Superbasicity of a bis-guanidino compound with a flexible linker: A theoretical and experimental study

Article abstract of DOI:10.1021/ja906618g

The bis-guanidino compound H₂C{hpp}₂ (I; hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) has been converted to the monocation [I-H]⁺ and isolated as the chloride and tetraphenylborate salts. Solution-state spect

Full text of DOI:10.1021/ja906618g

Published on Web 10/29/2009
Superbasicity of a Bis-guanidino Compound with a Flexible
Linker: A Theoretical and Experimental Study
Martyn P. Coles,*,† Pedro J. Arago´n-Sa´ez,† Sarah H. Oakley,† Peter B. Hitchcock,†
Matthew G. Davidson,‡ Zvonimir B. Maksic´,§ Robert Vianello,§ Ivo Leito,|
Ivari Kaljurand,| and David C. Apperley⊥
Department of Chemistry, UniVersity of Sussex, Falmer, Brighton BN1 9QJ, U.K., Department of
Chemistry, UniVersity of Bath, Bath BA2 7AY, U.K., Quantum Organic Chemistry Group,
DiVision of Organic Chemistry and Biochemistry, Rudjer BosˇkoVic´ Institute, P.O. Box 180,
HR-10 002 Zagreb, Croatia, Institute of Chemistry, UniVersity of Tartu, RaVila 14a,
50411 Tartu, Estonia, and Department of Chemistry, UniVersity Science Laboratories, UniVersity
of Durham, South Road, Durham DH1 3LE, U.K.
Received August 5, 2009; E-mail: m.p.coles@sussex.ac.uk
Abstract: The bis-guanidino compound H2C{hpp}2 (I; hppH ) 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-
a]pyrimidine) has been converted to the monocation [I-H]+ and isolated as the chloride and tetraphenylborate
salts. Solution-state spectroscopic data do not differentiate the protonated guanidinium from the neutral
guanidino group but suggest intramolecular “sNsH· · ·Nd” hydrogen bonding to form an eight-membered
C3N4H heterocycle. Solid-state CPMAS 15N NMR spectroscopy confirms protonation at one of the imine
nitrogens, although line broadening is consistent with solid-state proton transfer between guanidine
functionalities. X-ray diffraction data have been recorded over the temperature range 50-273 K. Examination
of the carbon-nitrogen bond lengths suggests a degree of “partial protonation” of the neutral guanidino
group at higher temperatures, with greater localization of the proton at one nitrogen position as the
temperature is lowered. Difference electron density maps generated from high-resolution X-ray diffraction
studies at 110 K give the first direct experimental evidence for proton transfer in a poly(guanidino) system.
Computational analysis of I and its conjugate acid [I-H]+ indicate strong cationic resonance stabilization of
the guanidinium group, with the nonprotonated group also stabilized, albeit to a lesser extent. The maximum
barrier to proton transfer calculated using the Boese-Martin for kinetics method was 2.8 kcal mol-1, with
hydrogen-bond compression evident in the transition state; addition of zero-point vibrational energy values
leads to the conclusion that the proton transfer is barrierless, implying that the proton shuttles freely between
the two nitrogen atoms. Calculations determining the gas-phase proton affinity and the pKa in acetonitrile
both indicate that compound I should behave as a superbase. This has been confirmed by spectropho-
tometric titrations in MeCN using polyphosphazene references, which give an average pKa of 28.98 (
0.05. Triadic analysis indicates that the dominant term causing the high basicity is the relaxation energy.
Introduction
functionality in a single molecular species, with a corresponding
increase in the sites at which cationic resonance can occur
(provided a suitable pathway is available for charge transfer
between units).
A series of bis-guanidino compounds is illustrated in Figure
1, including examples of both isolated (b, TMGB;4 c, TMGN;5
d, TMGBP;6 and e, DMEGN7) and theoretical (f, TMGF;8 and
g, TMGBH9) molecules. Detailed structural, spectroscopic, and
Substituted guanidines in which one or more groups replace
the hydrogens of HNdC(NH2)2 retain the strongly basic
characteristics of the parent compound and function through
protonation of the imine nitrogen to form the corresponding
guanidinium cation. The strength of the basicity is governed
by a number of factors that correlate to the ease with which the
resultant positive charge is delocalized throughout the “CN3”
core of the molecule.1 A simple strategy to generate “super-
bases” (defined as a compound with a pKa greater than that of
the proton sponge, DMAN (a),2 which has a pKa of 18.62 in
acetonitrile3) is the incorporation of more than one guanidino
(3) Kaljurand, I.; Ku¨tt, A.; Soova¨li, L.; Rodima, T.; Ma¨emets, V.; Leito,
I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019–1028.
(4) (a) Kawahata, M.; Yamaguchi, K.; Ito, T.; Ishikawa, T. Acta
Crystallogr. E 2006, 62, o3301–o3302. (b) Peters, A.; Wild, U.;
Hu¨bner, O.; Kaifer, E.; Himmel, H.-J. Chem.sEur. J. 2008, 14, 7813–
7821.
† University of Sussex.
‡ University of Bath.
(5) Raab, V.; Kipke, J.; Gschwind, R. M.; Sundermeyer, J. Chem.sEur.
J. 2002, 8, 1682–1693.
§ Rudjer Bosˇkovic´ Institute.
| University of Tartu.
(6) Pruszynski, P.; Leffek, K. T.; Borecka, B.; Cameron, T. S. Acta
Crystallogr. C 1992, 48, 1638–1641.
⊥ University of Durham.
(1) Maksic´, Z. B.; Kovacˇevic´, B. J. Org. Chem. 2000, 65, 3303–3309.
(2) Alder, R. W.; Bowman, P. S.; Steele, W. R. S.; Winterman, D. R.
Chem. Commun. (London) 1968, 723–724.
(7) Raab, V.; Harms, K.; Sundermeyer, J.; Kovacˇevic´, B.; Maksic´, Z. B.
J. Org. Chem. 2003, 68, 8790–8797.
(8) Kovacˇevic´, B.; Maksic´, Z. B. Chem.sEur. J. 2002, 8, 1694–1702.
9
16858 J. AM. CHEM. SOC. 2009, 131, 16858–16868
10.1021/ja906618g CCC: $40.75  2009 American Chemical Society

A Conformationally Flexible Superbase
A R T I C L E S
Figure 1. Superbases incorporating amine, amidine, and guanidine groups that have been previously studied (* denotes theoretical molecule only): 1,8-
bis(dimethylamino)naphthalene (a, DMAN), 1,2-bis(tetramethylguanidino)benzene (b, TMGB), 1,8-bis(tetramethylguanidino)naphthalene (c, TMGN), 2,2′-
bis(tetramethylguanidino)biphenyl (d, TMGBP), 1,8-bis(dimethylethyleneguanidino)naphthalene (e, DMEGN), 4,5-bis(tetramethylguanidino)fluorene (f, TMGF),
5,6-dimethyl-5,6-bis(tetramethylguanidino)bicyclo[2.1.1]hexane (g, TMGBH), 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (h, hppH), and pentacyclic
“proton sponge” with vinamidine structure (i).
theoretical data have been presented,10 leading to the conclusion
Scheme 1. Nucleophilic Activity of H2C{hpp}2 (I)
that these molecules do indeed behave as superbases. Similar
compounds were reported by Schwesinger, who employed
vinamidine residues consisting of tricyclic11 and pentacyclic (i)12
poly(amidino) compounds.
The tetrasubstituted, bicyclic guanidine hppH (h)13 represents
the most widely used member of a family of bicyclic
guanidines,14 in which the framework of the guanidine is
constrained such that, upon protonation, a favorable orbital
alignment for delocalization of π-electron density is present.
The interest for some of us in this molecule originated from its
the carbon-bridged variant I provided a stable framework for
further studies.
We have also noted that the reactivity of H2C{hpp}2 differs
application as a neutral ligand in coordination chemistry,15 where
it was noted that metal-ligand interactions predominantly
occurred through the Nimine. Extension to bidentate ligand
significantly from that of the parent guanidine. For example,
nucleophilic behavior with organic18 and inorganic19 substrates
systems that preserved the imino functionality was achieved in
the examples H2C{hpp}2 (I)16 and Me2Si{hpp}2.17 NMR studies
affords the eight-membered, dicationic heterocycles [H2C{hpp}2-
X]2+ (X ) CH2 and PPh, Scheme 1). We have also investigated
showed the silyl-bridged system was fluxional in solution while
the ability of I to act as a ligand for cationic metals, illustrated
(9) Singh, A.; Ganguly, B. New J. Chem. 2008, 32, 210–213.
(10) Ishikawa, T. Guanidines in Organic Synthesis. In Superbases for
Organic Synthesis; Ishikawa, T., Ed.; Wiley-Blackwell: New York,
2009; pp 93-136.
by the stable aluminum cation [AlMe2(H2C{hpp}2)][BPh4],
accessed via a guanidinium salt containing monocation [I-H]+.20
In this paper we present a detailed structural analysis of [I-H]+
in the solution and solid phases. These data are used in
conjunction with computational studies to examine the basicity
of H2C{hpp}2, the results of which are verified by experimental
measurements. Anticipating forthcoming results, we should
emphasize that the dominating structural and electronic pattern
(11) Schwesinger, R. Angew. Chem., Int. Ed. Engl. 1987, 26, 1164–1165.
(12) Schwesinger, R.; Missfeldt, M.; Peters, K.; von Schnering, H. G.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1165–1167.
(13) hppH is also referred to as 1,5,7-triazabicyclo[4.4.0]dec-5-ene, ab-
breviated to TBD. See ref 14 for a recent discussion of the
nomenclature of bicyclic guanidines.
(14) Coles, M. P. Chem. Commun. 2009, 3659–3676.
(15) (a) Coles, M. P. Dalton Trans. 2006, 985–1001. (b) Oakley, S. H.;
Soria, D. B.; Coles, M. P.; Hitchcock, P. B. Polyhedron 2006, 25,
1247–1255. (c) Oakley, S. H.; Soria, D. B.; Coles, M. P.; Hitchcock,
P. B. Dalton Trans. 2004, 537–546. (d) Oakley, S. H.; Coles, M. P.;
Hitchcock, P. B. Inorg. Chem. 2003, 42, 3154–3156. (e) Coles, M. P.;
Hitchcock, P. B. Polyhedron 2001, 20, 3027–3032.
(17) Oakley, S. H.; Coles, M. P.; Hitchcock, P. B. Dalton Trans. 2004,
1113–1114.
(18) Coles, M. P.; Lee, S. F.; Oakley, S. H.; Estiu, G.; Hitchcock, P. B.
Org. Biomol. Chem. 2007, 5, 3909–3911.
(19) Coles, M. P.; Hitchcock, P. B. Chem. Commun. 2007, 5229–5231.
(20) Arago´n-Sa´ez, P. J.; Oakley, S. H.; Coles, M. P.; Hitchcock, P. B. Chem.
Commun. 2007, 816–818.
(16) Oakley, S. H.; Coles, M. P.; Hitchcock, P. B. Inorg. Chem. 2004, 43,
7564–7566.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16859

A R T I C L E S
Coles et al.
Scheme 2. Synthesis of Cationic Guanidinium Salts Examined in
This Study: (a) HNEt3Cl, CH2Cl2; (b) NaBPh4, H2O
found in the protonated form of I is a cyclic, H-bond moiety
used as a motif in designing organic superbases by a number
of researchers.21
Monoprotonated Poly(guanidinium) Salts:
[I-H]+[Anion]-
Synthesis and Spectroscopic Properties. Protonation of
H2C{hpp}2 (I) using triethylamine hydrochloride in CH2Cl2
afforded the guanidinium salt, [H2C{hpp}{hpp-H}][Cl] ([I-
H][Cl], 1a), which was isolated as a hygroscopic white powder
Figure 2. Possible solution-state structures for the monocation [I-H]+.
1
(Scheme 2). The H NMR spectrum in acetonitrile showed a
clearly defined broad singlet at δ 13.25 ppm, attributed to the
NH proton. Previous work has denoted far downfield chemical
shifts (δ g 15 ppm) as indicative of the presence of strong
hydrogen bonding, with for example hydrogen-bound imino
protons in duplex and quadruplex DNA structures typically in
the range δ 10-14 ppm.22 The bridging methylene resonance
is a sharp singlet at δ 4.77 ppm, and six multiplets are observed
for the annular methylene groups, consistent with equivalent
guanidino units. These data are inconsistent with a structure in
which protonation has occurred exclusively at one nitrogen (A,
Figure 2) and are in agreement with either a symmetric cation
in which each ring is equally involved in hydrogen-bonding
(B) or a fluxional system in which proton transfer between the
protonated NH and the remaining Nimine occurs rapidly on the
NMR time scale (C/D).
To improve the solubility of [I-H]+, anion metathesis was
performed with NaBPh4 to afford the tetraphenylborate salt,
Figure 3. CPMAS 15N NMR spectrum for [H2C{hpp}{hppH}][BPh4] (1b).
Inset: Results from a dipolar dephasing experiment, showing suppression
of the peak at δ -279.8 ppm.
[I-H][BPh4] (1b).20 The room-temperature H NMR spectrum
1
is similar to that of 1a, with a low-field resonance for the NH
proton (δ 13.51 ppm), a sharp singlet for the bridging methylene
group, and six hpp-methylene environments. The increased
solubility of 1b enabled low-temperature 13C NMR spectra to
be acquired on the [I-H]+ cation. The lack of line broadening
at 223 K provided further evidence for equivalence of the two
guanidino groups in solution.
that the two rings are inequivalent (Figure 3). The four narrow
lines have a full width at half-height (fwhh) of ∼14 Hz and are
assigned to the four tertiary nitrogen atoms. The remaining two
signals at δ -254 and -280 ppm are broader (fwhh ) 66 and
83 Hz, respectively), which suggests that each atom experiences
1
Solid-State Structure of [H2C{hpp}{hppH}]+ ([I-H]+). To
determine the structure of cation [I-H]+ in the solid state,
tetraphenylborate salt 1b was investigated by solid-state NMR
spectroscopy and X-ray crystallography. The CPMAS 13C NMR
experiment was not particularly informative, as the carbon atoms
joined to nitrogen (i.e., all but one in the cation) were broadened
through residual dipolar coupling to 14N (Figure S2, Supporting
Information). The CPMAS 15N NMR spectrum, however,
consisted of six distinct lines that, given there is only one
molecule in the crystallographic unit cell (Vide infra), establish
an interaction with H. The different chemical shifts and line
widths, however, show that the 15N-1H interaction is not equal
for each nitrogen involved. This is consistent with an asymmetric
intramolecular hydrogen bond (IHB) of the form [NsH· · ·N′]+
(i.e., C or D), previously documented in other poly(guanidino)
compounds,5,7 or may be indicative of solid-state proton transfer
(SSPT), previously observed in examples of amidine23 and
guanidine24 dimers.
A dipolar dephasing experiment was performed (inset, Figure
3), showing that the line at δ -254 ppm loses very little intensity
(21) (a) Raczyn´ska, E. D.; Decouzon, M.; Gal, J.-F.; Maria, P.-C.; Gelbard,
G.; Vielfaure-Joly, F. J. Phys. Org. Chem. 2001, 14, 25–34. (b) Tian,
Z.; Fattahi, A.; Lis, L.; Kass, S. R. Croat. Chem. Acta 2009, 82, 41–
45.
(23) (a) Anulewicz, R.; Wawer, I.; Krygowski, T. M.; Ma¨nnle, F.; Limbach,
H.-H. J. Am. Chem. Soc. 1997, 119, 12223–12230. (b) Lopez, J. M.;
Ma¨nnle, F.; Wawer, I.; Buntkowsky, G.; Limbach, H.-H. Phys. Chem.
Chem. Phys. 2007, 9, 4498–4513.
(22) Engelhart, A. E.; Morton, T. H.; Hud, N. V. Chem. Commun. 2009,
647–649.
(24) Coles, M. P.; Khalaf, M. S.; Claramunt, R. M.; Garc´ıa, M. A.; Alkorta,
I.; Elguero, I. J. Phys. Org. Chem. 2009, DOI: 10.1002/poc.1636.
9
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A Conformationally Flexible Superbase
A R T I C L E S
Table 1. Selected Bond Lengths (Å) for 1b, Taken from Data
Collected at 273(2), 173(2), 110(2), and 50(2) K
273(2) K
173(2) K
110(2) K
50(2) K
C1-N1
C1-N2
C1-N3
C9-N4
C9-N5
C9-N6
N1· · ·N4
1.316(3)
1.350(3)
1.348(3)
1.304(3)
1.377(3)
1.356(3)
2.71
1.326(2)
1.357(2)
1.341(2)
1.300(2)
1.384(2)
1.362(2)
2.73
1.3406(10)
1.3623(9)
1.3489(9)
1.3070(10)
1.3946(10)
1.3683(10)
2.75
1.335(2)
1.350(2)
1.336(2)
1.300(2)
1.385(2)
1.363(2)
2.73
Protonated Group
∆
0.034
0.015
0.976
0.031
0
0.983
0.022
-0.003
0.989
0.015
-0.007
0.994
CN
∆′CN
F-ratio
Neutral Group
0.084
0.020
∆
0.073
0.016
0.954
0.088
0.018
0.946
0.085
0.021
0.946
CN
∆′CN
F-ratio
0.947
Figure 4. Thermal ellipsoid plot (20%) of [H2C{hpp}{hppH}][BPh4] (1b)
at 173(2) K. Hydrogen atoms, except NH and those on the bridging
methylene group, are omitted.
however, that the ∆CN value of the formally neutral guanidino
group in 1b is also less than that of the fully localized system
I, consistent with some degree of delocalization attributed to
“partial protonation” of this component.8 As the temperature
was lowered, ∆CN(protonated) decreased with a concurrent
but that the δ -280 ppm resonance is almost fully suppressed.
This indicates that one nitrogen is largely tertiary in character
and the other corresponds to an NH group, in agreement with
the asymmetry proposed above. In an attempt to ascertain
whether exchange of the proton between the two nitrogen
positions of the bridge was occurring in the solid state, EXSY
experiments were performed using both long (200 ms) and short
(30 ms) mixing times. However, no cross-peaks were identified
in either experiment, indicating that, if exchange is taking place,
it cannot be detected in this system using this technique.
X-ray diffraction data for 1b at 173(2) K showed a noncon-
tacted ion pair with an IHB in the cationic component (Figure
4),20 in agreement with the solution- and solid-state NMR data.
The N1 · · ·N4 distance, 2.73 Å, is long compared with the
corresponding values for [TMGN-H]+ and [DMEGN-H]+, in
which the two nitrogen atoms are in the 1,8-positions of a rigid
naphthalene framework (average N · · ·N′ separation of 2.59
Å).5,7 Accordingly the NH atom in 1b was located, refined, and
shown to be associated with only one nitrogen atom in an
asymmetric IHB, with a relatively linear bridge angle of 167°
(cf. 152° and 142° for [TMGN-H]+ and [DMEGN-H]+,
respectively). We note, however, that the N · · ·N′ distance alone
cannot be used to determine whether a single minimum is
present. For example, NH disorder is observed in the cyclic
N,N,N′,N′-tetramethylputrescine cation, with N · · ·N′ of 2.66 Å,25
while in even shorter NH · · ·N′ interactions, for example
2.526(3) Å in 1,6-diazabicyclo[4.4.4]tetradecane,26 an element
of doubt concerning the position of the proton remains.
Figure 5. Structural parameters used to describe bonding in guanidines.
X-ray diffraction data for 1b have been collected at 293(2),
173(2), 110(2), and 50(2) K (Tables 1 and S1, Supporting
Information), and bond lengths associated with the IHB have
been examined using previously defined parameters (Figure 5).27
The ∆CN values28 calculated for the protonated guanidino
group of 1b were less than that of the neutral precursor (∆CN
)
0.106 Å for I at 173(2) K18), in accord with the expected
increase in delocalization upon protonation (Figure 6). We note,
(25) Yaghmaei, S.; Khodagholian, S.; Kaiser, J. M.; Tham, F. S.; Mueller,
L. J.; Morton, T. H. J. Am. Chem. Soc. 2008, 130, 7836–7838.
(26) Alder, R. W.; Orpen, A. G.; Sessions, R. B. J. Chem. Soc., Chem.
Commun. 1983, 999–1000.
Figure 6. Graphical representation of differences in ∆CN with temperature.
The red triangle represents the value of the neutral precursor compound,
H2C{hpp}2 (I). ∆(∆CN) is taken as the difference ∆CN(nonprotonated) -
(27) Khalaf, M. S.; Oakley, S. H.; Coles, M. P.; Hitchcock, P. B. Cryst.
Eng. Commun. 2008, 10, 1653–1661.
(28) Ha¨felinger, G.; Kuske, F. K. H. The Chemistry of Amidines and
Imidates; Wiley: Chichester, 1991.
∆
CN(protonated); error bars are plotted at the 3σ level.
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J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16861

A R T I C L E S
Coles et al.
Scheme 3. Cationic Resonance Stabilization for the “[∼hppH]+
”
present calculations, which predict a very low barrier height
for the proton transfer (see later).
Guanidinium Group
Computational Analysis. The calculations have been carried
out at the DFT level using the Gaussian 03 suite of programs.31
The optimal gas-phase structures of the neutral species
H2C{hpp}2 (I) and the N-methylated compound hppMe (II)
along with their conjugate acids, [H2C{hpp}{hppH}]+ ([I-H]+)
and [hppMe-H]+ ([II-H]+), have been computed using the
B3LYP/6-31G(d) method (Figure 8). In the neutral form, II
displays a typical distribution of carbon-nitrogen bond lengths
within the guanidino portion of the molecule, with a relatively
large ∆CN (0.11 Å) indicating a localized bonding pattern with
little contribution from the lone pair at N3 (∆′CN ) 0.05 Å).
Upon protonation at the imine nitrogen, changes in the guanidino
C-N bond lengths indicate strong cationic resonance stabiliza-
tion (Scheme 3), reflected in the new ∆CN, ∆′CN, and F-values.
A very similar distribution of bond lengths is noted for bis-
guanidino I, implying that the presence of the second function-
ality does not significantly alter the geometric parameters of
the constituent fragments.
The optimized geometries for [I-H]+ indicate that the
protonated guanidino group is subject to cationic resonance
stabilization, although to a lesser extent than observed for [II-
H]+. This can be seen in the larger ∆CN (0.03 Å) and ∆′CN (0.01
Å) values compared with the corresponding values for [II-H]+
(0.00 and -0.01 Å, respectively). For the formally neutral
guanidino group in [I-H]+, the CdN bond (1.304 Å) shows a
significant increase compared with the value for either I (1.298
Å) or II (1.292 Å); in the same vein, the C-N bonds involving
the tertiary nitrogen atoms are significantly shortened upon
protonation. In [I-H]+, however, the correspondingly large
increase in the C-N single bond from 1.387 Å in I to 1.402 Å
in the cation implies that cationic resonance does not use all
possible pathways in the partially protonated fragment. The
reduction in ∆′CN and increase in the F-ratio for the formally
nonprotonated guanidino group are nevertheless strong evidence
that protonation of one guanidino unit promotes partial proton-
ation of the second guanidino framework. This is also evidenced
by the longer N+-H bond of 1.064 Å in [I-H]+ compared with
1.009 Å in [II-H]+. Finally we note the hydrogen bond angle
in [I-H]+ of 176.9°, close to the ideal linear arrangement that
is a prerequisite of a strong hydrogen-bonding interaction.
Results from natural bond orbital analysis32 show the atomic
charges of N1, N2, and N3 to be greater than their counterparts
in the nonprotonated guanidino group, indicating that the
positive charge is predominantly located on these atoms (Figure
9a). Second-order perturbation theory shows that, in the
nonprotonated guanidino group, significant stabilization energies
of 51.8 and 63.5 kcal mol-1 arise from delocalization of the
N5 and N6 lone pairs into the antibonding orbital of the imine
bond (π* C9-N4) and are similar in magnitude to those in hppH
(57.4 and 55.8 kcal mol-1).33 In the protonated group, these
stabilizing effects are more pronounced due to the greater
charge, with the corresponding energies calculated as 76.8 and
84.3 kcal mol-1, respectively. We also note a significant
stabilization of 40.1 kcal mol-1 derived from projection of the
N4 lone pair into the σ* orbital of the N-H bond.
increase in ∆CN(nonprotonated), resulting in a steady increase
in the difference between these two values, ∆(∆CN) in Figure
6.
To gauge the contribution of the lone pair of atoms N3 and
N6 to the overall bonding, the ∆′CN value has been defined.29
For compound I, ∆′CN ) 0.037 Å,18 indicating a relatively low
degree of lone-pair delocalization from the tertiary nitrogen. A
reduction of this value is observed in both guanidino groups in
1b, with the largest reduction in ∆′CN(protonated), consistent
with greater overall contribution from the resonance form iii
(Scheme 3) to offset the positive charge in this group.
Another parameter used when describing the bonding in
guanidines is the F-ratio, defined as a measure of the elongation
of the CdN double bond on protonation, relative to the
concomitant shortening of the average CsNR2 distance (Figure
5).7,8 The F-ratio for H2C{hpp}2 is 0.929,30 indicating that the
CdN double bond length is equal to 92.9% of the average
CsNR2 bond distance. While no clear temperature dependence
is noted for the F-ratio in 1b, the larger values for the protonated
group (97.6-99.4%) are consistent with more efficient delo-
calization when compared with I, in fitting with the ∆′CN values.
The corresponding values of F for the nonprotonated guanidino
group (94.6-95.4%) are also indicative of a lengthened CdN
double bond compared with that in I, giving further structural
evidence for partial protonation of the second guanidino group.
It is important to note that the ∆CN, ∆′CN, and F value ranges
for the formally neutral guanidino component of 1b are
intermediate between those of the protonated group and the
corresponding values for I. The presence of a (nondetectable)
static disorder in the NH position, which is associated with N4
rather than N1 in the minor component, would account for the
observed differences in bond length averages reported in the
crystal structures. However, the regular trends observed as the
temperature is varied suggest a dynamic process which, in
agreement with CPMAS 15N NMR data, is consistent with SSPT
between N1 and N4. Furthermore, a decrease in the rate of
proton transfer as the temperature is lowered would be expected,
resulting in a seemingly more ordered system and an increased
∆(∆CN), as noted in the X-ray diffraction data (Figure 6).
To directly observe the proton transfer between atoms N1
and N4, difference electron density maps were calculated from
high-resolution X-ray diffraction data acquired at 110(2) K
(Figure 7). At higher temperatures the proton is able to shuttle
between the two nitrogens at a faster rate. Indeed, the 110(2) K
data indicate electron density at the correct distance for an
N(4)-H component of 1b (peak ∼0.18 e Å-3), commensurate
with the incipient stage of the proton transfer to the second
guanidino group. To our knowledge, this is the first time that
this phenomenon has been directly detected experimentally, in
contrast to previous studies, in which this process is inferred
from perturbations of other bonds within the molecule, and the
(31) Frisch, M. J.; et al. Gaussian 03, revision 03W; Gaussian Inc.:
Wallingford, CT, 2004.
(32) Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102, 7211–7218.
(33) Khalaf, M. S.; Coles, M. P.; Hitchcock, P. B. Dalton Trans. 2008,
4288–4295.
(29) Coles, M. P.; Hitchcock, P. B. Organometallics 2003, 22, 5201–5211.
(30) The F-ratio for H2C{hpp}2 was incorrectly reported as 0.89 in ref 27.
9
16862 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

A Conformationally Flexible Superbase
A R T I C L E S
Figure 7. Difference electron density map (min, -0.23 e Å-3; max, 0.83 e Å-3) for the hydrogen-bonding region of 1b at 110 K, showing the position of
H1n, with evidence for partial protonation of N4.
TS), consisting of a single negative frequency corresponding
to the NsH· · ·N T N· · ·HsN vibration (Figure 9b). A
reorganization of π-electron density within both guanidino
functionalities accompanies the proton-transfer process, resulting
in a nearly symmetrical structure for [I-H]+-TS. The ∆CN, ∆′CN
,
and F-values reflect an increased delocalization in the formerly
neutral guanidino group, with a concomitant reduction in the
formerly protonated group, making them almost equivalent. The
N-H+ distance of the hydrogen bridge in the equilibrium
structure of [I-H]+ is increased by 0.218 Å on going to the TS
position in [I-H]+-TS. It is surprising that such a small step for
the positively charged Hδ+ atom leads to such a large change
in the electronic and spatial structure of both fragments.
The gas-phase barrier for proton transfer (calculated as the
difference in electronic energy between the transition state and
the equilibrium ground state) is +2.5 kcal mol-1, somewhat
higher than that reported for 1,8-bis(dimethylamino)naphthalene-
34
2,7-diolate (+0.9 kcal mol-1
)
and the corresponding 2,7-
35
dimethoxy-substituted proton sponge (+1.4 kcal mol-1
)
but
identical to the value for the protonated 8-aminoguanine dimer
(+2.5 kcal mol-1).22 A significant reduction in the N · · ·N
distance is noted in [I-H]+-TS (2.561 Å; cf. 2.749 Å in the
ground state), with the hydrogen atom positioned with the
N· · ·H· · ·N angle 177.3°. To validate this result, the computa-
tions were repeated by the Boese-Martin for kinetics (BMK)
method,36 which is advocated as the best DFT approach for
estimating the barrier heights. The corresponding barrier is
almost the same, being 2.7 kcal mol-1 at the BMK/6-
311+G(2df,p)//B3LYP/6-31G(d) level of theory and 2.8 kcal
mol-1 as obtained by the BMK/6-311+G(2df,p)//BMK/6-31G(d)
method. Therefore, it is gratifying that a more widely used DFT
functional, namely B3LYP, is able to accurately predict barrier
heights for the proton-transfer reactions within a few tenths of
a kcal mol-1 from the BMK results. However, explicit inclusion
of zero-point vibrational energy (ZPVE) values, obtained at the
B3LYP/6-31G(d) level of theory, removes the barrier for the
proton transfer. More precisely, the difference in the unscaled
ZPVE values between the transition-state structure [I-H]+-TS
Figure 8. Summary of key structural data from DFT analysis of II, [II-
H]+, I, and [I-H]+ in the gas phase (note that the two guanidino groups in
I are related by symmetry).
Figure 9. (a) Natural atomic charges on key atoms of [I-H]+. (b) Summary
of key structural data from DFT analysis of [I-H]+-TS.
(34) Ozeryanskii, V. A.; Milov, A. A.; Minkin, V. I.; Pozharskii, A. F.
Angew. Chem., Int. Ed. 2006, 45, 1453–1456.
(35) Ozeryanskii, V. A.; Pozharskii, A. F.; Bien´ko, A. J.; Sawka-
Dobrowlska, W.; Sobczyk, L. J. Phys. Chem. A 2005, 109, 1637–
1642.
The transition state for the interconversion of the different
tautomers (C/D) was located on the potential surface ([I-H]+-
(36) Boese, A. D.; Martin, J. M. L. J. Chem. Phys. 2004, 121, 3405–3416.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16863

A R T I C L E S
Coles et al.
Table 2. Calculated Basicity Constants for the Molecules of Interest in This Study
compound
PA (gas phase) (kcal mol-1
)
pKa (MeCN)
IHBa(kcal mol-1
)
ref
H2C{hpp}2 (I)
270.6b
176.7b
255.8b
245.1
28.6
17.8
25.3
19.9
24.0
25.4
this work
this work
this work
37a
37b
8
8
37b
7
7
7
8
8
[H2C{hpp}{hppH}]+ [I-H]+
hppMe (II)
14.8
DMAN (a)
TMGB (b)
254.3c
257.5c
178.7c
263.8c
250.8c
250.8c
TMGN (c)
[TMGN-H]+ ([c-H]+)
TMGBP (d)
12.5
25.9
23.0
22.4
DMEGN* (e)
DMEGN† (e′)
[DMEGN*-H]+ ([e-H]+)
TMGF (f)
9.2
263.7c
273.8d
27.8
[TMGF-H]+ ([f-H]+)
TMGBH (g)
17.6
9
a Calculated from the relevant homodesmotic reactions. b B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) model. c MP2(fc)/6-311+G(d,p)//HF/6-31G(d)
model. d B3LYP/6-311+G(d,p)//B3LYP/6-31+G(d) model. In the first column, the * indicates syn-DMEGN and the indicates anti-DMEGN.
†
and the ground-state protonated molecule [I-H]+ is -2.7 kcal
mol-1. This implies that ZPVE in the transition-state structure
is lower than that in the ground state, since there is one vibration
with imaginary frequency of -1118.7 cm-1, which is not
contributing to the ZPVE in the former system. Therefore, we
conclude that the proton transfer in the monoprotonated
compound [I-H]+ is barrierless and that the proton shuttles freely
between the two imino nitrogens, leading to two equivalent
guanidino moieties, if averaged over the longer time.
maintained in solution, we wished to examine the role that this
interaction plays on the high PA value. It is useful to note that
the gas-phase basicities (GBs) of I and II are 261.8 and 248.5
kcal mol-1, respectively.
A useful method for exploring the interaction between
different fragments derives from the concept of homodesmotic
reactions,40 from which we obtain eqs 1-3. The difference of
these equations gives the relationship PA(I) - PA(II) ) -(E1
- E2), which shows that I has larger PA than II by 14.8 kcal
mol-1 since the energies E1 and E2 are 6.7 and 21.5 kcal mol-1
,
Basicity Studies
respectively. This difference can be attributed to the hydrogen
bond energy in [I-H]+. Compared with values for the related
systems in Table 2 and a series of published diamines (for which
it was calculated that the IHB contributed 10-17 kcal mol-1
to the GB),41 the IHB in [I-H]+ may be considered relatively
strong.
Calculated Proton Affinities in the Gas Phase and in
Acetonitrile Solution. To examine the basicity of the molecules
described in this study, we have performed additional theoretical
studies on I and [I-H]+ in the gas phase and in acetonitrile
solution, involving the two different conformers [I-H]+-syn and
[I-H]+-anti. The basicity constants for the molecules of interest
are presented in Table 2, along with those of the bis-guanidino
compounds from Figure 1.7-9,37 It is reassuring to note that the
gas-phase proton affinity (PA) for hppMe (II) calculated during
In contrast to most systems investigated using these tech-
niques, for which the framework holding the two guanidino
moieties is rigid, the conformational flexibility of I has enabled
this result to be tested by calculating the PA for I with a
conformation of the conjugate acid that does not lead to
formation of a linear IHB (eq 3). For compound I this is the
[I-H]+-anti conformation, in which the protonated guanidino
fragment is rotated about the central methylene unit (Figure 2).
The proton affinity for this conformation, PA′(I), is 261.9 kcal
mol-1, giving a difference in the values calculated for the two
conformations of [I-H]+ of 8.7 kcal mol-1. This is in harmony
with the result obtained for eq 3, E3 ) 12.8 kcal mol-1, smaller
than E2 by approximately 50%. The difference between eqs 1
and 3 gives a H+-bond strength in [I-H]+-anti of 6.1 kcal mol-1,
which is a consequence of the interaction between the proton
attached to the imino nitrogen N1 and a lone pair of the N5(sp3)
atom. This N1sH+ · · ·N5 hydrogen bond has an angle of 137.8°.
The nonprotonated guanidine fragment is not stabilized by the
cationic resonance, because the H-bond acceptor atom N5 is
linked to the rest of the guanidine moiety by a N-C single
bond. The latter acts as an “insulator” for the cationic reso-
nance.1 This is another reason why the N1sH+ · · ·N5 hydrogen
bond is weaker, in addition to its pronounced nonlinearity.
this study (255.8 kcal mol-1) is in good agreement with the
38
experimentally determined value of 254.0 kcal mol-1
.
This
gives a theoretical estimate within chemical accuracy of (2.0
kcal mol-1, lending credibility to the other predicted values
presented in this study.
Monoprotonation of I to give cation [I-H]+ has an associated
proton affinity (PA) of 270.6 kcal mol-1. This is considerably
greater than those of the related bis-guanidino compounds in
Table 2 and a series of hypothetical bis(tetramethylguanidino)
systems supported by a range of rigid backbones (range
241-268 kcal mol-1). Similarly high PAs (up to 275.5 kcal
mol-1) have been calculated for 3-aminopropyl-substituted
N,N′,N′′-trimethylguanidines, with such high values in this
instance attributed to strong cationic resonance within the central
guanidine moiety, enhanced through the cooperative multiple
intramolecular hydrogen bonding.39 Given that the cation [I-H]+
has an observed IHB in the solid state that is believed to be
(37) (a) Kurasov, L. A.; Pozharskii, A. F.; Kumenko, V. V. Zh. Org. Khim.
1983, 19, 859–864. (b) Kovac´evic´, B.; Maksic´, Z. B.; Vianello, R.;
Primorac, M. New J. Chem. 2002, 26, 1329–1334.
(38) Lias, S. G. In NIST Chemistry WebBook; Linstrom, P. J., Mallard,
W. G., Eds.; National Institute of Standards and Technology: Gaith-
ersburg MD, June 2005; http://webbook.nist.gov/chemistry/.
(40) (a) George, P.; Trachtman, M.; Bock, C. W.; Brett, A. M. Tetrahedron
1976, 32, 317–323. (b) George, P.; Trachtman, M.; Bock, C. W.; Brett,
A. M. J. Chem. Soc., Perkin Trans. 2 1976, 1222–1227.
(41) Ro˜o˜m, E.-I.; Ku¨tt, A.; Kaljurand, I.; Koppel, I.; Leito, I.; Koppel, I. A.;
Mishima, M.; Goto, K.; Miyahara, Y. Chem.sEur. J. 2007, 13, 7631–
7643.
(39) (a) Kovacˇevic´, B.; Glasovac, Z.; Maksic´, Z. B. J. Phys. Org. Chem.
2002, 15, 765–774. (b) Glasovac, Z.; Kovacˇevic´, B.; Mesˇtrovic´, E.;
Eckert-Maksic´, M. Tetrahedron Lett. 2005, 46, 8733–8736.
9
16864 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

A Conformationally Flexible Superbase
A R T I C L E S
Table 3. Results Obtained from the Triadic Analysis of the Basicity
of I, [I-H]+, and II
a
b
molecule (B)
IE(B)nKoop IE(B)1ad E(ei)(n)
(BAE)•+ PA(B) PA(B)exp
rex
I
(233.1)5 147.2 85.9
(311.2)3 233.2 78.0
(232.9)3 158.1 74.8
104.1 270.5
[I-H]+
96.2
100.2 255.7 254.0
3.9 14.8
-7.9 -93.9
176.6
II
PA(I) - PA(II)
-0.2
11.1
-7.9
PA([I-H]+) - PA(I) -78.1
a The numerical subscripts n indicate the principal molecular orbital
(PRIMO) in such a way that n ) 1 represents the HOMO, n ) 2
represents the HOMO-1, and so on. b Experimental data are taken from
ref 37.
Brønsted basicities43 and acidities44 and has been shown to have
certain advantages over some other models.45 Considering
basicity, triadic analysis gives the gas-phase proton affinity of
a base B according to eq 6:
Koop
PA(B) ) -IE(B)n
+ E(ei)(n) + (BAE)•+
+
rex
313.6 kcal mol-1 (6)
This approach separates the protonation of a neutral organic
base B into three sequential stages: (a) ionization of B by
removal of an electron, generating a radical cation, (b) attach-
ment of the ejected electron to the incoming proton to form the
hydrogen atom (the released energy of 313.6 kcal mol-1
corresponds to the electron affinity of the proton),38 and (c)
creation of the chemical bond between the newly formed radical
cation of the base and the hydrogen atom.
The initial state implies that the properties of the neutral base,
B, and the effects on gas-phase basicities are reflected in
Koopmans’ ionization energies,46 IE(B)nKoop, calculated in the
frozen electron density and clamped atomic nuclei approxima-
tion. The IE(B)nKoop values reflect the energy cost of taking an
electron from the neutral molecule in a bond association with
the incoming proton, assuming ionization is an instantaneous
process, and since these energies depend exclusively on electron
distribution throughout B described by molecular orbitals (MOs),
they reflect genuine properties of the initial state. The orbitals
undergoing ionization are called principal molecular orbitals
(PRIMOs).
The protonation of [I-H]+ leading to the dication [I-H2]2+
has a second PA considerably lower than the first, with a
calculated value of only 176.7 kcal mol-1. The corresponding
homodesmotic reaction related to the diprotonated system
[I-H2]2+ is given in eq 4. In this model, E4 essentially reflects
repulsion when two protonated [II-H]+ fragments are combined
in the diprotonated base [I-H2]2+, with a value as high as -57.6
kcal mol-1. If the difference between eqs 4 and 2 is taken, one
obtains eq 5, where PA([I-H]+) is the second proton affinity
yielding diprotonated form [I-H2]2+
.
PA([I-H]+) ) PA(II) + E4 - E2
(5)
It appears that the second proton affinity, PA([I-H]+), is given
by the proton affinity of the fragment II corrected by the
repulsion energy E4 and by the negative of E2, because the
stabilizing IHB occurring in the monoprotonated species is no
longer present. The latter component is due to the fact that the
second bridgehead nitrogen, which served as a hydrogen-bond
acceptor in [I-H]+, is also protonated in the [I-H2]2+ molecule.
The estimated basicity values in acetonitrile are also presented
in Table 2. The difference in the gas-phase proton affinities
between I and II (14.8 kcal mol-1) yields a difference of only
3.3 pKa units in MeCN. This is predominantly due to the
inability of the protonation center to be efficiently solvated
(stabilized) in [I-H]+ because of the strong IHB. These
calculations have demonstrated that I can be classified as a
strong superbase according to the gas-phase proton affinity of
270.6 kcal mol-1 and the corresponding pKa value of 28.6, which
is in good accordance with the experimentally determined value
(see later).
In the second intermediate step, the cation radical is allowed
to fully relax in real time. The corresponding geometric and
electronic reorganization effects following ejection of the
electron are given by the relaxation energy E(ei)(n)rex, defined
ad
by eq 7, where IE(B)1 is the first adiabatic ionization energy
of the base.
Koop
ad
E(ei)(n) ) IE(B)n
- IE(B)1
(7)
rex
Finally, the bond association energy describing the ho-
molytic bond formation between created radicals is given
by the (BAE)•+ term, which represents features of the
conjugate acid [B-H]+.
The results from the triadic analysis of I, [I-H]+-syn, and II
are presented in Table 3. We have previously determined the
Study of the Gas-Phase Basicity of I Using the Triadic
Formula. To shed more light on the extremely high gas-phase
basicity of H2C{hpp}2, we have used the recently proposed
triadic formula,42 which has previously been used to interpret
(43) (a) Maksic´, Z. B.; Vianello, R. J. Phys. Chem. A 2002, 106, 419–430.
(b) Vianello, R.; Maskill, H.; Maksic´, Z. B. Eur. J. Org. Chem. 2006,
2581–2589. (c) Despotovic´, I.; Maksic´, Z. B.; Vianello, R. Eur. J.
Org. Chem. 2007, 3402–3413.
(44) Maksic´, Z. B.; Vianello, R. ChemPhysChem 2002, 3, 696–700.
(45) Deakyne, C. A. Int. J. Mass Spectrom. 2003, 227, 601–616.
(46) Koopmans, T. Physica 1933, 1, 104–113.
(42) Maksic´, Z. B.; Vianello, R. Pure Appl. Chem. 2007, 79, 1003–1021.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16865

A R T I C L E S
Coles et al.
Figure 10. Molecular orbital energy diagram drawn to scale (in atomic units) for hppMe (II), H2C{hpp}2 (I), and [H2C{hpp}{hppH}]+ ([I-H]+-syn). The
boxed orbital represents the PRIMO for each species.
difference in PA for I and II to be 14.8 kcal mol-1 (Vide supra).
To determine which of the three effects dominates, it is useful
to define the difference in the PA:
It is interesting to rationalize why it is energetically much
less favorable to attach the second proton to I, leading to the
formation of dication [I-H2]2+, than it is for the first protonation
(Vide supra). Triadic analysis offers a simple answer when we
consider [I-H]+ and [I-H2]2+ (Table 3), leading to
PA(I) - PA(II) ) ∆PA(I) )
[-∆(IE)nKoop; ∆E(ei)rex; ∆(BAE)•+] (8)
PA([I-H]+) - PA(I) ) [-78.1; -7.9; -7.9] )
-93.9 kcal mol-1
where square brackets imply summation of the three terms
within, defined as
The second protonation is as much as 93.9 kcal mol-1 less
exothermic than the first, and in this case it is predominantly a
consequence of the properties of the initial molecules. This is
mirrored through the differences in Koopmans’ ionization terms,
where in [I-H]+ the molecular orbitals are much more stabilized
because of an excess positive charge, so that it becomes much
more costly to ionize [I-H]+ than I (Table 3). Still, it is important
to note that the overall difference in the basicity of the two
molecules is determined by all three terms appearing in the
triadic expression, although Koopmans’ term is an order of
magnitude larger in absolute value than either of the other two
contributions.
Koop
Koop
Koop
-∆(IE)n
) -IE(I)n
+ IE(II)n
(9a)
(9b)
∆E(ei)rex ) E(ei)rex(I) - E(ei)rex(II)
∆(BAE)•+ ) BAE(I)•+ - BAE(II)•+
(9c)
Comparing data from Table 3, we obtain
PA(I) - PA(II) ) [-0.2; 11.1; 3.9] ) 14.8 kcal mol-1
The predominant influence leading to such a trend in basicity
is therefore exerted by the relaxation energy, which mirrors
properties of the intermediate stage in the protonation event.
Examining the PRIMOs of I and II (Figure 10), we note that
they are HOMO-4 and HOMO-2, respectively, which are of
approximately the same energy.
pKa Measurement of I by Spectrophotometric Titration. To
authenticate the calculations presented above, the acidic dis-
sociation of [I-H]+ has been studied in acetonitrile using
UV-vis spectrophotometric titrations, enabling the pKa value
9
16866 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

A Conformationally Flexible Superbase
A R T I C L E S
form the dication, [H2C{hppH}2]2+ ([I-H2]2+).20 Measurement
of accurate pKa values involving multiply charged species is,
however, complicated due to problems estimating reliable
activity coefficients.
Summary and Conclusions
The bis(guanidino) compound, H2C{hpp}2 (I), has been
converted to the monoprotonated salt [H2C{hpp}{hppH}][X]
(1a, X ) Cl; 1b, X ) BPh4), containing the mixed guanidino/
guanidinium cation, [I-H]+. Spectroscopic measurements in the
solution phase are consistent with a symmetric structure
containing an intramolecular hydrogen bond and rapid proton
exchange. Although solid-state measurements indicate associa-
tion of the proton predominantly at one nitrogen, both CPMAS
15N NMR spectroscopy and high-resolution X-ray diffraction
show partial protonation of the formally neutral guanidino group,
consistent with a solid-state proton-transfer process. The proton
affinity and basicity of I have been calculated in the gas phase
and in MeCN solution, both of which indicate this molecule
should be considered as a superbase. This was confirmed by
spectrophotometric titrations which gave pKa ) 28.98 ( 0.05
for [I-H]+.
The reasons for the high basicity of I are two-fold: (i) a high
intrinsic basicity of the hpp moiety, as evident by its PA value
of 254.6 kcal mol-1, and (ii) the formation of a strong IHB to
the second guanidino subunit, which in turn undergoes partial
cationic resonance stabilization due to partial protonation. The
increase in PA relative to that of hppH is 16 kcal mol-1.
Although it has been shown that (poly)alkylation generally
increases the basicity of the parent compound both in the gas
phase and in solution by enhancing the electron density
relaxation effect after protonation,1,49 the reverse is noted in
acetonitrile for the bicyclic guanidine system.3,50 Hence, the
N-methylated derivative hppMe less basic than the parent hppH
compound, attributed to the more efficient solvation of the
[hppH2]+ cation. The large increase in the basicity of I must
therefore derive from the presence of the second guanidino
functionality and its polarization by the proton linked to the
first one. This feature can be characterized as the partial
protonation of the second guanidino fragment in a static picture.
On the other hand, the dynamic picture is given by fast proton-
transfer reaction between equivalent nitrogens N1 and N4, in
which the proton is oscillating back and forth between the two
positions.
Figure 11. Polyphosphazene reference compounds used to determine the
pKa of [I-H]+.
Table 4. Comparison of the Measured Acetonitrile pKa Values for I
with Those of Related Amidine and Guanidine Bases
compound
pKa(obs)
ref
vinamidine proton sponge (i)
H2C{hpp}2 (I)
DMAGa
29.22
28.98
27.15
26.03
25.49
24.34
20.84
18.62
12
this work
48
3
3
3
3
3
hppH
hppMe (II)
DBUb
PhTMGc
DMAN (a) proton sponge
a N,N′,N′′-Tris(3-dimethylaminopropyl)guanidine.
b Diazabicycloundec-5-ene. c Phenyltetramethylguanidine.
for the attachment of the first proton to H2C{hpp}2 (I) to be
calculated. The experimental procedures for this process have
been described in detail in previous publications47 and are
discussed in more detail in the Supporting Information. In the
case of [I-H]+, measurements were made against two poly-
phosphazene references of known pKa (Figure 11).3 The results
show that I is a stronger base than 4-MeO-C6H4P2(pyrr)5 by
0.74 ( 0.04 pKa unit and a weaker base than 2,5-Cl2-
C6H3P3(pyrr)6(NEt2) by 0.17 ( 0.02 pKa unit, with the average
for these two results giving pKa ) 28.98 ( 0.05 for [I-H]+.
This is in excellent agreement with the theoretical estimate of
28.6 units. We note that the experimentally determined pKa for
the paradigmatic proton sponge DMAN (a), typically used as a
threshold for the classification of a “superbase”, is 18.62,3
emphatically confirming the designation of I as a superbase.
Table 4 compares the pKa of 1b with the experimentally
determined values of related amidine and guanidine bases.3,48
Results show that H2C{hpp} is a much stronger base than most
of the previously studied amidines and guanidines by between
approximately 3 (cf. hppH) and 10 (cf. DMEN) orders of
magnitude. Only a small selection of neutral organic bases,
notably substituted phosphazenes and vinamidine proton sponges,
show a greater pKa under identical experimental procedures.3
During the titration experiments for the ∆pKa determination
and after reaching the protonated form of the H2C{hpp}2 (I), it
was observed from the spectra that when an excess amount of
acidic titrant solution is added, [I-H]+ binds a second proton to
This is corroborated by the solid-state 15N NMR spectroscopy
measurements and theoretical studies, which have shown that
“hydrogen bond compression” occurs simultaneously as the
proton is transferred from one heavy atom to the other in
barrierless N · · ·H· · ·N hydrogen bonds,51 and this has now been
observed in a number of systems,52 including some R-amino
acids.53 We rationalize that the flexibility of the methylene group
linking the two guanidino groups in [I-H]+ enables the close
approach of the two nitrogen atoms, thereby facilitating proton
transfer by forming a strong, almost linear HB with no barrier
to proton transfer. Indeed, the gas-phase structure of [I-H]+-
TS shows a contraction of 0.19 Å in the N · · ·N distance
(47) (a) Leito, I.; Kaljurand, I.; Koppel, I. A.; Yagupolskii, L. M.; Vlasov,
V. M. J. Org. Chem. 1998, 63, 7868–7874. (b) Kaljurand, I.; Rodima,
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A R T I C L E S
Coles et al.
compared with the ground state. To be more specific, both
structures possess N · · ·H· · ·N angles approaching the optimal
value of 180° ([I-H]+ ) 176.9°; [I-H]+-TS )177.3°), enabling
facile proton transfer between nitrogen atoms.
which generates more acute N · · ·H· · ·N angles on protonation.
Conformational flexibility and linear N · · ·H· · ·N angles, how-
ever, do not always lead to simple proton-transfer processes.
Recent studies on protonated N,N,N′,N′-tetramethylputrescine
indicate that the proton is most likely near a potential energy
maximum between the two nitrogen atoms, likening the situation
to the Buridan’s ass paradox.25 In contrast, the combination of
a flexible linker and constituent guanidino groups leads us to
conclude that the proton in our system is smarter than Buridan’s
donkey, with rapid transfer enabling it to take “bites” from both
“haystacks”, thereby staying alive and kicking.
The conformational flexibility and the approximately linear
N· · ·H· · ·N angle derive from the structure of the neutral
compound and the size of the heterocycle formed by the IHB.
This, in turn, stems from the unique position of the bridging
atom that links the guanidino groups in I (Scheme 1), namely
via an amino nitrogen rather than the more usual case in which
the Nimino atom is a component of the linking group (Figure 1).
We also note that most bis-guanidino systems previously
developed are based on rigid frameworks which, while they may
favorably align the imine nitrogen atoms toward formation of
an IHB, restrict any hydrogen bond compression that would
facilitate proton transfer. Finally, the formation of an eight-
membered heterocycle in [I-H]+ is unusual, with most other
systems being comprised of either six- (i.e., [DMAN-H]+,
[TMGB-H]+, [TMGN-H]+, [DMEGN-H]+, and [TMGBH-H]+)
or seven-membered ([TMGBP-H]+ and [TMGF-H]+) rings,
Acknowledgment. This work was supported by Grants 6699
and 7374 from the Estonian Science Foundation (I.L., I.K.) and by
Grant No. 098-0982933-2932 from the Ministry of Science,
Education and Sports of the Republic of Croatia (Z.B.M.). R.V.
gratefully acknowledges financial support by the Unity through
Knowledge Fund (www.ukf.hr) of the Croatian Ministry of Science,
Education and Sports (Grant Agreement No. 20/08), together with
cofinancing provided by APO Ltd. Environmental Protection
Services, Zagreb, Croatia (www.apo.hr). We acknowledge the
EPSRC solid-state NMR service at Durham. Generous support of
theSRCEComputationalCenterinZagrebisthankfullyacknowledged.
(52) (a) Aguilar-Parrilla, F.; Scherer, G.; Limbach, H.-H.; Foces-Foces,
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Supporting Information Available: Full experimental details
and details of the X-ray analysis of 1b; variable-temperature
1H NMR spectra of 1b; solid-state CPMAS 13C NMR spectrum
of 1b; calculated vs observed bond lengths table for 1b; details
on energies and geometries of all compounds computationally
investigated; complete ref 31. This material is available free of
charge via the Internet at http://pubs.acs.org.
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