢀ1
ꢀ738.73856
2.55
THF solution
solv
E
/kcal molꢀ1
rel
10
TS
11
11.61
8.81
7.99
0.00
8.62
ꢀ1.07
Furthermore, in the 15N CP-MAS NMR spectra, the most
upfield signals between ꢀ290 and ꢀ300 ppm indicate the
presence of the amino/dimethylamino group attached to the
C4 atom (Fig. 2).
a
R1 = R2 = CH3, see Scheme 4. TS corresponds to the transition
structure for chain-tautomer cyclization.
The structures of compounds 1 and 2 were ultimately
confirmed by X-ray diffraction analysis. In the mass spectra,
all three compounds gave the expected molecular ion [MH+]
along with some fragment ions. The proposed structures were
supported by analysis of the solution and solid-state NMR
spectra. For instance, taking the 1H NMR spectra in the
solution of compound 3 as an example, we observe a broad
doublet at 6.15 for the C–NH proton, a singlet for the protons
of the N–CH3 group at 2.96 ppm, three multiplets for
the N–CH protons in the range of 3.96–4.76 ppm and
three doublets for the CH–CH3 protons in the range of
0.96–1.41 ppm. The corresponding 13C NMR spectrum in
solution displays three signals between 159.2–148.2, three
signals between 45.3–42.8 ppm, one signal at 35.5 ppm and
three signals between 24.5–19.4 ppm assigned to the ring
carbon atoms, CH carbon atoms of three chemically different
isopropyl groups, N–CH3 and C–CH3 carbon atoms,
respectively.
Fig. 1 13C CP-MAS NMR spectra of compounds 1 (a), 2 (b) and 3 (c).
c
88 New J. Chem., 2012, 36, 86–96
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Fig. 2 15N CP-MAS NMR spectra of compounds 1 (a) and 2 (b).
Fig. 4 ORTEP drawing of 2. Thermal ellipsoids are at the 30%
probability level.
Table 2 Selected bond lengths (A) for 1ꢁ0.5 MeOH and 2a
Bond
1a
1b
2
N1–C2
N1–C6
C2–N3
N3–C4
C4–N9
C4–N5
N5–C6
C2–N7
C6–N8
N1–Ph
N7–Ph
N8–Ph
1.416(2)
1.374(2)
1.360(2)
1.331(2)
1.325(2)
1.367(2)
1.302(2)
1.292(2)
1.359(2)
1.447(2)
1.423(2)
1.418(2)
1.419(2)
1.372(2)
1.370(2)
1.329(2)
1.333(2)
1.366(2)
1.317(2)
1.287(2)
1.343(2)
1.444(2)
1.416(2)
1.433(2)
1.433(2)
1.371(2)
1.354(2)
1.328(2)
1.346(2)
1.362(2)
1.308(2)
1.292(2)
1.361(2)
1.444(2)
1.411(2)
1.424(2)
Scheme 5 Possible tautomeric structures of molecule 1. 1T1-imino,
1T2-quinoid and 1T3-isomelamine structures.
Even more importantly, the signals for N3 and N5 atoms
have different chemical shifts. In the case of 1, this excludes the
existence of the quinoid and isomelamine structures 1T2 and 1T3
(Scheme 5), in which we would expect to observe a single
resonance for both atoms due to the symmetry of the molecule.
In order to obtain insights into the intrinsic stabilities of tautomers
1T1–1T3 of compound 1, their energies were calculated using the
B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) method. At this level of
theory, tautomer 1T1 was found to be more stable than 1T2 and
1T3 by 15.2 and 11.6 kcal molꢀ1, thus being in accordance with
NMR data (see Table S3 for energies in ESIw).
a
For numeration of atoms see Fig. 3 and 4.
from 1.302(2) A to 1.433(2) A, and are also in agreement with
this tautomeric form, albeit with extensive delocalization. Such
delocalized CQN bonds were also reported for the structurally
related 1,6-dihydro-1,3,5-triazine derivative.17
Finally, an interesting feature observed in the 15N CP-MAS
NMR spectrum of compound 1 concerns the presence of a
larger number of signals than in compound 2, indicating that
two molecules are present in the asymmetric unit of compound
1, while a single molecule is present in the asymmetric unit of
compound 2 in the solid state. This, as will be shown below,
was confirmed by X-ray diffraction data.
It is important to note that the NH2 group (NMe2 in 2) is
practically coplanar with the triazine moiety, thus enabling
effective delocalization of the nitrogen lone pair in the triazine
ring. Another notable feature concerns the difference in the
length of the exocyclic C2–N7 and C6–N8 bonds. While the
length of the C2–N7 bond (1.292(2) A and 1.287(2), 1.292(2) A
in 1a, 1b, and 2, respectively) corresponds to a typical CQN
double bond, the C6–N8 bond (ranging from 1.343(2) to
1.361(2) A) has a value closer to a typical Nsp2–Csp2 single
bond, such as in ref. 18.
X-Ray structure determination of 1 and 2
The crystal and molecular structures of the methanol solvate
of compound 1 (1ꢁ0.5 MeOH) and compound 2 were deter-
mined by the single crystal X-ray diffraction method (Table 3).
The asymmetric unit of 1ꢁ0.5 MeOH consists of two different
conformers of 1 (1a and 1b) and a methanol molecule, while
that of 2 contains a single molecule (Fig. 3 and 4). The selected
bond lengths are given in Table 2. Their perusal clearly indicates
that imino tautomer 1T1 is present in both compounds. The
carbon–nitrogen bond distances within the triazine ring range
In the crystal structure of 1ꢁ0.5 MeOH, the two conformers
are connected by hydrogen bonds of the type N–Hꢁ ꢁ ꢁN
(2.912(2) and 3.053(2) A), forming a ring that can be described
by the graph-set notation R22(8).
The methanol molecule is a donor in the hydrogen bond
O–Hꢁ ꢁ ꢁN (2.915(2) A) to molecule 1a and is an acceptor of
a weak hydrogen bond C–Hꢁ ꢁ ꢁO from a neighboring 1a
molecule (Fig. 5). Such supramolecular assemblies are inter-
connected in the crystal structure by weak interactions of the
type C–Hꢁ ꢁ ꢁO, C–Hꢁ ꢁ ꢁN, C–Hꢁ ꢁ ꢁp and N–Hꢁ ꢁ ꢁp.
In contrast, packing in the crystal structure of 2 is achieved
through weak interactions, mostly of the C–Hꢁ ꢁ ꢁp type. The
protonated nitrogen atom N8 is sterically hindered and not
involved in hydrogen bonding.
The effect of protonation on the molecular structure of 1–3
In order to confirm the site of proton attack and to obtain
insights into the effect of protonation on the structure of the
Fig. 3 ORTEP drawing of 1ꢁ0.5 MeOH. Thermal ellipsoids are at the
30% probability level.
c
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Table 3 General and crystal data, summary of intensity data collection and structure refinement
1ꢁ0.5 MeOH
2
2ꢁHClO4
3ꢁHClO4
Empirical formula
Formula weight
Crystal system, space group
Unit cell dimensions (A, 1)
2(C21H18N6), CH4O
740.87
Monoclinic, P 21/c
C23H22N6
382.47
Orthorhombic, P bca
C23H23N6, ClO4
482.92
Orthorhombic, P 212121
C14H29N6, ClO4
380.88
Monoclinic, P 21/c
a
B
c
a
14.1696(2)
17.3971(4)
15.0518(3)
90.00
19.0976(8)
9.1823(3)
21.9471(8)
90.00
6.9133(5)
15.5643(12)
20.7086(14)
90.000
9.4056(10)
9.3787(9)
22.2736(18)
90.00
b
g
91.7700(20)
90.00
3708.65(12)
4
1.327
90.00
90.00
3848.6(2)
8
1.320
90.000
90.000
2228.3(3)
4
1.440
98.682(7)
90.00
1942.3(3)
4
1.303
Volume/A3
Z
Dcalc/g cmꢀ3
T/K
100(2)
100(2)
150(2)
110(2)
Reflections observed/independent (Rint
Observed reflections [I 4 2s(I)]
Goodness-of-fit on F2
R/wR [I 4 2s(I)]a
R/wR (all data)b
Flack parameter
)
35 085/6866 (0.0366)
4991
0.979
0.0443/0.1067
0.0642/0.1172
—
12 539/3363 (0.0426)
2698
1.072
0.0454/0.0892
0.0642/0.0958
—
5090/3659 (0.0297)
2760
1.033
0.0632/0.1065
0.0910/0.1167
ꢀ0.04(12)
15 999/3799 (0.0317)
3083
1.121
0.0488/0.1235
0.0624/0.1317
—
P
P
a
b
R = ||Fo| ꢀ |Fc||/ Fo, w = 1/[s2(F2o) + (g1P)2 + g2P] where P = (F2o + 2Fc2)/3, S = S[w(Fo2 – Fc2)2/(Nobs ꢀ Nparam)]1/2
.
wR = [S(F2o ꢀ F2c)2/
S(F2o)2]1/2
.
Table 4 Comparison of the single-crystal measured bond lengths of
salts with the calculated distances in protonated 1–3.a The geometries
of the protonated species 1H+, 2H+ and 3H+ were optimized at the
B3LYP/6-31G(d) level of theory
d/A
Theory Measured Theory Measured Theory
1H+
2ꢁHClO4
2H+
3ꢁHClO4
3H+
Bond
N1–C2
N1–C6
C2–N3
N3–C4
C4–N9
C4–N5
N5–C6
C2–N7
C6–N8
1.401
1.402
1.317
1.349
1.336
1.349
1.317
1.343
1.343
1.397(5)
1.401(6)
1.304(5)
1.376(6)
1.318(5)
1.350(5)
1.307(5)
1.352(6)
1.333(5)
1.446(5)
1.437(5)
1.429(6)
1.401
1.401
1.311
1.357
1.340
1.357
1.311
1.347
1.347
1.448
1.432
1.432
1.393(2)
1.389(2)
1.320(3)
1.347(2)
1.336(2)
1.349(3)
1.322(2)
1.330(3)
1.333(3)
1.503(2)
1.478(3)
1.479(3)
1.400
1.401
1.317
1.354
1.341
1.355
1.316
1.340
1.344
1.505
1.483
1.484
Fig. 5 A supramolecular assembly in the structure of 1ꢁ0.5 MeOH
showing molecules interconnected by hydrogen bonds (blue and red
lines). Symmetry code * = 1 ꢀ x, ꢀy, ꢀz.
compounds considered, we measured the X-ray structure of
the monocrystals of the perchlorate salts of 2 and 3 (Fig. 6).
All attempts to prepare single crystals of the perchlorate salt
of 1 suitable for X-ray measurements were unsuccessful.
Therefore, in order to obtain insights into the structure of
protonated 1, its geometry was optimized using the B3LYP/
6-31G(d) method. The key structural parameters of the
calculated and experimentally determined structures of the
protonated species, 2ꢁHClO4 and 3ꢁHClO4, are listed in
Table 4, while the summary of all the calculated parameters
and relevant parameters for the neutral molecules is presented
in Tables S4–S6 in the ESI.w
N1–Ph (i-Pr) 1.449
N7–Ph (i-Pr) 1.432
N8–Ph (i-Pr) 1.432
a
For numbering of the atoms see Scheme 2 and Fig. 6.
Before analyzing the effect of protonation on 1–3 in detail,
we note that the trend of the changes in the calculated
structural parameters in 2H+ and 3H+ closely resembles those
found in the X-ray structures of their perchlorate salts. The
same holds for the comparison of the experimental and
calculated structures of 1 and 2 and their protonated forms
with those of the corresponding perchlorate salts. This, in
turn, lends credence to the structural parameters calculated for
the other species studied in this work.
The most striking feature of the experimental structures of
the protonated species concerns the elongation of the C2–N7
bond relative to that in the neutral molecule, confirming that
protonation occurs at the N7 atom. This results in a near
equalization of the exocyclic C2–N7 and C6–N8 bonds,
accompanied by changes in the bond lengths within the
triazine ring, which assumes a para quinonoid character with
Fig. 6 ORTEP drawings of (a) 2ꢁHClO4 and (b) 3ꢁHClO4. The
thermal ellipsoids are at the 30% probability level.
c
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Table 5 Results of basicity measurements in acetonitrile
and its conjugated acid,19 which are not present in dihydro-
triazines studied in this work. Replacement of the isopropyl
groups with the electron-withdrawing phenyl rings, leading to
2 and 1, leads to a decrease in basicity of 3.9 and 4.5 pKa units
(in acetonitrile), respectively. It is noteworthy that replace-
ment of the amino group with the dimethylamino moiety in 1
leading to 2 causes partial cancellation of the electron-
withdrawing effect of the phenyl rings, resulting in a slight
enhancement of basicity.
Compd.
(B)
pKa
Reference base (Rb) (Rb)
pKa Assigned pKa
a
DpKa (B)
b(B)
1
2-Cl–C6H4P1(pyrr) 20.17
2-Cl–C6H4P1(dma) 19.07
1.69 18.48 18.51
0.59 18.48
0.00 18.56
2,6-
18.56
Cl2–C6H3P1(pyrr)
PhP1(dma)2Me
2-Cl–C6H4P1(pyrr) 20.17
2
21.03
1.89 19.14 19.14
1.01 19.16
2-Cl–C6H4P1(dma) 19.07 ꢀ0.05 19.12
2-Cl–C6H4P2(dma) 24.23 1.23 23.00 23.02
PhP1(pyrr)
22.34 ꢀ0.72 23.06
Comparison of the measured acidity data (Table 6) with
those encompassed by the previously published acidity scale of
the neutral compounds indicates that the acidity of the
NH proton in 1–3 has been among the lowest measured in
acetonitrile so far. Thus, the acidity of 3 is ca. 2 pKa units
lower than that of 9-C6F5-fluorene (28.11), which has the
lowest acidity in the previously reported acidity scale20a and
thus 3 extends the previously established pKa scale of acidity in
acetonitrile. The acidity of the respective protons in 1 and 2 is
5.0 and 4.2 pKa units higher relative to 3. The observed
enhancement in acidity can be understood by comparing
the calculated charge density distribution in the molecules con-
sidered. Due to the delocalization of electronic density on the
deprotonation site into the neighboring phenyl ring in molecules
1 and 2, the loss of the proton from this site becomes easier and
the resulting anion more stabilized than in the case of 3, where
such delocalization is not possible (Tables S8–S10 in the ESIw).
3
a
b
pKa(Rb) ꢀ pKa(B). The standard uncertainties of the pKa values
relative to the acetonitrile pKa scale are estimated as 0.05 pKa units
(see ref. 20e).
the C2–N3 and N5–C6 bond lengths being close to typical
Csp2–Nsp2 bonds.
Basicity and acidity determination
The results of basicity and acidity measurements are presented
in Tables 5 and 6, respectively. Also included in Tables 5 and 6
are the reference bases and acids used in this work. The
basicity and acidity of a wide range of neutral heterocyclic
and acyclic nitrogen-containing compounds have been measured
previously in acetonitrile by several groups,19–21 resulting in
well-defined acidity scales covering 24 orders of acidity20a,b
and a base scale covering 28 orders of basicity,20c,d thus
facilitating comparison of the pKa values of the compounds
studied in this work with previously measured ones.
Comparison of the measured and calculated pKa values of bases
1–3 in acetonitrile
Due to the wide interest in the design of strong organic bases
in synthetic work, considerable efforts have been devoted in
the past to the development of practical theoretical methods
capable of predicting pKa values in organic solvents. The
a priori estimates of the pKa values from the first principles22
are, unfortunately, still not feasible in larger molecules of
practical interest. Therefore, it is necessary to resort to simpler
models of the polarized continuum (PCM)23 and its isodensity
(IPCM) variant form.24 We have recently demonstrated that
the latter approach in conjunction with the B3LYP/
6-311+G(d,p)//B3LYP/6-31G(d) method for a large number
of strong neutral nitrogen bases yields a fair correlation with
the experimental pKa values of a large number of nitrogen
bases.25
Analysis of the results for the basicity measurements of 1–3
(Table 5) reveals that the basicity of 3 is the highest among the
studied dihydrotriazines. Its pKa value lies between those for
the 2-Cl-C6H4P2(dma) and PhP1(pyrr) reference bases. In
relation to our current interest in the basicity of guanidine
compounds,19 which, similarly to the present compounds,
undergo protonation at the imino group, we note that this
pKa value is of the same order of magnitude as that of
tetramethylguanidine (23.3 pKa units)20f and 3.9 pKa units
smaller than the pKa value of N,N0,N0 0-tris(3-dimethylamino-
propyl)guanidine, which is the most basic acyclic guanidine
derivative studied so far.19 It should be, however, emphasized
that the high basicity of the latter compound is to a large
extent due to the presence of cooperative intramolecular
hydrogen bonds and their impact on the stabilities of the base
Having measured the pKa values of guanidines 1–3, we
decided to test the applicability of such correlations for
calculating the pKa values of these types of bases. For this
purpose, we used a slightly modified approach as employed
in ref. 25. Specifically, the IEF-PCM model was used for
calculating solvation energies instead of the IPCM method,
due to a problem in the convergence of the isodensity surfaces
for several structures. The same approach was subsequently
used to evaluate the effect of a series of selected substituents in
the para position of the phenyl rings, using molecule 2 as an
example. All the optimized geometries were verified to be
minima by vibrational analysis at the same level of theory.
The resulting internal coordinates of all the optimized species
are shown in Table S11 in the ESI.w The electronic energies
and Gibbs energy corrections were calculated by the B3LYP/
Table 6 Results of acidity measurements in acetonitrile
b
Compd.
(A)
pKa
pKa Assigned pKa
a
Reference acid (Ra)
(Ra) DpKa (A) (A)
1
2
(C6F5)(C6H5)CHCN
(C5F4N)(C6H5)NH
(C6F5)(C6H5)CHCN
(C5F4N)(C6H5)NH
26.14 0.31 25.83 25.83
26.34 0.51 25.83
26.14 ꢀ0.47 26.61 26.6
26.34 ꢀ0.32 26.66
(4-Me-C6F4)(C6F5)NH 24.94 ꢀ1.48 26.42
3
9-C6F5-Fluorene
2,3,4,5,6-(CF3)5-Toluene 28.7 ꢀ2.1 30.8
28.11 ꢀ2.7 30.8 30.8
a
b
pKa(Ra) ꢀ pKa(A). The standard uncertainties of the pKa values
relative to the acetonitrile pKa scale are estimated as 0.06 pKa units for
1 and 0.2 pKa units for 2 and 3 (see ref. 20e).
c
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New J. Chem., 2012, 36, 86–96 91

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6-311+G(d,p) and B3LYP/6-31G(d) methods, respectively.
Zero point vibrational energies were used unscaled. pKa values
for the examined dihydrotriazines were calculated using linear
eqn (1).26
Their use in further studies could lead to fine refinement of
the existing scales of basicity in the range of ca. 14 to 24 pKa
values.
pKa(calc) = 0.617 ꢂ GB0(B)AN ꢀ 155.585
(1)
Conclusions
where GB0 stands for the ‘‘reduced basicity’’ of the neutral
One-pot synthesis of hitherto unknown 1,2-dihydro-1,2,3-tria-
zine derivatives, starting from the corresponding guanidine
and carbodiimide derivatives and their characterization using
spectroscopic (IR, 1H and 13C solution-state and 13C and 15
base B in acetonitrile and is calculated according to eqn (2)
GB0(AN) = GB0(B)gas + DG(BH+)AN ꢀ DG(B)AN (2)
N
where DG(BH+)AN and DG(B)AN correspond to solvation
energies of the protonated and neutral bases, respectively.
The parameters for eqn (1) were evaluated from the linear
relationship calculated for the test set of the 57 different
nitrogen bases also used in our previous calculations, which
span a range of ca. 40 pKa units. The calculated GB0(B)AN and
pKa(calc) values of the compounds considered (as bases) are
summarized in Table 7.
solid-state NMR) methods, is described. The structures of two
of the prepared compounds and their perchlorate salts were
also confirmed by the X-ray diffraction method. This is, to the
best of our knowledge, the first report on the preparation and
structural determination of 1,2-dihydro-1,3,5-triazines possessing
exo-cyclic imino group at ring position 2, thus opening a new
avenue in exploring chemistry of this family of compounds. Due
to the presence of exo-cyclic imino- (N7) and amino-type (N8)
nitrogen atoms, the parent compounds were assumed to possess
the ability either to donate or accept a proton, i.e., to act as either
an acid or a base. This was confirmed by measuring basicity and
acidity in acetonitrile and quantum chemical calculations. The
most basic species was found to be compound 3, the basicity of
which was of the same order of magnitude as that of tetra-
methylguanidine. Acidity measurements revealed that all the
compounds studied behave like very weak acids, having pKa
values in the range of 25.8–30.8 pKa units in acetonitrile.
Finally, the pKa values were also calculated by the IEF-
PCM model employing the B3LYP/6-311+G(d,p)/B3LYP/
6-31G(d) method and were found to be in excellent agreement
with the measured values, confirming high predictive power of
the theoretical approach used. The same method was used to
calculate the effect of a series of substituents in the para
positions of the aromatic rings in 2, suggesting that in this
way a fine-tuning of the basicity of the examined compound in
the range of ca. 10 pKa units could be attained. It is quite
plausible that all of these species can be easily prepared and
their use in further basicity measurements could have significant
impact on fine refinement of the existing scales of basicity in the
range of ca. 14 to 24 pKa values, and could presumably lead to
new types of strongly basic organocatalysts.
Before considering the effect of substituents on the basicity
of compound 2, we note that the calculated pKa values for
bases 1–3 are in excellent agreement with the experimentally
measured values. Analysis of the data calculated for
compound 2 substituted in the para position of the phenyl
rings shows the strong impact of the electronic properties of
the substituents on basicity. As expected, the effect of strong
electron-donating dimethylamino groups is the most
profound, causing an increase in basicity by ca. 5 pKa units.
It is interesting to note that the effect of the dimethylamino
group is additive; the largest contribution arises from the
dimethylamino group at the phenyl ring attached to the N7
(2.12 pKa units), at which protonation takes place. This is
followed by the contribution of the dimethylamino group at
the N1 (1.73 pKa units) and N8 (0.94 pKa units) (Table 7).
A somewhat weaker effect is observed for the amino substituted
species, while methoxy and methyl groups increase basicity only
moderately. On the other hand, substitution by the electron-
accepting groups lowers basicity, with the largest effect encoun-
tered for the nitro-substituted species. To summarize, the
chosen set of substituents facilitates fine-tuning of the basicity
of the examined compound in the range of ca. 10 pKa units. It is
quite plausible that all of these species can be easily prepared.
Table 7 Solvation-free energies, proton affinities and calculated and experimental pKa values of the bases 1–3 in acetonitrile (AN)a
DG(X)AN/kcal molꢀ1
GB(B)gas
(kcal molꢀ1
GB0(B)gas
GB0(B)AN/kcal molꢀ1
pKa(calc)
pKa (exp)
D(pKa)
)
X = B
X = BH+
Molecule
1
2
3
247.35
249.49
250.42
226.77
230.09
242.59
243.97
253.53
255.71
260.28
264.77
255.46
259.37
253.63
255.77
256.70
233.05
236.37
248.87
250.25
259.81
261.99
266.56
271.05
261.74
265.65
3.80
9.30
14.66
ꢀ0.26
1.10
10.82
10.41
13.42
8.67
ꢀ25.18
ꢀ18.36
ꢀ18.50
ꢀ42.10
ꢀ39.37
ꢀ22.57
ꢀ22.53
ꢀ12.68
ꢀ16.43
ꢀ22.49
ꢀ6.46
282.61
283.43
289.86
274.89
276.84
282.26
283.19
285.91
287.09
289.32
291.19
286.86
288.39
18.78
19.29
23.26
14.02
15.23
18.57
19.14
20.82
21.55
22.93
24.08
21.41
22.35
18.51
19.14
23.02
ꢀ0.27
ꢀ0.15
ꢀ0.24
2-NO2
2-CN
2-Cl
2-F
2-Me
2-OMe
2-NH2
2-NMe2
2-N7PhNMe2
2-N7,N8PhNMe2
0.27
13.68
10.60
11.92
ꢀ14.52
ꢀ10.82
a
For numeration of atoms see Scheme 2.
c
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92 New J. Chem., 2012, 36, 86–96

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in dry dichloromethane (10 cm3) at room temperature for
2 hours. The resulting black reaction mixture was filtered off
over a sintered funnel and the precipitate was rinsed with
dichloromethane (10 cm3). Evaporation of the filtrate afforded
a pale yellowish oily product which was identified as N,N0-
diphenylcarbodiimide (6) (0.32 g, 95%). The product was used
without further purification.
Experimental section
Materials and methods
All reagents and solvents were purchased from commercial
sources and were further purified by the standard methods, if
necessary. 1H and 13C NMR spectra were recorded on Brucker
Avance (300 and 600 MHz) spectrometers with tetramethylsilane
as an internal standard, while IR spectra were obtained on an
ABB Bomem MB102 spectrophotometer (CsI optics, DTGS
detector, KBr pellets technique).
4-Amino-6-phenylamino-2-phenylimino-1-phenyl-1,2-dihydro-
1,3,5-triazine (1)
Guanidine to N,N0-diphenylcarbodiimide molar ratio = 1 : 2.
To a solution of N,N0-diphenylcarbodiimide (6), (0.98 g,
5.0 mmol, prepared as previously described) in dry THF
(10 cm3) guanidine (4) (0.15 g, 2.5 mmol) was added and the
reaction mixture was heated under reflux for 24 hours. The
pale yellowish crude mixture remaining upon the removal
of the solvent was suspended in acetonitrile (10 cm3), the
precipitated white solid was filtered off, washed with cold
acetonitrile (5 cm3) and dried in air (0.45 g, 51%). Evaporation
of the filtrate yielded a yellow residue, which was suspended in
3.0 cm3 of acetonitrile. The crystals that precipitated were
separated by filtration and washed with 2.0 cm3 of cold
acetonitrile, affording 0.53 g (60%) of product 1 in total.
NMR spectra of solid samples were recorded on a Varian
NMR System 600 MHz NMR spectrometer equipped with a
3.2 mm NB Double Resonance HX MAS Solids Probe. The
Larmor frequencies of protons, carbon and nitrogen nuclei
were 599.77 MHz, 150.83 MHz and 60.78 MHz, respectively.
1
The H MAS NMR spectra were externally referenced using
adamantane. The 13C CP-MAS NMR spectra were externally
referenced using hexamethylbenzene (HMB). The 15N CP-MAS
NMR spectra were externally referenced using ammonium
sulfate (d ꢀ355.7 ppm regarding nitromethane at d 0.0 ppm).
Samples were spun at the magic angle at 20 kHz during
1H measurement and 10 kHz during 13C and 15N measurements.
The 1H spectra were acquired using an echo pulse sequence. The
repetition delay was 5 s and the number of scans was 16. The
pulse sequences used for acquiring the 13C and 15N spectra
were standard cross-polarization MAS pulse sequences with
high-power proton decoupling during acquisition. The repetition
delay was 5 s. The numbers of scans were between 600 and 2200
for the 13C measurements and 22 000 and 27 000 for 15N
measurements.
Guanidine to N,N0-diphenylcarbodiimide molar ratio = 1 : 3.
To a solution of N,N0-diphenylcarbodiimide (6), (0.314 g,
1.6 mmol, prepared as previously described) in dry THF
(3 cm3) guanidine (4) (0.031 g, 0.53 mmol) was added and
the mixture was refluxed for 24 hours. The crude reaction
mixture remaining upon the removal of the solvent was first
suspended in diethylether (5 cm3), the precipitated white solid
was filtered off and then again suspended in acetonitrile
(2 cm3), followed by filtration and additional washing with
acetonitrile (2 cm3). The solid was dried in air to afford pure
dihydrotriazine 1 (0.184 g, 98%).
HPLC analyses were performed on a Varian ProStar
Instrument supplied with a UV/Vis detector using a Restek
UltraIBD C18 (reversed phase) 5 mm 250 ꢂ 4.6 mm column
operated at room temperature with a flow rate of 1 mL minꢀ1
;
gradient of 2% acetic acid (solvent A) and methanol (solvent
B): 95% A + 5% B, 0–5 min; 85% A + 15% B, 5–45 min,
35% A + 65% B, 45–55 min, 5% A + 95% B, 55 min.
Melting points were determined on a Kofler hot-stage apparatus
and are uncorrected. Elemental analyses were performed on a
Perkin Elmer 2400 Series II CHNS/O Analyzer.
Evaporation of the filtrate afforded a pale yellowish residue
as a mixture of N,N0-diphenylbiguanide (B8%) and N,N0,
N0 0-triphenylguanidine (8) (B92%, by HPLC). An analytically
pure sample of guanidine by-product 8 was obtained by the
recrystallisation of the residue from ethanol.
A single crystal suitable for X-ray crystallographic measurement
was obtained by dissolving a sample of 1 (0.10 g) in an
ethanol–methanol 2 : 1 mixture (15 cm3). After 4 days of slow
evaporation, the product was crystallized in the form of colorless
prisms (65 mg, 65%).
mp 277–278 1C (from EtOH–MeOH 2 : 1 mixture) (lit.,1
270–271 1C). Found: C, 70.0%; H, 5.4%; N, 23.0% C21H18N6ꢁ
0.5CH3OH requires C, 69.7%; H, 5.45%; N, 22.7%. umax/cmꢀ1
3393, 3154, 1637, 1588, 1534, 1463, 1362, 1295, 1143, 772, 743,
700. dH(600 MHz; d6-DMSO; Me4Si) 6.40–7.40 (12 H, m,
overlapped Ph and NH2 protons), 7.44–7.46 (3 H, m, Ph),
7.52–7.55 (2 H, m, Ph), 7.61 (1 H, s, NH). dC(150 MHz,
d6-DMSO; Me4Si) 119.5–121, 123–125 (br), 127.9, 128.4,
129.62, 129.64, 136.5, 162.4. HRMS-MALDI found: 355.1683;
calc. for C21H19N6 (MH+): 355.1666.
Synthesis
N,N-Dimethylguanidine (5). To a freshly prepared solution
of sodium methoxide in methanol (0.46 g, 0.02 mol Na in
10 cm3 of dry methanol), N,N-dimethylguanidinium sulfate
(2.72 g, 0.01 mol) was added under an argon atmosphere and
stirred first at ambient temperature for 60 minutes and then at
50 1C for another 30 minutes. The solvent was then evaporated
under vacuum, the residue treated with dry dichloromethane
and filtered off over a sinter funnel. Evaporation of the
remaining filtrate afforded neutral N,N-dimethylguanidine
(5) as a white solid (1.60 g, 92%).
u
Me4Si) 2.74 (6 H, s, CH3), 4.30–4.70 (3 H, br s, NH).
max/cmꢀ1 3352, 1638, 1430, 1070. dH(600 MHz; d6-DMSO;
dC(150 MHz, d6-DMSO; Me4Si) 37.5, 160.0.
4-Dimethylamino-6-phenylamino-2-phenylimino-1-phenyl-1,2-
dihydro-1,3,5-triazine (2)
N,N-Dimethylguanidine to N,N0-diphenylcarbodiimide molar
ratio = 1 : 2. To a solution of N,N0-diphenylcarbodiimide (6),
N,N0-Diphenylcarbodiimide (6). N,N0-Diphenylthiourea
(0.39 g, 1.7 mmol), yellow mercury oxide (0.37 g, 1.7 mmol)
and anhydrous sodium sulfate (0.24 g, 1.7 mmol) were stirred
c
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New J. Chem., 2012, 36, 86–96 93

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(1.01 g, 5.2 mmol) in dry THF (10 cm3) N,N-dimethylguanidine
(5) (0.22 g, 2.5 mmol, prepared as previously described) was
added and the reaction mixture was heated under reflux for
24 hours. The mixture of yellow oil and solid remaining upon
removal of the solvent was removed and the residue suspended
in diethylether (5 cm3). The precipitated white solid was filtered
off and washed with ether (0.44 g, 46%). Evaporation of the
filtrate produced yellow oil, which solidified upon standing at
room temperature (0.83 g, contains approximately 12% of the
product according to HPLC analysis). Subsequent crystal-
lization from the mother liquor afforded an additional 0.05 g
of product 2, thus increasing the yield to 51%.
1319, 1253, 750, 734, 692. dH(600 MHz; d6-DMSO; Me4Si)
6.71–6.82 (5 H, m, Ph), 6.97–7.30 (10 H, m, Ph), 8.23 (2 H, s,
NH). dC(150 MHz, d6-DMSO; Me4Si) 118.2 (br), 120.7, 121.7
(br), 128.4, 141.6 (br), 144.9.
4-Dimethylamino-6-isopropylamino-2-isopropylimino-1-isopropyl-
1,2-dihydro-1,3,5-triazine (3). A solution of N,N-dimethylguanidine
(5) (0.87 g, 0.01 mol) and N,N0-diisopropyl-carbodiimide (7)
(3.15 cm3, 0.02 mol) in dry THF (50 cm3) was heated under
reflux for 24 hours. The solvent was evaporated and the pale
yellowish residue subjected to high vacuum distillation. The
unreacted carbodiimide 2 was removed at room temperature
and pressure of 2 ꢂ 10ꢀ4 mbar, while the main product was
distilled at the same pressure and 130 1C as viscid colorless oil,
which solidified upon cooling in a refrigerator (2.23 g, 80%).
mp 42–43 1C. umax/cmꢀ1 3301, 3214, 2969, 2931, 2874, 1602,
1565, 1547, 1491, 1410, 1168, 778. dH(600 MHz; d6-DMSO;
Me4Si) 0.96 (6 H, d, J 6.3, (CH3)2CH), 1.17 (6 H, d, J 6.6,
(CH3)2CH), 1.41 (6 H, d, J 6.8, (CH3)2CH), 2.96 (6 H, s, CH3),
3.96–4.03 (1 H, m, (CH3)2CH), 4.16–4.24 (1 H, m, (CH3)2CH),
4.68–4.76 (1 H, m, (CH3)2CH), 6.15 (1 H, d, J 7.2, NH).
dC (150 MHz, d6-DMSO; Me4Si) 19.4, 22.1, 24.5, 35.5, 42.8,
45.0, 45.3, 148.2, 155.1, 159.2. HRMS-MALDI found:
281.2437; calc. for C14H29N6 (MH+): 281.2448.
N,N-Dimethylguanidine to N,N0-diphenylcarbodiimide molar
ratio = 1 : 3. To a solution of N,N0-diphenylcarbodiimide (6),
(0.314 g, 1.6 mmol, prepared as previously described) in dry
THF (3 cm3) N,N-dimethylguanidine (5) (0.047 g, 0.53 mmol)
was added and the mixture was refluxed for 24 hours. The
crude reaction mixture remaining upon the removal of the
solvent was suspended in diethylether (4 cm3), the precipitated
white solid was filtered off and dried in air to afford pure
dihydrotriazine 2 (0.193 g, 94%).
Evaporation of the filtrate yielded a pale yellowish residue
of N,N0,N00-triphenylguanidine (8) (495% by HPLC analysis,
crude product yield 97%).
A single crystal suitable for X-ray crystallographic studies
was obtained by dissolving a sample of 2 (0.10 g) in methanol
(8.0 cm3). The product crystallized in the form of pale yellowish
prisms (66 mg, 66%).
4-Dimethylamino-2,6-bis(isopropylamino)-1-isopropyl-1,3,5-
triazinium perchlorate (3ꢁHClO4). A sample of 3 (0.52 g,
1.85 mmol) was dissolved in a mixture of methanol (6 cm3)
and 1 mol dmꢀ3 perchloric acid (1.85 cm3, 1.85 mmol). The
solution was left overnight at room temperature, the colorless
crystals of the triazine perchlorate salt 3ꢁHClO4 were filtered
off and dried in air (0.48 g, 68%).
mp 197–198 1C (from MeOH). Found: C, 71.4%; H, 5.7%;
N, 21.9% C23H22N6 requires C, 72.2%; H, 5.8%; N, 22.0%.
u
max/cmꢀ1 3390, 2923, 2853, 1629, 1611, 1584, 1534, 1487,
1467, 1401, 1218, 765, 694. dH(600 MHz; d6-DMSO; Me4Si)
2.97 (6 H, s, CH3), 6.60–7.60 (15 H, m, overlapped Ph
protons), 7.75 (1 H, s, NH). dC(150 MHz, d6-DMSO; Me4Si)
35.7, 120, 123, 124, 127.7, 128.5, 129.58, 129.63, 136.3, 137,
150, 151, 155, 160.0. HRMS-MALDI found: 383.1971; calc.
for C23H23N6 (MH+): 383.1979.
mp 178–179 1C (from MeOH). Found: C, 44.15%; H,
7.25%; N, 21.4% C14H29N6O4Cl requires C, 44.15%; H,
7.7%; N, 22.05%. umax/cmꢀ1 3215, 2969, 1607, 1559, 1453,
1411, 1166, 1140, 1118, 1087, 778, 627. dH(300 MHz;
d6-DMSO; Me4Si) 1.24 (12 H, d, J 6.6, (CH3)2CH), 1.49
(6 H, d, J 7.0, (CH3)2CH), 3.12 (6 H, s, CH3), 4.27–4.40
(2 H, m, (CH3)2CH), 4.51–4.64 (1 H, m, (CH3)2CH), 7.13
(2 H, d, J 7.5, NH). dC(75 MHz, d6-DMSO; Me4Si) 19.1, 21.3,
36.1, 44.7, 48.7, 153.5, 159.3.
4-Dimethylamino-6-phenylamino-2-phenylimino-1-phenyl-1,2-
dihydro-1,3,5-triazinium perchlorate ((2ꢁHClO4). A sample of
2 (0.10 g, 0.26 mmol) was dissolved in methanol (5 cm3),
followed by the addition of 1 mol dmꢀ3 perchloric acid
(261 mL, 0.26 mmol). The mixture was evaporated and the
remaining solid was suspended in water (2.5 cm3). The suspension
was gently heated and ethanol was added until the solution
became clear. The solution was left overnight at room temperature
and the precipitated colorless needle-like crystals of the triazine
perchlorate salt 2ꢁHClO4 were filtered off and dried in air
(0.09 g, 74%).
mp 203–205 1C (from H2O–EtOH mixture). umax/cmꢀ1
3402, 3063, 2930, 1657, 1622, 1589, 1543, 1462, 1411, 1225,
1120, 1095, 764, 745, 722, 692, 623, 561. dH(600 MHz;
d6-DMSO; Me4Si) 3.01 (6 H, s, CH3), 7.22–7.27 (2 H, m, Ph),
7.32–7.41 (8 H, m, Ph), 7.70–7.84 (5 H, m, Ph), 8.81 (2 H, s,
NH). dC(150 MHz, d6-DMSO; Me4Si) 36.1, 125.7, 126.1, 128.1,
129.4, 130.8, 131.62, 131.64, 136.3, 154.1, 159.9.
X-Ray structure determination
Crystallographic data were collected on an Oxford Diffraction
Xcalibur CCD diffractometer with graphite-monochromated
Mo Ka radiation at low temperature (Table 3) and room
temperature (only for 2, Table S7 in ESIw). The programs
CrysAlis CCD and CrysAlis RED27 were used for data
collection, cell refinement and data reduction. The structure
was solved by direct methods. A refinement procedure by
full-matrix least squares methods based on F2 values against
all reflections included anisotropic displacement parameters
for all non-H atoms. The positions of hydrogen atoms were
geometrically optimized applying the riding model except in 1ꢁ
0.5 MeOH where they were found in the difference Fourier
map and isotropically refined (only those on MeOH were
geometrically optimized). Calculations were performed with
SHELXS9728 and SHELXL9729 (both operating under the
WinGX30 program package). The molecular graphics were
N,N0,N00-Triphenylguanidine (8). mp 150–151 1C (from
EtOH). umax/cmꢀ1 3384, 3015, 1630, 1581, 1542, 1494, 1436,
c
94 New J. Chem., 2012, 36, 86–96
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View Article Online
done with PLATON9831 and Mercury.32 Supplementary
crystallographic data sets for the structures 1ꢁ0.5 MeOH, 2
(at low and room temperature), 2ꢁHClO4 and 3ꢁHClO4 are
available through CCDC 830994–830998.
the zero-point vibrational energy contributions to the proton
affinity, respectively. Here, B and BH+ denote the base
in question and its conjugate acid, respectively. Solvation
energies were calculated at the IEF-PCM/HF/6-31G(d) level
of theory using radii optimized for COSMO-RS35 for cavity
construction. All the calculations were performed using the
Gaussian 03 program package with default parameters.
pKa determination
The UV-Vis spectrophotometric titration method used in this
work was described in detail in ref. 20a, c, and d. For each
investigated compound, the relative acidity and basicity were
measured against at least two (mostly three) different reference
compounds with known pKa values in AN.20a,b,d To determine
the relative acidity of two compounds, a mixture of two
different acids was titrated with UV-Vis radiation non-absorbing
acidic and basic titrants to obtain several spectra of solutions
containing both neutral and anionic forms of the two acids in
different proportions. Both of the acids were also titrated
separately to obtain the spectra of the neutral and anionic forms
of the pure compounds. The relative basicities were determined
in a similar way, although in this case the solutions contained
neutral and cationic forms. From the titration data, the relative
acidity of the acids or the relative acidity of the conjugate acids
of the bases—the difference between the pKa values (DpKa
values)—was calculated (see ref. 20a, c, d). During titrations,
the protonation–deprotonation processes were reversible with
all the compounds and sharp isosbestic points (at which the
absorption of neutral and ionic forms are the same) were
obtained. All the compounds investigated in this work have
significantly different spectra of protonated and deprotonated
forms in the UV region (major changes between 250–300 nm
for 1 and 250–350 nm for 2 and 3) and calculation methods
using only spectral data obtained from the titration of pure
compounds and mixture were used to obtain DpKa values.
From the DpKa values of measurements carried out in this
work and from the absolute pKa values assigned to the
reference compounds in previous works,20a,b,d the absolute
pKa values of the investigated compounds were obtained as
the average of absolute values. From each titration experiment
of the mixture of two compounds, the DpKa value was
determined as the mean of 10–20 values. Concentrations of
the measured compounds were mostly in the order of nꢁ10ꢀ5 M
and never exceeded 2 ꢂ 10ꢀ4 M, while concentrations of acidic
and basic titrants were in the 3 ꢂ 10ꢀ3 M range.
Acknowledgements
Financial support of this work by the Ministry of Science,
Education and Sports of Croatia (Project No. 098-0982933-
2920 (M.E.-M.) and 119-119079-1084 (D.M.-C.) is acknowledged.
The work of I. L. and J. S. was supported by Grant No. 7374 from
the Estonian Science Foundation. We also thank Dr Z. Glasovac
for assistance in calculations of basicities and Dr Mario Cindric
´
(Center for Proteomics and Mass Spectrometry, Rudjer Boskovic
´
Institute) for HRMS analyses.
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