Out-Basicity of 1,8-bis(dimethylamino)naphthalene: The experimental and theoretical challenge

Article abstract of DOI:10.1039/c3ob41986j

A possibility of non-conventional two-step protonation of 1,8-bis(dimethylamino)naphthalene (proton sponge) is discussed. Unlike the generally accepted mechanism, involving relatively slow direct penetration of a proton into the cleft between the peri-NMe₂ groups, it consists of the rapid addition of a proton to the out-inverted NMe₂ group with the subsequent slower rotational transfer of the proton into the inter-nitrogen space to produce a stable chelated cation. The following approaches were employed during the work: (1) competitive hydrogen bond formation in a specially designed alcohol in which the OH group might chelate either the proton sponge 1-NMe₂ group or another basic center (N,N-dimethylaniline) of known basicity; (2) measuring the basicity of naphtho[1,8-b,c]diazabicyclo[3.3.3] undecane considered to be a close analogue of the proton sponge capable exclusively of out-protonation; (3) X-ray, spectral and DFT studies of structure, energy and stereodynamics of compounds obtained, including their conformers. For the first time, the pK_a value of an organic base with a perfectly flat nitrogen atom is reported. The final conclusion is made that both pathways of proton sponge protonation, traditional and non-conventional, contribute in parallel with a still undefined ratio. The estimated out-basicity of the proton sponge is at least 5.5 orders of magnitude lower than the directly measured in-basicity. the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob41986j

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Page 1 of 24
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DOI: 10.1039/C3OB41986J
Out-Basicity of 1,8-bis(dimethylamino)naphthalene:
The experimental and theoretical challenge
Valery A. Ozeryanskii,a Alexander F. Pozharskii,∗,a Alexander S. Antonova and Alexander
Filarowskib
a Department of Organic Chemistry, Southern Federal University, Zorge str. 7, 344090 Rostov-on-
Don, Russian Federation, b University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland
E-mail: apozharskii@sfedu.ru
Dedicated to Professor Roger W. Alder, the proton sponge creator and outstanding contributor into
acid-base theory and physical organic chemistry
Abstract:
A
possibility
of
nonconventional
twoꢀstep
protonation
of
1,8ꢀ
bis(dimethylamino)naphthalene (proton sponge) is discussed. Unlike generally accepted
mechanism, involving relatively slow direct penetration of a proton into the cleft between the periꢀ
NMe2 groups, it consists in the rapid addition of a proton to the outꢀinverted NMe2 group with the
subsequent slower rotational transfer of the proton into the internitrogen space to produce a stable
chelated cation. The following approaches were employed during the work: 1) a competitive
hydrogen bond formation in a specially designed alcohol in which the OH group might chelate
either the proton sponge 1ꢀNMe2 group or another basic center (N,Nꢀdimethylaniline) of known
basicity; 2) measuring basicity of naphtho[1,8ꢀb,c]diazabicyclo[3.3.3]undecane considering as a
close analogue of the proton sponge capable exclusively to outꢀprotonation; 3) Xꢀray, spectral and
DFT studies of structure, energy and stereodynamics of compounds obtained, including their
conformers. For the first time, the pKa value of an organic base with perfectly flat nitrogen atom is
reported. The final conclusion is made that both pathways of proton sponge protonation, traditional
and nonconventional, contribute in parallel with still indefinite ratio. The estimated outꢀbasicity of
the proton sponge is at least 5.5 orders of ten lower than the directly measured inꢀbasicity.
Introduction
It is well known that proton sponges including the parent 1,8ꢀbis(dimethylamino)naphthalene (1)
and a vast majority of its derivatives normally exist in the soꢀcalled in,in-conformation 1, in which
the methyl groups are turned outside and axes of the free nitrogen electron pairs point inside of the

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internitrogen space.1,2 This has two crucial consequences. The first one is emerging an electrostatic
repulsion between the unshared electron pairs that strongly destabilizes the neutral base. Along with
the steric repulsion of the four methyl groups, these are the key factors determining the exceedingly
high proton sponge basicity (pKa = 12.1 in H2O,3 18.62 in MeCN,4 7.5 in DMSO5). Indeed, the
protonation resulting in the formation of chelated cation 1H+ removes the electrostatic and steric
strain and thus provides a considerable free energy gain. The second outcome of the in,inꢀform is
the appearance of a deep and tight hydrophobic pocket between the NMe2 groups. To date, a
general agreement exists that the protonationꢀdeprotonation of 1 occurs exclusively through the
cleft in this pocket (Scheme 1a, structure 2). Xꢀray picture of hydrofluoride of 1 gives a visual
representation of this strictly unproven dogma: the situation looks as if the counteranion has already
aimed to extract the NH proton from its cavity (Fig. 1).6 From this, one can conclude that the
experimentally measured pKa values of 1 and its derivatives with the in,inꢀconformation are
attributed to the inside protonation.
Scheme 1 Inside (a) and outside (b) modes for protonationꢀdeprotonation of 1,8ꢀ
bis(dimethylamino)naphthalene (1)

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Fig. 1 Incipient deprotonation of hydrofluoride of the proton sponge as realized by room
temperature Xꢀray structure showing close interaction (Å) between the proton and fluoride
counterion.6
Meanwhile, another kind of proton sponge conformation, namely 1(in,out), is also known
(Scheme 1b). Its existence in the gas phase as an admixture to the more stable 1(in,in) form was
first suggested by SzemikꢀHojniak and coꢀworkers on the basis of fluorescence spectroscopy studies
and ab initio calculations.7 They estimated the energy gap between the forms as equal to 4.7 kcal
mol–1. Such the difference implies that conformer 1(in,in) strongly prevails under ordinary
conditions; however, as it was shown experimentally, both forms start to equilibrate on heating to
o
give as much as 33% of 1(in,out) at 180 C.7 Later, it has been found that the in,outꢀconformation
can be stabilized by placing in position 2(7) tertiary alcoholic group8–10 or bulky substituent,10–12
which are able to form the O–H…N intramolecular hydrogen bond (IHB) or render a steric pressure
onto the 1ꢀNMe2 group causing its inversion, respectively.
The reality of the in,outꢀconformation allows to put forward an alternative mechanism of the
proton sponge protonation, namely from the outside either via the direct outꢀprotonation of the
1(in,out) form (Scheme 1b, structure 3) or through the outꢀinversion of 1(in,in) induced
electrostatically by a proton approaching from the outside to give 3 with a subsequent transfer of the
proton into the internitrogen space: 1H+(out) ꢀ 1H+(in). Virtually, such transfer might occur

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simply via rotation of the outꢀprotonated NMe2 group around the Car–N bond.13 In this context, one
can draw an analogy with some caged nitrogen polyamines for which both the outside and the
inside protonation are well documented.14,15 What kind of protonation occurs mostly depends on the
stereochemical flexibility of the molecule and the presence of the inner cavity of an appropriate
size. For example, Alder has demonstrated that 1,6ꢀdiazabicyclo[4.4.4]tetradecane (4) undergoes
1
outside protonation, which results in the formation of monoꢀ 5 or dication 6 with pKa ~ 6.5 and
pKa = –3.25, respectively (Scheme 2).16 At the same time, the inside protonation giving
2
thermodynamically more favorable chelated cation 7 cannot be achieved via normal protonꢀtransfer
procedure. The formation of 7 together with a variable amount of the rearranged ion 8 takes place in
the presence of K2S2O8 that implies one electron oxidative mechanism. Similar difficulties for the
inside protonationꢀdeprotonation were reported for [1.1.1]cryptand,17 adamanzanes18–20 and some
related compounds.21 The reason for this lies in an extraordinary slowness of the proton penetration
into the sterically hindered base cavity because in solution a tiny proton is always transferred with
the help of a much more bulky base B. Until now, no direct method to determine pKa for the inside
protonation has been developed and all estimates were made indirectly, predominantly by quantumꢀ
chemical calculations. For instance, in accordance with DFT the aqueous pKa(in) value for 4 is
about 21 log units.22
Scheme 2 Outꢀ and inꢀprotonation of 1,6ꢀdiazabicyclo[4.4.4]tetradecane
From the above it follows that the pKa(in) value for the caged diamines is always much higher
than pKa(out). In the present work we aimed to study whether this regularity remains true for openꢀ

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caged systems such as 1,8ꢀbis(dimethylamino)naphthalene. We realized that unlike caged bases, the
pKa(out) constant for proton sponges cannot be measured directly. Therefore, we tested three
indirect approaches which were based on 1) a competitive hydrogen bonding in a specially designed
compound permitting the formation of N…H–O intramolecular hydrogen bond either with the
proton sponge 1ꢀNMe2 group or with an alternative basic centre of known strength, 2) measuring
basicity of a model proton spongeꢀlike compound unambiguously undergoing outꢀprotonation and
3) DFT study of interconversion between the 1H+(in) and 1H+(out) forms.
Results and discussion
Hydrogen bonding in the proton sponge with specially designed ortho-substituent. We started
with previously unknown tertiary alcohol 11 containing linked proton sponge and N,Nꢀ
dimethylaniline (DMA) residues (Scheme 3). We assumed that a competition for the OHꢀproton
between the both amine moieties to form IHB as in 11a or 11b could allow at least qualitative
comparison of their basicity since that of N,Nꢀdimethylaniline is known (pKa = 5.16 in H2O,23 11.43
in MeCN4).
Scheme 3 Preparation of alcohol 11
Alcohol 11 was obtained by two different ways starting either from proton sponge ketone 9 or
benzophenone derivative 12,24 which were treated with aryllithium compounds 10 and 13,
respectively. The second protocol turned to be more efficient as providing the higher yield of 11

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(65% against 20%). Compound 11 forms yellowish crystals whose structure was proven by a set of
analytical methods.
1
In the H NMR spectrum of 11 in CDCl3 the OH peak resonates at δ = 10.22 ppm, what is
1
characteristic for the chelated hydroxyl group in related alcohols.8–10 The H and 13C NMR
1
assignments for compound 11 were deduced from HSQC and HMBC experiments, including H–
15N correlations (Supplementary information, Fig. S1) and compared with the data already
published for model alcohols 14,9 15,25 and 16.10 The only exception relates to the peaks of C6H5
group whose exact assignment was difficult because of a slow dynamic behavior in the NMR timeꢀ
scale and intrinsic asymmetry of the whole molecule. Notably, that some of the phenyl hydrogens at
room temperature in CDCl3 (in a lesser extent in DMSOꢀd6) are spread within the 7.0–8.0 ppm
1
region and can be detected only on cooling (Fig. S2). Much weaker dynamics is observed for H
signals of the naphthalene ring, whereas those of the dimethylaniline moiety remain narrow and
sharp under wide range of conditions.
For our purpose, the most essential was an exact assignment of signals of the NMe2 groups as
directly connected with the chelation process. This was done by analyzing reference NMR spectra
and 2D NMR experiments. The chemical shift values for the NMe2 and OH groups are given in
Table 1.
o
At elevated temperature (60 C) all NMe2 groups of 11 are displayed as separate sixꢀproton
peaks (see Table 1 and Fig. S3). The most highꢀfield peak at δ 2.37 ppm definitely belongs to the
aniline moiety that follows from the correlation experiments, comparison with model compound 15
and very low dependence of its appearance on conditions. The latter testifies a spatial fixation of
this fragment possibly due to chelation (see below). Similarly, an assignment of the 1ꢀNMe2 and 8ꢀ
NMe2 groups was done using 2D NMR experiments and parallels with the reference compounds 14
and 16. At lowering temperature (CDCl3, 60 ꢀ –55 oC) only signals of 1ꢀNMe2 and 8ꢀNMe2 groups
undergo changes (broadening and doubling), likely caused by differences in nitrogen hybridization,
available free space and response on naphthalene ring flipping (Fig. S3).14,26 The estimated free

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energies of activation for the conformational processes giving rise to these spectral changes are ꢀG≠
16.0 kcal mol–1 for 8ꢀNMe2 (Tc 54 oC) and 13.2 kcal mol–1 for 1ꢀNMe2 (Tc 15 oC). For parent proton
sponge 1, the Nꢀmethyl singlet was shown to broaden and split below –120 oC what corresponds to
a ꢀG≠ 7.5 kcal mol–1 energetic barrier.26
Table 1 1H and 13C chemical shifts of NMe2 and OH groups in 11, its protonated form 11H+, and
reference compounds 14–16
Compd
Solvent
T, oC
δ, ppm
1ꢀNMe2
8ꢀNMe2
2.69
2’ꢀNMe2
2.37
2.37
(45.6)
2.36
2.35
2.35
2.29
(45.6)
2.54
–
OH
9.97
CDCl3
CDCl3
60
30
2.58
2.57
11
11
2.81/2.57a
(48.5/44.4)b
2.81/2.55
2.81/2.52
2.82/2.51
2.72/2.47
(48.4/44.7)
2.99/3.11
2.57
10.22
(44.8)
2.82/2.32
2.88/2.14
2.89/2.09
2.47
CDCl3
CDCl3
10
–30
–55
30
10.34
10.56
10.67
10.04
11
11
11
11
CDCl3
DMSOꢀd6
(44.9)
3.18/3.25
2.56
11H+
14
DMSOꢀd6
CDCl3
20
25
10.59
10.56
(47.5)
(43.4)
–
CDCl3
CDCl3
20
20
–
2.38
(46.3)
–
9.80
15
16c
2.77/2.56
2.60
10.78
(48.7/46.2)
(44.8)

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a
b
c
Separate peaks for each Nꢀmethyl fragment. Carbon shifts in parentheses. Due to very fast
rechelation of the OH proton between two proton sponge moieties at r.t. the averaged values of
chemical shifts are given.
As for chelation in 11, it is not easy to judge firmly about it from the data of Table 1. However,
1
o
based on the clear H–15N correlation between the H(OH) and N(2’) nuclei (DMSOꢀd6, 30 C, Fig.
S1), one can suggest that at least in DMSO the hydroxyl group forms IHB with the dimethylaniline
fragment as shown in structure 11a. Notably, such correlation is absent in CDCl3 at 30 oC, although
1
NOESY H–1H experiments in CDCl3 (Fig. S1) give rise to a correlation between hydroxyl and
N(2’) methyl protons indicating their spatial closeness and thus overall preferential attraction of the
OH group to the 2’ꢀNMe2 fragment in solution. On the whole, it follows that in CDCl3 the
rechelation 11a ⇄ 11b with a predominance of 11a may occur, whereas in DMSO the chelate 11a
is likely the only existing conformer. Such difference can be assigned to a somewhat higher dipole
moment of 11a in DMSO over that in CDCl3 and therefore to better solvation of this conformer in
more polar DMSO (see Table 3 below). However, this approach cannot be used for comparison of
these two conformers together since 11b is definitely more polar than 11a (Table 3). Obviously,
more powerful factors determine the preference of 11a in this case (see below).
Next, we have performed Xꢀray measurements for alcohol 11 and disclosed, in accord with the
above solution experiments, that it exists in crystals in form 11a (Fig. 2). In general, structural
characteristics of 11 are typical for such kind of compounds (Table 2, see also Table S1).9,10 At the
same time, several points deserve special comments. The most remarkable of them is the outꢀ
inversion of the 1ꢀNMe2 group. However, such a small 'outness' (sum of the CNC angles at the
nitrogen atom ΣN1 = 357.5o against 350.4o for ΣN1 in chelates like 1610) questions the participation
of the 1ꢀNMe2 group in the formation of enough strong IHB with the OH group.27 In contrast, the
pronounced pyramidalization (335.1o) of the aniline NMe2 group in 11 looks much more favorable
for chelation on the DMA residue. The second point is the parameters of IHB in 11a, which on the
whole lie closer to those of model compound 15, rather than to 14 and 16 (Table 2).

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Fig. 2 ORTEP plot for Xꢀray structure of 11 containing O–H…N(3) hydrogen bond
(P = 40%, 120 K).
Table 2 XꢀRay parameters of O–H…N bonding in 11, 11H+, and reference compounds 14–16
Compd
T, K
Distances (Å) and angles (o)
O–H
N…H
O…N
∠OHN
154
120
100
0.94
0.84
1.79
1.91 (N3…H)
1.34 (N1…H)
1.24 (N2…H)
1.74
2.666
2.677
11
11H+
152
14a
15b
16c
115
213
100
0.96
0.95
0.85
2.626
2.660
2.642
152
146
145
1.82
1.90
a Reference 9. b Reference 25. c Reference 10.
It seemed rather intriguing to look at protonation mode of alcohol 11. The question was,
whether it would bring to the formation of outꢀprotonated structure 11H+(A) with two coupled
N…H…O hydrogen bonds or to chelate 11H+ with isolated N–H…N and O–H…N ones (see Table
1
1). The H NMR spectroscopy leaves no doubt that the second option is implemented in solution.
1
Indeed, in the H NMR spectrum of perchlorate 11H+ in DMSOꢀd6 a very lowꢀfield peak (δ 19.54
ppm) of the chelated [NHN]+ proton, which is characteristic for the proton sponge cations,2 was
registered. All other spectral features, including those for the O–H…N hydrogen bond, were also
typical for such kind of compounds with a common lowꢀfield correction on the positively charged
species. As it was established by Xꢀray analysis, the same structure 11H+ is true for the crystal state

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(Fig. 3). Notably, that the N1…N2 distance in 11H+ equal to 2.54 Å is one of the shortest among all
known proton sponge cations2,28 and the N1 nitrogen atom is highly planarized (ΣCN1C = 348.1o)
unlike two other nitrogens: ΣN2 = 337.8o and ΣN3 = 335.6o (crystallographic numbering of the N
atoms as in Figs. 2 and 3).
Fig. 3 ORTEP plot for Xꢀray structure of 11·HClO4 containing both O–H…N neutral and N–H…N
–
charged hydrogen bonds (ClO4 anion is omitted for clarity, P = 50%, 100 K).
For a deeper insight into the structure of conformers 11a and 11b, we have conducted their DFT
calculations on the B3LYP/6ꢀ311+G(d,p) level of theory using the Gaussian 09 program complex
(see the Supplementary information for details). The theoretical analysis has been carried out in the
gas phase and solution (CHCl3 and DMSO) and the results obtained are presented in Table 3 and
Fig. S4. All conformers that are being discussed here correspond to minima on the potential energy
surface and their relative energies are also in favor of chelate 11a regardless of the media employed
(cf. experimental data above). As seen (Table 3), the calculated values of the bond lengths and
angles for the IHB in 11a are in a good agreement with the Xꢀray data (Table 2).

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Table 3 The calculated structural parameters of IHB, energy difference and dipole moments of
conformers 11a and 11b
Conformer
State
Distances and bond lengths, Å
∠OHN, ꢀE = E(11a) – ꢁ, D
degree
E(11b),a
kcal mol–1
O…N
O–H
N…H
gas phase
CHCl3
2.691
2.682
2.672
2.626
2.622
2.622
0.984
0.987
0.990
0.986
0.988
0.989
1.794
1.777
1.761
1.694
1.688
1.687
149.7
150.6
151.4
155.9
156.2
156.2
–
2.42
3.07
3.52
3.45
4.30
4.69
11a
11b
–
DMSO
gas phase
CHCl3
–
–2.76
–2.81
–2.93
DMSO
a For DFT optimized structures of conformers 11a and 11b and their energies see Fig. S4.
Although the IHB in chelate 11b looks geometrically more favorable (it is shorter and more
linear) than in 11a, the latter is by 2.76–2.93 kcal mol–1 more stable depending on conditions (Table
3). In principle, these values give a chance for crude estimating the outꢀbasicity of the 1ꢀNMe2
group in 11. Taking into account previously reported correlation between the hydrogen bond
basicity and pKa scale for a series of closely related compounds, for example secondary amines,29
and using the thermodynamic equation ꢀꢀGo = 2.3RTꢀpKa one can calculate that the pKa(out)
value for the N1 atom is about 3.1 in water and 9.3 in acetonitrile (see the Supplementary
information for details). However, this evaluation does not cause much confidence as unlikely
dimethylaniline and proton sponge can be considered as closely related compounds owing to large
stereochemical differences.30 Besides, quite a number of compounds are known whose protonation
and hydrogen bonding formation occurs at different basic centers. Michler’s ketone is especially
instructive example since on its treatment with a strong acid the corresponding ammonium ion is
formed, while the interaction with pentafluorophenol leads to the =O…H–O hydrogenꢀbonded
dimer.31
Out-protonation of the caged proton sponge-like compound. With the above in mind we then
selected a close and possibly the simplest proton sponge analogue with a rigid configuration

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allowing exclusively outꢀprotonation. To date, naphtho[1,8ꢀb,c]diazabicyclo[3.3.3]undecane (17)
seems to be the best, if not the only, model of such a kind. This compound was first described by
Alder and coꢀworkers who, however, did not report its basicity and proton salts.32 From structural
point of view, the most remarkable peculiarity of 17 consists in the ideally flat nitrogen atoms (ΣN
= 360o!).33 Besides, due to a very small inner cavity, such caged diamines as 17 are normally unable
to encapsulate a proton.21
Following the Alder’s procedure (somewhat simplified by us, see the Experimental section) we
prepared compound 17 and confirmed its original physical characteristics. Then, we estimated the
basicity strength of 17 by the competitive transprotonation technique using 1H NMR
spectroscopy.34 For this, tetrafluoroborate 17·HBF4 was obtained and subjected to the action of
neutral proton sponges of varying basicity. Salt 17·HBF4 was found to be completely deprotonated
by proton sponge 1, but when equilibrated with equimolar amount of 1,8ꢀbis(dimethylamino)ꢀ4ꢀ
nitronaphthalene in CD3CN, a much weaker base with pKa 14.11 in MeCN,35 only 77% of the initial
salt was deprotonated. This gave for 17 pKa ~13.1 (6.6 at extrapolation to water; cf. our alternative
estimate in note 30), that is 5.5 orders of ten lesser than that for the parent sponge 1. To our
knowledge, this is the first case of measuring basicity of the nitrogen atom whose free electron pair
occupies pure pꢀorbital.36
Then, we managed to grow crystals of 17·HBF4 appropriate for Xꢀray analysis and made sure
that the protonation of 17 indeed occurs from the outside (Fig. 4).38 Notably, that the protonated
nitrogen atom adopts somewhat pyramidal configuration with ΣN1 = 349.6o while its counterpart
remains practically planar with the negligible outꢀinversion (ΣN2 = 359.6o; cf. manxine 18 and its

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protonated form 18H+33,36). Another interesting point is that the internitrogen distance in 17H+
(2.887 Å) seems to be one of the largest among all known monoprotonated 1,8ꢀ
diaminonaphthalenes.39 The relative arrangement of the N–H proton and the counterion in salt
17·HBF4 is also significant. As seen, there is a F...H–N hydrogen bond with the F…H distance of
1.91 Å. This value is almost identical with the same value (1.92 Å) for the tetrafluoroborate of outꢀ
protonated N,N,N’ꢀtrimethylꢀ1,8ꢀdiaminonaphthalene40 and strongly differs from that of the proton
sponge salt 1·HBF4 (2.91 Å).41 Under these circumstances there is little doubt that the protonationꢀ
deprotonation of 17 should be diffusionꢀcontrolled (k ~1010 L mol–1 s–1) unlike proton sponges
which are protonatedꢀdeprotonated by 4–6 powers of ten slower.42 Such difference in the rates
might at least partially compensate much higher inꢀ over outꢀbasicity of the proton sponge thus
enhancing probability of its protonation from the outside (Scheme 1b).
Fig. 4 The molecular structure of salt 17·HBF4 showing close interaction (Å) between the NH
proton and counteranion (P = 50%, 100 K).
DFT study of interconversion between in- and out-protonated proton sponges. Evidently, the
second by importance question (after possibility of outꢀprotonation) is how easy the conversion
1H+(out) ꢀ 1H+(in) can proceed. To shed light on it we performed the DFT calculations of the
+
barrier to rotation of the NHMe2 group in conformer 1H+(out) around the C(1)–N bond with
control of the rotation angle defined as Θ(CCNH), where CC are the Cꢀ2 and Cꢀ1 carbon atoms of
the naphthalene core. A stepꢀbyꢀstep twisting from 20 to 180o gave a potential energy curve shown

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in Fig. 5. It should be noted, that as in many other proton sponge derivatives with the outꢀinverted
+
1ꢀNMe2 group,9,10 the NHMe2 group in the optimized structure 1H+(out) is already turned
relatively the mean ring plane on ca. 20o with the nitrogens being 3.080 Å apart. Before the NHꢀ
proton in structure 1H+(out) will anchor between the nitrogen atoms, one methyl group of the
+NHMe2 fragment must penetrate through the "eye of the needle" of the internitrogen cleft
overcoming strong repulsion with its methyl counterpart in the NMe2 fragment. The maximal
+
repulsion is reached at rotation of the NHMe2 group by 45o, what corresponds to a transition state
(Fig. 5, onset). At this state, the hydrogen atoms of the two opposing methyl groups are separated
by 2.448 Å only, while the nitrogen atoms are at a distance of 3.325 Å [2.632 Å in 1H+(in)]. As
seen, the gas phase activation barrier is as low as 11.3 kcal mol–1 that makes the transition 1H+(out)
ꢀ 1H+(in) rather easily reachable, especially in solution. This circumstance combined with the
much higher kinetic activity of the outꢀinverted nitrogen atom in the 1(in,out) form gives a
convincing support for the twoꢀstep mechanism beginning with preliminary outꢀprotonation of 1
(Scheme 1b). Of course, the conventional inside mechanism (Scheme 1a) looks still very attractive
because of its simplicity, much larger proportion of the 1(in,in) conformer and a strong negative
electrostatic potential inside the internitrogen space caused by the repulsion of the free nitrogen
electron pairs.43 Thus, our overall impression is that both protonation pathways shown in Scheme 1
can operate simultaneously though with yet indefinite proportion.

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TS
1H+(out)
1H+(in)
Fig. 5 Potential energy curve for the rotational interconversion of inꢀ and outꢀforms of
monoprotonated 1,8ꢀbis(dimethylamino)naphthalene (optimized key structures are shown with side
and top views with the amino groups directed to the viewer; TS ≡ transition state).
Conclusions
In summary, we have questioned for the first time the generally accepted mechanism of protonation
of the naphthalene proton sponge via a direct penetration of a proton into the internitrogen space to
form the highly stable chelated cation. It was opposed to the alternative twoꢀstep mechanism
involving preliminary protonation of the outꢀinverted NMe2 group with the following rotational
transfer of the NH proton into the internitrogen space. To estimate a possibility of this suggestion
two specially configured model compounds, 11 and 17·HBF4, were obtained and studied by
combination of physical and theoretical methods. The final conclusion is that each of these reaction
pathways has its own advantages and drawbacks and most likely that both contribute in the overall
process in a ratio which presently is difficult to determine accurately.
Experimental
1
General. Solution H and 13C NMR experiments were performed with 250 MHz and 600 MHz
spectrometers using the solvent residual peaks as the internal reference. EI MS were obtained at 70

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eV. All reagents and starting materials were from commercial sources and used without further
purification.
2-(Imino(phenyl)methyl)-N,N-dimethylaniline (A). To a solution of dimethylaniline (0.5 mL, 4.0
mmol) in absolute diethyl ether (25 mL), dry TMEDA (0.9 mL, 6.0 mmol) and nꢀbutyllithium (1.6
o
M solution in hexanes, 3.8 mL, 6.0 mmol) were added at 20 C. The reaction mixture was stirred
o
under argon atmosphere at room temperature for 24 h, cooled to –20 C and benzonitrile (0.6 mL,
6.0 mmol) was then added. The dark red colored reaction mixture was kept for additional 12 h
under inert atmosphere at –20 oC with stirring. After addition of water (25 mL), the orange colored
organic layer was separated and the water layer was extracted with Et2O (2 × 5 mL). The combined
organic phase was evaporated to dryness and the residue was chromatographed on Al2O3 with
Et2O/nꢀhexane (1:1) elution to give main orange fraction, which after removal of solvents afforded
1
imine A as orange oil (0.7 g, 77%). H NMR (250 MHz, CDCl3): δ 7.86–7.77 (m, 2H), 7.57–7.47
(m, 1H), 7.46–7.36 (m, 3H), 7.36–7.26 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H),
2.68 (s, 6H), the NH signal is not observable. 13C NMR (63 MHz, CDCl3): δ 178.6, 151.7, 139.4,
133.1, 132.5, 131.8, 130.8, 130.6, 128.5, 120.9, 118.0, 43.8. IR (CCl4, ν/cm–1): 3267 (NH), 3066,
3028, 2983, 2948, 2866, 2837, 2789 (CH), 1660 (C=N), 1600, 1574, 1495 (Ar). MS, m/z (I (%)):
224 [M]+ (23), 208 (79), 193 (32), 180 (19), 147 (78), 104 (59), 91 (30), 77 (100), 51 (54), 42 (25).
C15H16N2 (224.31): calcd. (%) C 80.32, H 7.19, N 12.49; found C 80.24, H 7.25, N 12.57.
o-Dimethylaminobenzophenone (12). A red colored solution of imine A (0.3 g, 1.3 mmol) in 10%
aqueous HCl (10 mL) was refluxed for 30 min, cooled to ambient temperature and neutralized with
10% aqueous ammonia. The product was extracted with CH2Cl2 (2 × 10 mL) and the solvent was
removed to dryness to give pure 12 as yellow oil (0.3 g, 99%), which crystallizes on storage; mp
o
1
49–50 C (compare with ref. 24). H NMR (250 MHz, CDCl3): δ 2.68 (s, 6H), 6.89 (m, 1H), 6.97
(d, J = 8.2 Hz, 1H), 7.27–7.46 (m, 4H), 7.48–7.58 (m, 1H), 7.77–7.87 (m, 2H).
(R,S)-[1,8-Bis(dimethylamino)naphthalene-2-yl][2-(dimethylamino)phenyl]-(phenyl)methanol
(11). A solution of ketone 12 (0.27 g, 1.2 mmol) in absolute diethyl ether (10 mL) was added

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dropwise to a solution of 2ꢀlithiumꢀ1,8ꢀbis(dimethylamino)naphthalene (13)9 (0.31 g, 1.4 mmol) in
absolute diethyl ether (20 mL) under argon atmosphere at –20 oC with stirring. The reaction mixture
was kept under these conditions for 72 h and mixed with water (50 mL). The orange colored
organic layer was separated, the water layer was extracted with Et2O (2 × 10 mL), the combined
organic phase was evaporated to dryness and the residue was twice recrystallized from acetonitrile.
o
1
This gave compound 11 (0.40 g, 65%) as pale yellow prisms with mp 158–159 C. H NMR (600
1
MHz, CDCl3, assignments made are based on H–13C HSQC and HMBC experiments): δ 2.37 (s,
6H, 2’ꢀNMe2), 2.57 (br m, 9H, 1ꢀNMe2 and 8ꢀNMe), 2.81 (br s, 3H, 8ꢀNMe), 6.64 (dd, 1H, 3J = 7.9,
4J = 1.3 Hz, Hꢀ6’), 6.76 (br d, 1H, 3J = 8.6 Hz, Hꢀ3), 6.99 (td, 1H, 3J = 8.1, 4J = 1.3 Hz, Hꢀ5’), 7.10
3
(br d, 1H, 3J = 6.0 Hz, Hꢀ7), 7.20–7.34 (m, 8H), 7.39 (br d, 1H, J = 7.8 Hz, Hꢀ5), 7.58 (very br m,
1
o
1H, Ph), 10.22 (br s, 1H, OH). H NMR (600 MHz, DMSOꢀd6, 30 C): δ 2.29 (s, 6H, 2’ꢀNMe2),
2.47 (br m, 9H, 1ꢀNMe2 and 8ꢀNMe, obscured with the solvent signal), 2.72 (br s, 3H, 8ꢀNMe),
6.48 (dd, 1H, 3J = 7.9, 4J = 1.3 Hz, Hꢀ6’), 6.60 (d, 1H, 3J = 8.6 Hz, Hꢀ3), 7.01 (td, 1H, 3J = 7.9, 4J =
3
4
1.3 Hz, Hꢀ5’), 7.10 (dd, 1H, J = 7.4, J = 1.1 Hz, Hꢀ7), 7.21–7.28 (m, 4H, Hꢀ4,4’,6,Ph), 7.31 (m,
3
3
3H, Ph), 7.37 (dd, 1H, J = 8.1, 4J = 1.1 Hz, Hꢀ5), 7.45 (dd, 1H, J = 8.1, 4J = 1.3 Hz, Hꢀ3’), 10.04
13
(br s, 1H, OH). C NMR (150 MHz, DMSOꢀd6, 30 oC): δ 44.7 (8ꢀNMe), 44.9 (1ꢀNMe2), 45.6 (2’ꢀ
NMe2), 48.4 (8ꢀNMe), 84.2 (C–OH), 115.2 (Cꢀ7), 122.6 (Cꢀ4), 123.5 (Cꢀ5), 124.1 (Cꢀ3’), 124.8 (Cꢀ
5’), 125.9 (Cꢀ6), 126.8 (Ph), 127.5 (Cꢀ9), 127.9 (Cꢀ4’, Ph), 128.3 (Ph), 128.6 (Cꢀ3), 129.3 (Cꢀ6’),
136.9 (Cꢀ10), 143.0 (Cꢀ2), 143.2 (Cꢀ1’), 148.2 (Cꢀ1), 149.4 (Ph), 151.6 (Cꢀ2’), 152.8 (Cꢀ8).
C29H33N3O (439.60): calcd. (%) C 79.23, H 7.57, N 9.56; found C 79.09, H 7.78, N 9.36.
Perchlorate 11·HClO4 was prepared on addition of 1 equiv of aqueous 60% HClO4 to a solution of
compound 11 in a minimum volume of EtOAc followed by 5ꢀfold dilution with Et2O. The residue
thus formed was washed with Et2O, vacuum dried and recrystallized from MeCN to give the desired
salt with 74% yield. Grey plates with mp 210–212 oC (decomp.). 1H NMR (250 MHz, DMSOꢀd6): δ
2.54 (s, 6H, 2’ꢀNMe2), 2.99 and 3.11 (both s, 6H), 3.18 and 3.25 (both d, 6H, 3J = 2.3 Hz), 6.56 (dd,
3
4
1H, J = 7.9, J = 1.4 Hz), 6.94–7.13 (m, 2H), 7.20–7.56 (m, 6H), 7.74–7.83 (m, 2H), 7.95 (d, 1H,

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3
3J = 8.0 Hz), 8.07 (br d, 1H, 3J = 7.9 Hz), 8.16 (br d, 1H, J = 6.8 Hz), 10.59 (br s, 1H, OH), 19.54
(br s, 1H, NH). C29H34ClN3O5 (540.06): calcd. (%) C 64.50, H 6.35, N 7.78; found C 64.32, H 6.46,
N 7.89.
Naphtho[1,8-b,c]-1,5-diazabicyclo[3.3.3]undecane (17) was synthesized in 5–6% yield according
to the published procedure32b using anhydrous K2CO3 as base, 2 equivs of 1,3ꢀdibromopropane and
refluxing in a 1:1 MeCN/PhMe solvent mixture for 16 h. Spectral and physical properties are as
1
those described in ref. 32b. H NMR (250 MHz, CDCl3): δ 1.30–1.50 (m, 4H, βꢀCH2), 3.28–3.39
and 3.46–3.57 (both m, 4H and 4H, αꢀCH2), 7.32 (br d, 2H, J = 6.8 Hz, Hꢀ2,7), 7.38 (t, 2H, J = 7.7
Hz, Hꢀ3,6), 7.72 (dd, 2H, J = 7.9, 1.8 Hz, Hꢀ4,5). Tetrafluoroborate 17·HBF4 was prepared on
addition of 1 equiv of aqueous 40% HBF4 to a solution of compound 17 in a minimum volume of
EtOAc followed by 5ꢀfold dilution with Et2O. The residue thus formed was washed with Et2O,
vacuum dried and recrystallized from Et2O–CH2Cl2 by diffusion to give the desired salt with 61%
o
yield. Colorless plates with mp 196–197 C. 1H NMR (600 MHz, CD3CN, 72 oC): δ 1.60–1.67 and
1.96–2.02 (both m, 2H and 2H, βꢀCH2), 3.40–3.97 (m, 8H, αꢀCH2), 7.63–7.72 (m, 4H, Hꢀ2,3,6,7),
1
8.03–8.19 (br s, 2H, Hꢀ4,5), 9.8 (very br s, 1H, NН). H NMR (600 MHz, CD3CN, 10 oC): δ 1.49–
1.56 and 1.88–1.99 (both m, 2H and 2H (the second being interfered with the solvent peak), βꢀ
CH2), 3.31–3.93 (m, 8H, αꢀCH2), 7.60–7.70 (m, 4H, Hꢀ2,3,6,7), 8.01 (br s, 1H, Hꢀ5), 8.17 (br s, 1H,
Hꢀ4), 10.04 (br s, 1H, NН). 1H NMR (600 MHz, CD3CN, –40 oC): δ 1.54–1.61 and 1.93–1.99 (both
m, 2H and 2H (the second being obscured by the solvent peak), βꢀCH2), 3.22–3.28, 3.47–3.60,
3.86–3.92 (all m, 2H, 4H, 2H, αꢀCH2), 7.57–7.63 (m, 3H, Hꢀ3,6,7), 7.69 (t, 1H, J = 7.6 Hz, Hꢀ2),
13
8.00 (br d, 1H, J = 8.2 Hz, Hꢀ5), 8.16 (br d, 1H, J = 8.0 Hz, Hꢀ4), 10.45 (br s, 1H, NН). C NMR
o
(150 MHz, CD3CN, 50 C): δ 24.3 (βꢀC), 53.5 and 59.6 (αꢀC), 125.4, 126.4, 129.4, 130.1, 131.9,
133.8 (2C), 134.7, 137.7, 142.8. 13C NMR (150 MHz, CD3CN, 10 oC, 1H–13C HSQC): δ 23.9 (βꢀC),
53.0 and 58.9 (αꢀC), 125.2 (Cꢀ3), 126.2 (Cꢀ7), 129.2 (Cꢀ5), 129.8 (Cꢀ2), 131.6 (Cꢀ9), 133.5 (Cꢀ4),
133.7 (Cꢀ6), 134.5 (Cꢀ1), 137.3 (Cꢀ10), 142.5 (Cꢀ8). C16H19BF4N2 (326.14): calcd. (%) C 58.92, H
5.87, N 8.59; found C 59.03, H 5.74, N 8.62.

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X-Ray diffraction analysis. Crystals suitable for Xꢀray studies were grown up by slow evaporation
from solutions of compounds in appropriate solvents or solvent mixtures: 11 (nꢀhexane), 11·HClO4
o
(MeCN), 17·HBF4 (obtained at –20 C by slow diffusion of Et2O into CH2Cl2 solution). The
structures were solved by direct method and refined by the fullꢀmatrix leastꢀsquares against F2 in
anisotropic (for nonꢀhydrogen atoms) approximation. All hydrogen atoms were placed in
geometrically calculated positions and were refined in isotropic approximation in riding model with
the Uiso(H) parameters equal to n·Ueq(Ci) (n = 1.2 for CH and CH2 groups and n = 1.5 for CH3
groups), where U(Ci) are respectively the equivalent thermal parameters of the atoms to which
corresponding H atoms are bonded. The H(N) hydrogen atoms were found in difference Fourier
synthesis and refined in isotropic approximation in riding model with the Uiso(H) parameters equal
to 1.2 Ueq(Ni), where U(Ni) are the equivalent thermal parameters of the N atom to which
corresponding H atom is bonded. The main crystallographic data and some experimental details are
given in Table S2. CCDC 956636–956638 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Financial support from the Russian Foundation for Basic Research (projects RFBR 11ꢀ03ꢀ00073
and 12ꢀ03ꢀ31172) is greatly acknowledged. We also thank Dr. Gennady S. Borodkin (Institute of
Physical and Organic Chemistry at Southern Federal University, RostovꢀonꢀDon) for NMR
measurements and Dr. Alexander V. Degtyarev (Southern Federal University, RostovꢀonꢀDon) for
his participation in the synthesis and crystal growing of compound 11. The authors acknowledge the
Wrocław Center for Networking and Supercomputing for generous computer time. XꢀRay
experiments were performed by Dr. Zoya A. Starikova (deceased on September 5, 2013) from A. N.
Nesmeyanov Institute of Organoelement Compounds, Moscow, Russian Federation.

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Electronic supplementary information available: NOESY 1H–1H and HMBC 1H–15N correlation
plots for alcohol 11; selected geometrical parameters and 1H NMR plots showing dynamic behavior
of substituents in 11; details of quantumꢀchemical calculations and DFT optimized structures of
1
conformers 11a and 11b; calculation of pKa(out) for the N1 atom in alcohol 11; H NMR plots
1
showing dynamic behavior of salt 17·HBF4; copies of H and 13C NMR spectra; crystal data and
structure refinement for compounds 11, 11·HClO4, and 17·HBF4. For ESI see DOI: …
References and notes
1 P. R. Mallinson, K. Wozniak, C. C. Wilson, K. L. McCormack and D. C. Yufit, J. Am. Chem.
Soc., 1999, 121, 4640–4646.
2 A. F. Pozharskii and V. A. Ozeryanskii, in The Chemistry of Anilines, ed. Z. Rappoport, J. Wiley
& Sons, Chichester, 2007, Part 2, ch. 17, pp. 931–1026.
3 (a) F. Hibbert, J. Chem. Soc., Perkin Trans. 2, 1974, 1862–1866; (b) R. W. Alder, P. S. Bowman,
W. R. S. Steele and D. R. Winterman, J. Chem. Soc., Chem. Commun., 1968, 723–724.
4 I. Kaljurand, A. Kütt, L. Soovali, T. Rodima, V. Mäemets, I. Leito and I. A. Koppel, J. Org.
Chem., 2005, 70, 1019–1028.
5 R. L. Benoit, D. Lefebvre and M. Frechette, Can. J. Chem., 1987, 65, 996–1001.
6 M. Darabantu, T. Lequeux, J.ꢀC. Pommelet, N. Ple, A. Turck and L. Toupet, Tetrahedron Lett.,
2000, 41, 6763–6767.
7 A. SzemikꢀHojniak, J. M. Zwier, W. J. Buma, R. Bursi and J. H. Van der Waals, J. Am. Chem.
Soc., 1999, 120, 4840–4844.
8 A. F. Pozharskii, O. V. Ryabtsova, V. A. Ozeryanskii, A. V. Degtyarev, Z. A. Starikova, L.
Sobczyk and A. Filarowski, Tetrahedron Lett., 2005, 46, 3973–3976.
9 A. F. Pozharskii, A. V. Degtyarev, O. V. Ryabtsova, V. A. Ozeryanskii, M. E. Kletskii, Z. A.
Starikova, L. Sobczyk and A. Filarowski, J. Org. Chem., 2007, 72, 3006–3019.

Page 21 of 24
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10 A. F. Pozharskii, A. V. Degtyarev, V. A. Ozeryanskii, O. V. Ryabtsova, Z. A. Starikova and G.
S. Borodkin, J. Org. Chem., 2010, 75, 4706–4715.
11 A. F. Pozharskii, O. V. Ryabtsova, V. A. Ozeryanskii, A. V. Degtyarev, O. N. Kazheva, G. G.
Alexandrov and O. A. Dyachenko, J. Org. Chem., 2003, 68, 10109–10122.
12 N. J. Farrer, R. McDonald and J. S. McIndoe, J. Chem. Soc., Dalton Trans., 2006, 4570–4579.
13 One of the referees called our attention that LloydꢀJones in order to explain why the
dialkylamino groups stay still stereolabile in some proton sponge salts put forward an idea that
the stereodynamics observed in the in-protonated form can be realized through IHB fission and
rotationꢀinversion of the non-protonated nitrogen center: P. Hodgson, G. C. LloydꢀJones, M.
Murray, T. M. Peakman and R. L. Woodward, Chem. Eur. J., 2000, 6, 4451–4460. However,
this interesting work is not directly related to the mechanisms of protonation raised in the
present paper.
14 R. W. Alder and S. P. East, Chem. Rev., 1996, 96, 2097–2111.
15 J.ꢀC. Chambron and M. Meyer, Chem. Soc. Rev., 2009, 38, 1663–1673.
16 R. W. Alder, A. Casson and R. B. Sessions, J. Am. Chem. Soc., 1979, 101, 3652–3653.
17 P. B. Smith, J. L. Dye, J. Cheney and J.ꢀM. Lehn, J. Am. Chem. Soc., 1981, 103, 6044–6048.
18 Y. Miyahara, Y. Tanaka, K. Amimoto, T. Akazawa, T. Sakuragi, H. Kobayashi, K. Kubota, M.
Suenaga, H. Koyama and T. Inazu, Angew. Chem., Int. Ed. Engl., 1999, 38, 956–959.
19 J. Springborg, C. E. Olsen and I. Sotofte, J. Chem. Soc., Perkin Trans. 2, 1999, 2701–2706.
20 J. Springborg, B. Nielsen, C. E. Olsen and I. Sotofte, J. Am. Chem. Soc., 2002, 124, 5084–5090.
21 R. W. Alder, R. E. Moss, R. B. Sessions, J. Chem. Soc., Chem. Commun., 1983, 997–998.
22 R. W. Alder, J. Am. Chem. Soc., 2005, 127, 7924–7931.
23 A. J. Hoefnagel, M. A. Hoefnagel and B. M. Wepster, J. Org. Chem., 1981, 46, 4209–4211.
24 In this work, ketone 12 was obtained via previously unknown procedure (see Experimental
section). To specify, benzonitrile was treated by 2ꢀlithiumꢀN,Nꢀdimethylaniline (10) to give
isolable and rather stable imine A, which then was subjected to acid hydrolysis. This approach,

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as compared with recently described method (A. V. Dubrovskiy and R. C. Larock, Org. Lett.,
2011, 13, 4136–4139), provides nearly the same efficiency but utilizes more available starting
reagents.
25 H. T. AlꢀMasri, J. Sieler, P. Lönnecke, S. Blaurock, K. Domasevitch and E. HeyꢀHawkins,
Tetrahedron, 2004, 60, 333–339.
26 R. W. Alder and J. E. Anderson, J. Chem. Soc., Perkin Trans. 2, 1973, 2086–2088.
27 The hydrogen chelation of a nitrogen atom with so pronounced planarity as in 16 was previously
claimed as a record8,10 and apparently remains so. In any case, we found no such precedents in
the Cambridge Structural Database.
28 Up to now, the shortest [N–H…N]+ bond (2.524 Å) has been registered for HClO4 salt of 1,8ꢀ
bis(dimethylamino)ꢀ2,7ꢀbis(trimethylsilyl)naphthalene: A. V. Degtyarev, O. V. Ryabtsova, A.
F. Pozharskii, V. A. Ozeryanskii, Z. A. Starikova, L. Sobczyk and A. Filarowski, Tetrahedron,
2008, 64, 6209–6214.
29 J. Graton, M. Berthelot and C. Laurence, J. Chem. Soc., Perkin Trans. 2, 2001, 2130–2135.
30 In this respect it might be more reasonable to draw the parallels not between the proton sponge
and dimethylaniline fragment but rather between the proton sponge and benzo[b]quinuclidine
system, whose nitrogen pyramidal configuration is not significantly changed on protonation.
Such approach gives much more reasonable outꢀpKa value of 5.7 (see the Supplementary
information for details).
31 T. Gramstad, S. Husebye, K. MaartmannꢀMoe and J. Saebo, Acta Chem. Scand., 1987, B41,
555–563.
32 (a) R. W. Alder, N. C. Goode, T. J. King, J. M. Mellor and B. W. Miller, J. Chem. Soc., Chem.
Commun., 1976, 173–174; (b) R. W. Alder, M. R. Bryce, N. C. Goode, N. Miller and J. Owen,

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J. Chem. Soc., Perkin Trans. 1, 1981, 2840–2847; (c) R. W. Alder, M. R. Bryce and N. C.
Goode, J. Chem. Soc., Perkin Trans. 2, 1982, 477–483.
33 Actually, there are very few examples of organic nitrogen bases with the perfectly flat nonꢀ
conjugated nitrogen atoms (R. W. Alder, Chem. Rev., 1989, 89, 1215–1223). Remarkably, that
in all of them the high planarity is reached via introduction of special auxiliary groups or
heteroatoms (for some examples see Chart S1). In none of these cases the pKa values were
determined. The only exception may be manxine 18, for which no Xꢀray information is
available, but whose nitrogen planarity was indirectly deduced from the photoelectron spectrum:
D. H. Aue, H. M. Webb and M. T. Bowers, J. Am. Chem. Soc., 1975, 97, 4136–4137.
34 H. A. Staab, A. Kirsch, T. Barth, C. Krieger and F. A. Neugebauer, Eur. J. Org. Chem., 2000,
1617–1622.
35 L. A. Kurasov, A. F. Pozharskii, V. V. Kuz’menko, N. A. Klyuev, A. I. Chernyshev, S. S.
Goryaev and N. L. Chikina, Zh. Org. Khim., 1983, 19, 590–597; Chem. Abstr., 1983, 99,
22064v.
36 Strictly speaking, the pKa value of 6.6 should not be associated with the basicity of the perfectly
planar nitrogen atom because the later in 17 is under the influence of –Iꢀeffect of the aromatic
system. A comparison of basicities of quinuclidine (pKa = 10.95, H2O/EtOH, 1:1, v/v) and
benzoquinuclidine (pKa 7.79, H2O, 25 oC) shows that the –Iꢀeffect of the benzene ring decreases
basicity of the nonꢀconjugated nitrogen by c.a. 3 pKa units. This means that the freeꢀofꢀ
inductiveꢀeffect pKa value of 17 would be about 10, which lies surprisingly close to the above
pKa value for the nonꢀconjugated manxine 18. Importantly, that planar nitrogen atom on
protonation uses for bonding not pure pꢀorbital but partially hybridized one. This provides
higher stereodirection of the orbital and therefore the formation of a stronger N–H bond.
Simultaneously, the nitrogen atom undergoes some pyramidalization to minimize the repulsion
of the bonding orbitals in thus forming ammonium ion (Gillespie rule). Nevertheless, in case of
17·HBF4 the nitrogen flattening is still remarkably large (ΣN1 = 349.6o against 346.5o for 18·H+

Organic & Biomolecular Chemistry
Page 24 of 24
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DOI: 10.1039/C3OB41986J
[A. H.ꢀJ. Wang, R. J. Missavage, S. R. Byrn and I. C. Paul, J. Am. Chem. Soc., 1972, 94, 7100–
+
7104] and 328.5o for NH4 ion) that corresponds to a 93% pꢀcharacter of hybridization.37
Possibly, the value of ΣN1 = 349.6o found for 17·HBF4 is the largest among all known
ammonium salts with expanded C–N–C angles if neglecting the hydrogen bonded flattened
amines like 16 (ΣN1 = 350.4o).8,10
37 (a) N. G. Korzhenevskaya, M. M. Mestechkin and A. A. Matveev, Zh. Obshch. Khim., 1992, 62,
626–628 [Russ. J. Gen. Chem., 1992, 62, Engl. Trans.]; (b) N. G. Korzhenevskaya, V. I.
Rybachenko and G. Schroeder, Tetrahedron Lett., 2002, 43, 6043–6045.
38 The 1H NMR spectra of salt 17·HBF4 are temperatureꢀdependent displaying a tendency to proton
averaging (Fig. S5). Thus, although most protons in the CD3CN solution appears as a complex
set of overlapping signals, the peaks of the periꢀhydrogens Hꢀ4 and Hꢀ5 are rather indicative.
o
o
Below 60 C they are nonꢀequivalent, at 60 C they coalesce and give a broaden twoꢀproton
o
signal at 72 C. We assign this behavior to a proton exchange between two nitrogen atoms, in
which the solvent, water molecules, counter ion or even 17H+ act as the shuttles.
39 C. Cox, H. Wack and T. Lectka, Angew. Chem., Int. Ed. Engl., 1999, 38, 798–800.
40 V. A. Ozeryanskii, A. F. Pozharskii, A. Filarowski and G. S. Borodkin, Org. Lett., 2013, 15,
2194–2197.
41 K. Wozniak, T. M. Krygowski, B. Kariuki, W. Jones and E. Grech, J. Mol. Struct., 1990, 240,
111–118.
42 F. Hibbert, Acc. Chem. Res., 1984, 17, 115–120.
43 Notably, the energy difference between the 1H+(in) and 1H+(out) forms equal to 18.8 kcal mol–1
is in favor of the former; what is more important, the reverse conversion of 1H+(in) into
1H+(out) is definitely impossible, at least under wide range of reasonable conditions, due to a
very large activation barrier of 30 kcal mol–1.