4,5-bis(dimethylamino)quinolines: Proton sponge versus azine behavior

Article abstract of DOI:10.1021/ol301777s

Two first representatives, 5 and 6, of the still unknown 4,5-bis(dimethylamino)quinoline have been synthesized and studied. While the former, being protonated either at the peri-NMe₂ groups or at the ring nitrogen, has been shown to display pro

Full text of DOI:10.1021/ol301777s

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4134–4137
4,5-Bis(dimethylamino)quinolines:
Proton Sponge versus Azine Behavior
Olga V. Dyablo,† Elena A. Shmoilova,† Alexander F. Pozharskii,*,†
Valery A. Ozeryanskii,† Oleg N. Burov,† and Zoya A. Starikova‡
Department of Organic Chemistry, Southern Federal University, Zorge str. 7,
Rostov-on-Don 344090, Russian Federation, and A. N. Nesmeyanov Institute of
Organoelement Compounds, Russian Academy of Sciences, Vavilova str. 28,
Moscow 119991, Russian Federation
apozharskii@sfedu.ru
Received June 28, 2012
ABSTRACT
Two first representatives, 5 and 6, of the still unknown 4,5-bis(dimethylamino)quinoline have been synthesized and studied. While the former,
being protonated either at the peri-NMe2 groups or at the ring nitrogen, has been shown to display properties of both a proton sponge and azine, its
counterpart 6 behaves exclusively as azine giving only a quinolinium salt.
It is well-known that the abnormally high basicity
(pKa = 12.1, H2O;1 7.5, DMSO2) of 1,8-bis(dimethyl-
amino)naphthalene 1 (‘proton sponge’) is commonly at-
tributed to (1) the steric and electrostatic repulsion of peri-
NMe2 groups and (2) the formation of rather strong
intramolecular H-bonding in protonated form 2.3 Both
of these structural principles are widely used for the
design of many other superbases.4 For example, quino-
[7,8:70,80]quinoline 3issomewhatmorebasic (pKa =12.8)5
than 1 although, strictly speaking, it cannot be classified as
a proton sponge because of its high kinetic activity and
nucleophilicity.4a In view of this, still unknown 4,5-bis-
(dimethylamino)quinoline 4 appears to a much larger
extent as a member of the proton sponge family. In the
present letter we report the synthesis and some properties
of the two first derivatives of 4, namely quinolines 5 and 6
(Scheme 1). Our interest in the compounds of this group
was initiated by not only their basic properties but also
close structural proximity to 4-dimethylaminopyridine 7, a
popular catalyst (known as DMAP) for acylation and
alkylation reactions.6 Compound 7with a rather high basicity
(pKa = 9.66, H2O)6c is protonated exclusively at the ring
N-atom producing cation 7Hþ due to the strong þM-effect
of the 4-NMe2 group. Therefore, an intriguing question
about the protonation site in molecules 4ꢀ6 arises: will
they behave more as proton sponges or azines similar to 1
or 7, respectively? Obviously, answering the question can
be important for the catalytic activity of compounds 4ꢀ6.
Quinolines 5 and 6 together with minor quantities of
monomethylated products 10 and 11 were obtained by
alkylation of 8 and 9 in accordance with the protocol pre-
viously suggested for such kinds of diamines (Scheme 2).7,8
Amines 8 and 9, in turn, were prepared via quite simple
† Southern Federal University.
‡ Institute of Organoelement Compounds.
(1) Hibbert, F. J. Chem. Soc., Perkin Trans. 2 1974, 1862.
(2) Benoit, R. L.; Lefebvre, D.; Frechette, M. Can. J. Chem. 1987,
65, 996.
(3) (a) Pozharskii, A. F.; Ozeryanskii, V. A. In The Chemistry of
Anilines; Rappoport, Z., Ed.; J.Wiley & Sons: Chichester, 2007; Part 2,
Chapter 17, pp 931ꢀ1026. (b) Alder, R. W. Chem. Rev. 1989, 89, 1215.
(c) Howard, S. T. J. Am. Chem. Soc. 2000, 122, 8238.
(4) (a) Pozharskii, A. F.; Ozeryanskii, V. A.; Filatova, E. A. Chem.
Heterocycl. Compd. 2012, 48, 200. (b) Ishikawa, T., Ed. Superbases for
Organic Synthesis; J. Wiley & Sons: 2009.
(6) (a) Scriven, F. V. Chem. Soc. Rev. 1983, 12, 129. (b) Heinrich,
M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H. Angew. Chem., Int.
(5) (a) Zirnstein, M. A.; Staab, H. A. Angew. Chem., Int. Ed. 1987, 26,
€
€
€
460. (b) Wustefeld, H.-U.; Kaska, W. C.; Schuth, F.; Stucky, G. D.; Bu,
Ed. 2003, 42, 4826. (c) Soovali, L.; Rodima, T.; Kaljurand, I.; Kutt, A.;
X.; Krebs, B. Angew. Chem., Int. Ed. 2001, 40, 3182.
Koppel, I. A.; Leito, I. Org. Biomol. Chem. 2006, 4, 2100.
r
10.1021/ol301777s
Published on Web 08/03/2012
2012 American Chemical Society

Scheme 1. Naphthalene Proton Sponge 1, 4-Dimethylamino-
pyridine 7, and Their Quinoline Analogues 3ꢀ6
multistep synthesis starting from o-toluidine (Schemes
S1ꢀS3, Supporting Information (SI)).
Scheme 2. Methylation of 5-Amino-4-dimethylaminoquino-
lines 8 and 9
Figure 1. Molecular structures of ammonium-type 5HþA
(above) and quinolinium-type cations 6HþB (below) (picrate
anions are omitted for clarity; thermal ellipsoids drawn at the
50% probability level).
Heterocyclic diamines 5 and 6 are pale yellow oils with
yellow-green fluorescence, whose structure was proven by
1H, 13C NMR and mass spectra. Both bases were also
characterized as picrates and perchlorates. For the mono-
picrates, X-ray structural analysis has been performed
(Figure 1), which revealed the completely different behav-
iors of bases 5 and 6 upon protonation.9 The molecular
structure of 5 PicOH is formed by two independent
proton-sponge-like cations 5HþA having an asymmetric
hydrogen bridge between the peri-NMe2 groups with the
3
˚
following parameters: N(1)ꢀH, 0.88 A; N(2)...H,
˚
˚
1.80ꢀ1.81 A; N...N, 2.620ꢀ2.634 A; —NHN, 155ꢀ. To
our knowledge, this is the first example of protonation of
a dimethylamino group conjugated with the aza-group
in the azine series. Unlike 5, base 6 is protonated ex-
clusively at the ring nitrogen atom giving quinolinium
cation 6HþB.
(7) Sorokin, V. I.; Ozeryanskii, V. A.; Pozharskii, A. F. Eur. J. Org.
Chem. 2003, 496.
(8) The high total yields of 5,6 and 10,11 testify that no alkylation at
the ring heteroatom seems to occur under these conditions. Obviously,
such low nucleophilicity of the quinoline nitrogen atom in these com-
pounds results from its strong shielding by 2- and 8-substituents (see, for
example, Pozharskii, A. F. Theoretical bases of heterocyclic chemistry;
Khimia: Moscow, 1985; p 135).
A more complicated picture is observed for the proto-
nation of compounds 5 and 6 in solution. According to the
1H NMR spectra, the equilibrium of two protonated forms
(5HþA and 5HþB) is established for hydrogen picrate or
hydrogen perchlorate of quinoline 5. Indeed, proton NMR
spectroscopy demonstrates two clear sets of hydrogen
signals, of which NH-peaks are especially indicative
(Figure 2). Thus, the proton bound to the pyridine nitro-
gen (5HþB form) resonates at δ 7.4ꢀ9.1 ppm, while the
(9) Selected data for 5H PicO: C22H27N7O7, M = 501.51, orthor-
3
˚
˚
˚
hombic, Pca21, a = 20.6019(14) A, b = 7.0886(5) A, c = 32.075(3) A,
˚
3
V = 4684.2(6) A , Z = 8, Dcalcd = 1.422 g/cm3, μ = 0.108 mmꢀ1
,
T = 100 K, independent reflections 9151, variables 663, R1 = 0.0535
(I > 2σ(I)), wR2 (all data) = 0.1015, CCDC Ref. No. 888288. Selected
data for 6H PicO H2O: C21H26N6O8, M = 490.48, monoclinic, P21/n,
3
3
3
˚
˚
˚
a = 17.4712(13) A, b = 6.9550(5) A, c = 19.6475(14) A, β = 108.812(2)ꢀ,
V = 2259.9(3) A , Z = 4, Dcalcd = 1.442 g/cm3, μ = 0.112 mmꢀ1
,
˚
T = 100 K, independent reflections 5948, variables 317, R1 = 0.0562
(I > 2σ(I)), wR2 (all data) = 0.1045, CCDC Ref. No. 888289.
Org. Lett., Vol. 14, No. 16, 2012
4135

Table 1. Chemical Shifts of NH Protons in the 1H NMR Spectra of Quinolinium Picrates Containing Cations 5Hþ and 6Hþ, Polarity of
the Protonated Forms, and Their Ratio
calculated gas-phase dipole
δNH (ppm)
content (%)
moment for forms A and B (D)
dipole moment of
the solvent (D)14
cation
solvent
CDCl3
A
B
A
B
Aa
B
5Hþ
1.15
1.85
3.38
4.26
“
17.07
17.45
17.37
17.07
17.07
17.78
9.12
7.36
8.17
9.12
9.12
8.85
15
5
85
95
7.14
2.82
ClD2CCD2Cl
CD3CN
50
55
55
58
0
50
DMSO-d6
45
b
DMSO-d6
45
acetone-d6
CDCl3
2.70
1.15
1.85
3.38
4.26
“
42
6Hþ
12.97
11.92
10.07
11.58
11.57
11.42
100
100
100
100
100
100
7.02
4.04
ClD2CCD2Cl
CD3CN
0
0
DMSO-d6
0
b
DMSO-d6
0
acetone-d6
2.70
0
a Average value for two forms A0 and A00 with protons localized on the 4- or 5-NMe2 groups, respectively. The difference in calculated dipole moments
for both of these forms does not exceed 3%. b Data for perchlorates.
1
Figure 2. Equilibrium mixture of protonated forms 5HþA and 5HþB of compound 5 (as 5 PicOH) as evidenced by H NMR in
DMSO-d6 solution (only selected regions are presented).
3
proton captured by the amine nitrogens (5HþA tautomer)
gives a signal ata muchlower field (17.1ꢀ17.8ppm) typical
for the cations of all proton sponges.3a The ratio of both
forms is highly sensitive to the solvent used (Table 1).
While form B strongly predominates in media of low
polarity (CDCl3, ClD2CCD2Cl), a percentage of two
forms becomes commensurable in more polar solvents
such as CD3CN, DMSO-d6, or CD3COCD3. This is in
accord with the theoretical estimations (Table S1, SI),
which show a much higher polarity of form 5HþA that
enables its more effective solvation in polar media.
Under similar conditions protonated 4,5-bis(dimethyl-
amino)-2,8-dimethylquinoline (6Hþ) behaves differently.
1
First, only one NH signal is observed in its H NMR
spectra with the δNH chemical shift varying, depending on
the solvent, from 10.1 to 13.0 ppm; obviously, this corre-
sponds to a protonation of the aza-group only. Second, a
transition from nonpolar to polar solvents does not
4136
Org. Lett., Vol. 14, No. 16, 2012

influence the picture though form 6HþA is again more
polar than 6HþB (Table 1). Using a competitive method,10
1H NMR spectra of equimolar mixtures of salts
between base 6 and perchlorate 5HþClO4 (Figure
ꢀ
S3.20, SI). We assume that using 2-Me instead of the
much more electron-donating 2-NMe2 group causes
such dramatic consequences in protonation because of
solvation factors. This assumption is in agreement with
the DFT calculations of gas-phase proton affinities (PA)
of both bases. Indeed, PA values of 5 and 6 are equal to 264.9
and 263.9 kcal molꢀ1, respectively; that is, in the absence of
solvation factors the former is more basic (Table S1, SI).13
Further studies on the synthesis of the parent proton
sponge 4 as well as a more detailed exploration of the
properties of compounds 4ꢀ6 are underway.
5HþClO4 or 6HþClO4 and proton sponge 1 were
measured in DMSO-d6. From this, the pKa value for
protonation of 6 at the aza-group has been estimated as
being 7.2 which is only slightly lower than that for the
naphthalene sponge 1. The pKa values for protonation of
5 at the peri-NMe2 groups and ring nitrogen atom are
roughly equal to 6.5 and 6.3, respectively (Figures S3.21
and S3.22, SI). Thus, the proton sponge site in 5 is by one
power of ten less basic than that in 1. Evidently, such
a difference reflects an interplay between the electron-
acceptor action of the aza-group and the electron-donor
ability of the 2-NMe2 and 8-Me groups. Indeed, the
basicity of structurally related 1,8-bis(dimethylamino)-4-
nitronaphthalene is considerably lower (pKa =3.5,DMSO)11
despite the fact that the electron-accepting strength of
aza- and NO2 groups is actually close.12
ꢀ
ꢀ
In summary, we have synthesized two first representa-
tives of 4,5-bis(dimethylamino)quinoline and have found
that they behave at protonation either as typical azines
(2,8-dimethyl derivative) or as proton sponge and azine
simultaneously (2-dimethylamino derivative). The proton
sponge pattern is strongly dependent on the aggregate state,
the solvent used and the nature of substituents. A possibility of
protonation of the NMe2 group in azine series conjugated with
the ring heteroatom has been demonstrated for the first time.
One of the most interesting phenomena observed in this
work is an essentially higher basicity of 6 in comparison
with 5. This difference in basicity has been independently
confirmed by the 1H NMR competitive experiment
Acknowledgment. This work was supported by the
Russian Foundation for Basic Research (Project No.
11-03-00073).
(10) (a) Birchal, T.; Jolly, W. L. J. Am. Chem. Soc. 1966, 88, 5439.
(b) Staab, H. A.; Kirsch, A.; Barth, T.; Krieger, C.; Neugebauer, F. A.
Eur. J. Org. Chem. 2000, 1617.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Ozeryanskii, V. A.; Pozharskii, A. F.; Vistorobskii, N. V. Russ.
Chem. Bull. 2000, 49, 1212.
(12) Deady, L. W.; Shanks, R. A. Aust. J. Chem. 1972, 25, 431.
(13) Geometrically, compound 5 is similar to 2,6-diisopropylpyridine
(pKa = 5.34, EtOHꢀH2O, 1:1, v/v, 25 ꢀC) which is less basic than 2,
6-dimethylpyridine (pKa = 5.77) despite the larger þI-effect of an i-Pr
group in comparison with the methyl. It is generally accepted that this is
caused by the lower solvation of the 2,6-diisopropylpyridinium cation
because of steric hindrances. (a) Roithova, J.; Exner, O. J. Phys. Org.
Chem. 2001, 14, 752. (b) Brown, H. C.; Kanner, B. J. Am. Chem. Soc.
1966, 88, 986.
(14) Reichardt, Ch. Solvents and Solvents Effects in Organic Chem-
istry; VCH: Weinheim, 1988.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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