A concept for stimulated proton transfer in 1-(phenyldiazenyl)naphthalen-2-ols

Article abstract of DOI:10.1016/j.dyepig.2018.03.070

A series of aryl azo derivatives of naphthols (1–3) were studied by means of UV–Vis and NMR spectroscopy in different solvents as well as by quantum chemical calculations and X-ray analysis. Previous studies have shown that Sudan I (1) exists as a tautomeric mixture. The effect of the solvents is minimized by the existing intramolecular hydrogen bond. Therefore, the influence on the tautomeric state in structurally modified 1 has been investigated. Structure 2 contains an additional OH-group, which deprotonates easily and affects the position of the tautomeric equilibrium by changing the electronic properties of the substituent. The implementation of a sidearm in 3 creates a condition for competition between the nitrogen from the azo group and from the piperidine unit for the tautomeric proton. In this case the use of acid as a stimulus for controlling the tautomeric process was achieved.

Full text of DOI:10.1016/j.dyepig.2018.03.070

Accepted Manuscript
A concept for stimulated proton transfer in 1-(phenyldiazenyl)naphthalen-2-OLS
S. Hristova, V. Deneva, M. Pittelkow, A. Crochet, F.S. Kamounah, K.M. Fromm, P.E.
Hansen, L. Antonov
PII:
S0143-7208(18)30216-X
10.1016/j.dyepig.2018.03.070
DYPI 6655
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 29 January 2018
Revised Date: 7 March 2018
Accepted Date: 29 March 2018
Please cite this article as: Hristova S, Deneva V, Pittelkow M, Crochet A, Kamounah FS, Fromm KM,
Hansen PE, Antonov L, A concept for stimulated proton transfer in 1-(phenyldiazenyl)naphthalen-2-OLS,
Dyes and Pigments (2018), doi: 10.1016/j.dyepig.2018.03.070.
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ACCEPTED MANUSCRIPT
A CONCEPT FOR STIMULATED PROTON TRANSFER IN 1-
(PHENYLDIAZENYL)NAPHTHALEN-2-OLS
S. Hristovaa, V. Denevaa, M. Pittelkowb, A. Crochetc, F. S. Kamounahb, K. M. Frommc, P. E.
Hansend, L. Antonova
a Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of
Sciences, Acad. G. Bonchev str., bl. 9, 1113 Sofia, Bulgaria
b University of Copenhagen, Department of Chemistry, Universitetsparken 5, DK-2100
Copenhagen, Denmark
c University of Fribourg, Department of Chemistry, Chemin du Musée 9, CH-1700 Fribourg,
Switzerland
d Roskilde University, Department of Science and Environment, Roskilde, DK-4000,
Denmark
Abstract:
A series of aryl azo derivatives of naphthols (1-3) were studied by means of UV-Vis and
NMR spectroscopy in different solvents as well as by quantum chemical calculations and X-
ray analysis. Previous studies have shown that Sudan 1 (1) exists as a tautomeric mixture. The
effect of the solvents is minimized by the existing intramolecular hydrogen bond. Therefore,
the influence on the tautomeric state in structurally modified 1 has been investigated.
Structure 2 contains an additional OH-group, which deprotonates easily and affects the
position of the tautomeric equilibrium by changing the electronic properties of the substituent.
The implementation of a sidearm in 3 creates a condition for competition between the
nitrogen from the azo group and from the piperidine unit for the tautomeric proton. In this
case the use of acid as a stimulus for controlling the tautomeric process was achieved.
Keywords: tautomerism, molecular switches, molecular spectroscopy, azo dyes
1

ACCEPTED MANUSCRIPT
1. Introduction:
Aromatic azo derivatives are one of the largest and the most important classes of colorants.
Their practical and theoretical importance has been reflected in textiles, food, paper printing,
nonlinear optical (NLO) devices and liquid crystalline displays (LCDs) [1]. Most of the
azodyes are tautomeric ones, and therefore the study of their tautomerism is of practical and
fundamental significance. Moreover, some structurally modified tautomeric azonaphthols are
recently considered as a promising prototype compounds for the development of new systems,
exploiting controlled proton transfer for signal conversion and for use in molecular electronics
[2]. This can be achieved by implementing an antenna - host (crown ethers or similar
macrocyclic receptors), which transfers the signal from external stimuli to the tautomeric
backbone [3,4]. In such a way, the change in the tautomeric state results from
appearance/disappearance of the external stimuli. The sensitivity of the electronic ground and
excited states of the tautomeric forms to the environment stimuli (light, pH, T, solvents), and
to the presence of a variety of substituents or hydrogen bonding motifs are used as tools to
tune the expected action. Our previous studies on 4-(phenyldiazenyl)naphthalen-1-ol
derivatives, in which a side moiety is connected to a tautomeric unit [4], showed that, when
the tautomeric proton becomes part of a stabilizing, intramolecular hydrogen-bonding system,
a full shift of the tautomeric equilibrium to the enol form is achieved. In such compounds
controlled shift in the position of the tautomeric equilibrium can be accomplished through
protonation/deprotonation or complexation. In these systems, the tautomeric proton is
transferred through a long distance, which makes it very sensitive to the solvent used.
Therefore, it is interesting to see how the antenna could behave, when the proton exchanges
through intramolecular hydrogen bonds within the tautomeric unit.
Sudan I (1-(phenyldiazenyl)naphthalene-2-ol), the most intensively used azo dye [5,6], is a
typical example for the effect of the intramolecular hydrogen bonding on the proton transfer.
Previous studies have shown that Sudan I (1) always exists as a tautomeric mixture in solution
[7,8]. Having in mind that the specific effects of the solvents are minimized by the existing
intramolecular hydrogen bond, the solvent polarity plays an important role - in non-polar
solvents such as i-octane and tetrachloromethane 1a (enol, azo) form predominates, while in
more polar solvents (like methanol) the opposite effect is observed and form 1b (keto-
hydrazo) prevails (Scheme1).
The aim of this study is to investigate how structural modifications in 1 can influence its
tautomerism. Structure 2 contains an additional OH-group which is expected to deprotonate
2

ACCEPTED MANUSCRIPT
easily and to affect the position of the tautomeric equilibrium by changing the electronic
properties of the substituent (from OH to O-). The implementation of a sidearm in the newly
synthesized compound 3 creates conditions for a competition between the nitrogen atom from
the azo group and the nitrogen atom from the piperidine unit (3a vs. 3a,, Scheme 2) for the
tautomeric proton. The overall idea is to investigate if these modifications could provide
possibilities for controlling the tautomeric equilibrium in the backbone of 1 in solution. The
investigations were performed by using UV-VIS and NMR spectroscopy in various solvents,
quantum-chemical calculations and crystallographic analysis.
H O
N
H O
N
N
N
1b
1a
H O
N
N
H O
N
N
N
2.
3.
OH
Scheme 1. Tautomeric equilibrium in 1 and structures of the investigated compounds 2 and 3.
Scheme 2. Possible equilibria in 3.
3

ACCEPTED MANUSCRIPT
2. Experimental part:
Compounds. 3-Hydroxy-2-naphthoic acid A and 2,6-dihydroxynapthalene were purchased
from TCI research chemicals. All other reagents and solvents were analytical grades
purchased from Sigma-Aldrich Chemical Co. and used as received unless otherwise stated.
Fluka silica gel /TLC-cards 60778 with fluorescence indicator 254 nm were used for TLC
chromatography. Merck silica gel 60 (0.040-0.063 mm) was used for flash chromatography
purification of the products. The HRMS LC/MS experiments were carried out on a Bruker
MicrOTOF-QII-system with ESI-source with nebulizer 1.2 bar, dry gas 8.0 l/min, dry
temperature 200 oC, capillary 4500 V and end plate offset -500 V.
2.1. Synthesis
1-(Phenyldiazenyl)naphthalen-2-ol 1:
A solution containing of aniline (0.93 g, 10 mmol) and concentrated HCl (5.0 ml) in distilled
water (25.0 ml) was stirred at 0-5oC for 30 minutes. To this solution was added slowly a cold
solution of sodium nitrite (0.83 g, 12 mmol) in distilled water (10.0 ml) and the mixture left
stirred at 0-5oC for 45 minutes. The diazonium salt solution was then added dropwise with
vigorous stirring over 25 minutes to a solution of 2-naphthol (1.5 g, 10.05 mmol), sodium
hydroxide (0.8 g, 20 mmol) in distilled water (50.0 ml) maintained at 0-5oC. After complete
addition, the mixture stirred in cold for 45 minutes and 1 h at room temperature, and then
acidified with 6M HCl to pH 2-3. The red precipitate was collected and washed with water
until neutral. The solid was dried in vacuum at room temperature and recrystallized three
times from absolute ethanol (15 ml) to give red needles (1.96 g, 76%). The NMR data are
consistent with that reported in literature [9]. HRMS-ESI calculated for C16H13N2O (M+H)+
249.10279, found 249.10252.
1-(Phenyldiazenyl)naphthalene-2,6-diol 2:
A solution containing aniline (1.02 g, 11 mmol) and concentrated HCl (3.25 ml) in distilled
water (5.0 ml) was stirred at 0-5oC for 30 minutes. To this solution was added slowly an ice-
cold solution of sodium nitrite (0.77 g, 11 mmol) in distilled water (5.0 ml) and the mixture
o
left stirred at 0-5 C for 45 minutes. The diazonium salt solution was then added dropwise
with vigorous stirring over 30 minutes to a solution of 2,6-dihydroxynaphthalene (1.76 g, 11
mmol) in 10% aqueous sodium hydroxide (9.15 ml)) maintained at 0-5oC. After complete
4

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addition, the mixture stirred in the cold for 45 minutes and then 1 h at room temperature. The
red precipitate was treated with distilled water (50.0 ml) and filtered, the solid washed with
water until neutral and the red solid residue dried in vacuum at room temperature. The crude
product was purified by flash column chromatography on silica gel with
dichloromethane/ethyl acetate (10:1) and recrystallization from 75% aqueous ethanol (12 ml)
1
to obtain 2 as a dark-red solid (0.89 g, 31%) as a dark- red solid. H NMR (DMSO-d6, 400
MHz) δ 15.59 (s, XH), 9.77 (bs, OH-6), 8.36 (d, H-8, J = 8.8 Hz), 7.81 (d, H-4, J =9.6), 7.80
(d, H-2´.H-6´, J =7.7), 7.52 (“t”, H-3´,H-5´, J =7.7 and J = 8.1 Hz), 7.33 (t, H-4´, J =7.3 Hz),
7.10 (d,d, H-7, J =2.5 and J =8.8 Hz), 7.08 (d, H-5, J =2.4 Hz), 6.82 (d, H-3, J = 9.4 Hz). 13C
NMR data are given in Table 1. HRMS-ESI calculated for C16H13N2O2 (M+H)+ 265.09770,
found 265.09783.
Table 1. 13C chemical shifts of compounds 1-3. The numbering is shown in Scheme 3.
Carbon/
Compounds
C-1
1 a
CDCl3
129.67
171.56
124.48
139.64
127.71
128.27
125.35
128.48
121.44
133.26
144.44
118.26
129.23
127.03
3 b
3 e
DMSO-d6
129.58
173.40
m c
1
2
2
DMSO-d6 Acetonitril-d3 DMSO-d6
CDCl3
129.17
168.77
123.89
139.92
127.80
129.07
125.81
128.87
121.28
132.73
145.08
118.93
129.79
128.06
130.20
169.74
125.20
139.66
127.32
112.81
155.78
119.26
123.95
m c
129.26
169.97
124.54
140.00
129.68
112.48
155.83
119.05
123.13
125.35
144.73
118.2
129.95
C-2
174.80
m c
144.09 br d m c
C-3
C-4
C-4a
C-5
127.49
129.71
126.43
129.90
121.61
133.84
143.47
118.13
129.90
127.32
126.92
128.99
126.32
129.27
121.20
132.98
143.08
117.91
129.87
127.20
C-6
C-7
C-8
C-8a
C-1´
C-2´
C-3´
C-4´
146.23
119.32
130.26
128.05
129.74
127.19
a Assignment according to [9]; b The resonances for CH2 and the piperidine ring, 54.53 ppm, 53.90
ppm, 24.43 ppm, 23.33 ppm; c Missing; d br means broad; e The resonances for CH2 and the
piperidine ring, 54 ppm (br), 52.97 ppm, 23.65 ppm, 22.07 ppm.
5

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Scheme 3. Numbering of the tautomeric backbone.
Compound 3 was synthesized in three steps starting with 3-hydroxy-2-naphthoic acid A as
shown in Scheme 4.
Step 1: 3-Hydroxy-2-naphthoic acid-N-piperidinylamide B:
A solution of 3-hydroxy-2-naphthoic acid (6.18 g, 32 mmol) in dry dichloromethane (250 ml)
was treated with 8 drops of dry DMF followed by slow addition of oxalyl chloride (8.6 ml,
98.4 mmol). The reaction mixture was stirred at 25oC under nitrogen atmosphere for 24h. The
solvent was evaporated under reduced pressure and the crude solid residue was diluted with
dry dichloromethane (75 ml) and dry THF (75 ml) and the solution was stirred at 0oC for 20
minutes under a nitrogen atmosphere. A 2 M solution of piperidine in THF (49.2 ml) was
added dropwise and the heterogeneous mixture left stirred at 25oC under nitrogen atmosphere
for 72h. The white solid was filtered and the filtrate evaporated under reduced pressure to
afford a crude amber solid. This was purified by flash column chromatography on silica gel
with dichloromethane/ethyl acetate (10:1) to obtain the amide compound B as a white solid
1
(6.2 g, 74%) as a white solid. The H NMR (CDCl3, 500 MHz) data are consistent with that
reported in literature [10] 13C NMR ((CDCl3, 126 HMz) δ 170.2 (CO), 154.6 (C-3) 135.9 (C-
4a), 128.7 C-5 or C-8), 128.5 (C-5 or C-8), 128.0 (C-4a) 127.0 (C-6 or C-7), 124.1 (C-6 or C-
7), 120.4 (C-2), 112.3 (C-4), 26.3, 24.7. HRMS-ESI calculated for C16H18NO2 (M+H)+
256.09770, found 256.09762.
Step 2: 3-(1-Piperidinylmethyl)naphthalen-2-ol C:
A solution of the amide B (1.84 g, 7.2 mmol) in dry THF (35 ml) was added dropwise under
nitrogen atmosphere to a suspension of LiAlH4 (0.56 g, 14.7 mmol) in dry THF at 0oC with
vigorous stirring. After complete addition, the mixture stirred at 25oC for 15 minutes and then
refluxed under nitrogen atmosphere for 2 h. Cooled to 0oC and quenched with saturated
6

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aqueous potassium fluoride solution (20 ml). The product was then extracted with
dichloromethane (3x50 ml), washed with brine and dried over anhydrous magnesium
sulphate. Filtration and subsequent evaporation of solvent under reduced pressure afforded a
solid residue, that was purified by flash column chromatography on silica gel with
dichloromethane/n-heptane (2:1) and finally with dichloromethane to obtain compound C as a
1
white solid (1.4 g, 82%). H NMR (CDCl3, 500 MHz) δ 11.23 (broad s, 1H), 7.57-7.55 (m,
2H), 7.37 (d, 1H J = 8.2 Hz), 7.26 (t, 1H J = 7.4 Hz), 7.15 (t, 1H J= 7.4 Hz), 7.07 (s, 1H). 13C
NMR (CDCl3, 126 MHz) δ 156.3 (C-2), 134.6 C-8a), 128.1 (C-4a), 127.8 C-8), 127.4 (C-5),
126.3 (C-7), 126.1 ,124.6 (C-3), 123.1 (C-6), 110.4 (C-1), 62.4 (CH2), 54.0 (C-2´), 25.9 (C-
3´), 24.1 (C-4´). HRMS-ESI calculated for C16H20NO (M+H)+ 242.15449, found 242.15435.
Step 3: 1-(Phenyldiazenyl)-3-(1-piperidinylmethyl)naphthalene-2-ol 3:
A solution containing of aniline (0.28 g, 3.0 mmol) and concentrated HCl (3.0 ml) in distilled
water (50.0 ml) was stirred at 0-5oC for 45 minutes. To this solution a cold solution of sodium
nitrite (1.02 g, 14.5 mmol) in distilled water (5.0 ml) was added slowly and the mixture was
left stirring at 0-5oC for 45 minutes. The diazonium salt solution was added dropwise with
vigorous stirring over 30 minutes to a solution of compound C (0.24 g, 1.0 mmol) in 0.2 M
aqueous sodium hydroxide (10.0 ml) and THF (10 ml) maintained at 0-5oC. After completion
of the addition the mixture was stirred in the cold for 45 minutes and subsequently 30 minutes
at room temperature and the red-orange solid was filtered off. The filtrate was neutralized to
pH 7 and extracted with dichloromethane (3x30 ml), then washed with water and finally dried
over anhydrous sulphate and evaporated under reduced pressure. The solid residue was
purified by flash column chromatography on silica gel, first with dichloromethane and then
with dichloromethane/ethyl acetate (10:2) and finally with dichloromethane/methanol (95:5)
to obtain the pure compound 3 as an orange solid (0.22 g, 58 %). 1H NMR (CDCl3, 500 MHz)
δ 16.64 (s, OH), 8.47 (d, H-8, J= 8.2 Hz), 8.25 (broad s, H-4), 7.69 (d, H-5, J=7.6 Hz), 7.67
(dd, H-2´,H-6´ J= 8.5 Hz, J=2.0 Hz), 7.55 (“t”, d H-7 J= 8.4 Hz and J=1.2 Hz), 7.48 (“t”, H-
3´and H-5, J= 8.3 Hz), 7.42 (t,d, H-6, J= 7.3 Hz and 1.2 Hz) 7.31 (t, H-4´, J=7.5 Hz), 3.94
13
(s,CH2), 2.86 (s, H-2´,H-6´), 1.86 (s, H-3´, H-5´) and 1.26 (s, H-4´). For C NMR data see
Table 1. HRMS -ESI calculated for C22H24N3O (M+H)+ 346.19194, found 346.19182.
7

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Scheme 4. Synthesis of compound 3.
2.2 NMR measurements
13
1H NMR and C NMR spectra were recorded either at 500 MHz and 126 MHz on a Bruker
Ultrashield Plus 500 or 400 MHz spectrometer using CDCl3, CD3CN or DMSO-d6 as a
solvent and TMS as internal standard. The low temperature experiments were recorded in
CDCl3. APT and HMBC (tuned to a CH coupling of 7 Hz) spectra were recorded according to
the Bruker standard procedures.
13
The assignments of the C chemical shifts of 1 in CDCl3 are given in [9] based on carbon-
carbon coupling constants. The chemical shift changes in DMSO-d6 are minor (see Table 1)
and as the changes mostly will be due to a change in the equilibrium, the variations are well
13
documented for C-2 and the benzene ring chemical shifts [11]. The assignments of the C
resonances of compound 2 are based on APT and HMBC spectra and on those of compound 1
combined with OH substituent effects and so are those of the titrated spectra. The assignment
of the 13C NMR spectrum of 2 in CD3CN was done by extrapolations as explained above.
The assignment of 3 is partially based on APT and HMBC spectra. However, the assignment
is complicated by the broadening of some lines and of one or two missing resonances in the
aromatic region. These missing resonances are likely appearing at 223 K. The 1H spectrum is
showing a broad H-4 resonance and C-4 is likewise broad at ambient temperature. C-2´ and
C-3´ can be assigned based on intensities and confirmed together with C-4´ from the HMBC
spectrum. C-1´and C-2 can be assigned based on chemical shifts. C-6 and C-8 can be
assigned from the HMBC spectrum and C-4a and C-8a are identified from the APT spectrum
8

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and distinguished based on chemical shift arguments and supported by a H-7 to carbon cross
peak to C-8a in the HMBC spectrum.
2.3. UV-Vis measurements
Spectral measurements were performed on a Jasco V-570 UV-Vis-NIR spectrophotometer,
0
equipped with a thermostatic cell holder (using Huber MPC-K6 thermostat with 1 C
o
precision) in spectral grade solvents at 20 C. Protonation was made with 96% sulfuric acid.
Deprotonation was made with 25% NH3. The derivative spectra were calculated according to
the “step-by-step filter” procedure [12].
2.4. Quantum chemical calculations
Quantum-chemical calculations were performed by using the Gaussian 09 D.01 program suite
[13]. DFT and time-dependent (TD)-DFT [14,15] were used to explore the ground- and
excited-state properties of each molecule. For all cases, the solvent effect was described by
applying the polarizable continuum model (PCM) in its integral equation formalism variant
(IEFPCM) [16]. For all calculations, an M06–2X-fitted hybrid meta-GGA functional [17] and
the TZVP basis set [18] were used, keeping in mind that this level of theory was shown to
provide very good results in predicting tautomerism of azonaphthols [19]. All tautomeric
forms of the investigated compounds were optimized without restrictions and then were
characterized as true minima using vibrational frequency calculations.
The NMR calculations were done using the GIAO approximation [20] and B3LYP/6-31G(d)
functional and basis set.
2.5. Single crystal x-ray diffraction
Single red block-shaped crystals of 3 were recrystallized from methanol by slow evaporation.
A suitable crystal (0.20×0.15×0.08) mm3 was selected and mounted on a MiTeGen holder in
oil on a STOE IPDS 2 diffractometer. The crystal was kept at T = 250 K during data
collection. Using Olex2 [21], the structure was solved with the ShelXT [22] structure solution
program, using the Intrinsic Phasing solution method. The model was refined with version
2017/1 of ShelXL [23] using Least Squares minimization.
Crystal Data. C22H23N3O, Mr = 345.43, triclinic, P-1 (No. 2), a = 10.8103(10) Å, b =
11.2369(12) Å, c = 17.1688(18) Å,
α β γ
= 80.314(10)°, = 75.096(7)°, = 64.142(7)°, V =
1809.8(3) Å3, T = 250 K, Z = 4, Z' = 2, m(MoKa) = 0.079, 23416 reflections measured, 6462
9

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unique (Rint = 0.1037) which were used in all calculations. The final wR2 was 0.1013 (all data)
and R1 was 0.0426 (I > 2(I)).
The single crystal data of 3 has been deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC-1587825.
3. Results and Discussion:
In solution:
The absorption spectra of compounds 1-3, shown on Figure 1, clearly show the presence of
the tautomeric mixture in solution, irrespective of the solvent used, with absorption maxima
of the enol form in the range 410 – 430 nm and red shifted keto form absorbance around 500
nm. Detailed information can be found in the second derivative spectra. On Figure 2, the
maximum of the enol form can be seen at 420 nm for 1, 430 nm for 2 and 420 nm for 3.
According to the derivative spectra, the keto form absorbance consists of several sub bands as
shown previously from curve decomposition [8]. As seen from Figure 1a, compound 1 exists
as tautomeric mixture in acetonitrile and DMSO with predominance towards the keto
tautomer in chloroform, which can be expected because of the proton donor nature of the
solvent [24].
10

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Figure 1. Absorption spectra of a) 1, b) 2 and c) 3 in various solvents.
Figure 2. Second derivative spectra of a) 1, b) 2 and c) 3 in various solvents.
This conclusion is supported by the NMR results, taking into account the discussion in [25]
about comparability of the UV-Vis and NMR data in tautomeric dyes. For 1 in CDCl3 a 70:30
ratio 1b:1a was found [11]. As seen from Table 1 both C-1`and C-4´are shifted towards
higher frequency in DMSO-d6 which means a shift towards the enol form.
In the case of 2, the quantity of the enol form decreases from acetonitrile to chloroform and
DMSO. According to the NMR a comparison with the calculated nuclear shielding (Table 2)
gives that the hydrazo form is about 90% in DMSO.
Table 2. Calculated 13C nuclear shielding for both tautomers of 2 as well as of the anions.
2a-
2b
2b-
2-
Carbons/
2a
tautomer
C-1
64.2 (63.8)a 60.1 64.0 (63.5) 59.5 59.9
43.3 (43.9) 46.0 18.2 (18.0) 13.1 32.4
74.8 (76.3) 84.0 66.7 (68.0) 74.3 59.7
C-2
C-3
11

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C-4
59.3 (59.8) 53.7 54.2 (53.8) 44.4 67.5
66.7 (66.9) 62.7 66.0 (61.6) 65.8 70.6
83.9 (84.8) 80.8 81.3 (81.6) 72.8 86.5
44.7 (41.9) 27.6 43.4 (41.1) 23.9 50.6
78.8 (75.3) 60.2 80.3 (77.6) 68.9 85.4
71.7 (71.7) 75.3 71.7 (71.4) 70.3 73.5
67.5 (68.1) 81.8 67.7 (68.8) 87.0 60.4
46.0 (45.8) 43.7 54.9 (54.6) 52.2 37.2
66.1 (66.4) 71.0 78.7 (79.1) 83.9 67.9
81.4 (81.3) 81.2 81.8 (81.3) 83.8 84.5
67.3 (67.5) 69.7 67.3 (67.5) 69.9 70.3
67.4 (67.5) 66.5 66.5 (66.6) 67.8 70.5
66.8 (67.3) 75.2 71.8 (72.6) 81.9 78.8
C-4a
C-5
C-6
C-7
C-8
C-8a
C-1´
C-2´
C-6´
C-3´
C-5´
C-4´
a Values in brackets are for a molecule with a DMSO molecule hydrogen bonded to the non-
tautomeric OH hydrogen.
The absorption spectra of 3 are similar as shape of the curve and position of the absorption
maxima as those in 1, proving that the sidearm chain does not influence the position of the
tautomeric equilibrium.
The presence of the tautomeric mixture in 2 and 3, can be confirmed by a simple experiment.
It is well known that the addition of water shifts the tautomeric equilibrium towards the keto
form in azonaphthols [25,26]. As shown on Figure 3, in both compounds, the addition of
water leads to a decrease of the maximum of the enol form and correspondingly increase of
the band belonging to the keto tautomer. If only the keto form is presented in solution, no
spectral shifts could be observed.
12

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Figure 3. Absorption spectra of a) 2 and b) 3 in ACN and DMSO, upon water addition: (____
without water addition; ____ final spectrum upon water addition).
Figure 4. Relative energies (M06-2X/TZVP, in kcal/mol) of the tautomers of 1 in ACN (left).
Relative energies (M06-2X/TZVP, in kcal/mol) of the neutral tautomers (center)
and deprotonated forms of 2 in ACN (right).
13

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The coexistence of the tautomers in the studied compounds is confirmed by the theoretical
calculations as well. The moderate energy gap between the enol and the keto tautomeric
forms, suggests that compound 1 always exists as a tautomeric mixture (1a and 1b, Figure 4,
left) in solution as it is actually observed [8]. The implementation of an additional non-
tautomeric hydroxyl group (compound 2) does not change the situation dramatically.
Actually, it acts as a simple electron acceptor substituent shifting the tautomeric equilibrium
towards the keto form 2b (Figure 4, centre). Compound 2 has two options for deprotonation:
loss of the tautomeric proton giving non-tautomeric anion 2- or deprotonation of the additional
OH group, which could affect the tautomeric equilibrium (2a- vs 2b-, Figure 4, right). As seen
from the calculations, the anion 2- is energetically unfavourable, which means that the
deprotonation occurs at the additional OH group. As a result, the tautomeric equilibrium
between 2a- and 2b- is almost fully shifted to the keto tautomer 2b- with an energy gap of 1.67
kcal/mol.
Figure 5. Relative energies (M06-2X/TZVP, in kcal/mol) of the neutral tautomers of 3 (left)
and the protonated species in ACN (right).
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Compound 3 possesses an option for competitive hydrogen bonding in the enol form, where
the tautomeric proton interacts either with the nitrogen from the azo group (3a, Scheme 2), or
with the nitrogen atom from the piperidine unit (3a’). As seen from Figure 5 left, the structure
3a is preferred. Actually, there is no competition for the tautomeric proton, between the
nitrogen atom from the chromophore backbone and the nitrogen atom from the piperidine unit
(energy gap of 2.5 kcal/mol between 3a’ and 3b). Although the overall effect of the existence
of the sidearm stabilizes the keto tautomer 3b (in comparison with 1), a substantial amount of
3a could be expected in solution as the energy gap of 0.86 kcal/mol suggests. Obviously, the
sidearm acts as a simple alkyl substituent, because when the whole sidearm is replaced by a
methyl group the energy gap between tautomers 3a and 3b remains almost the same - 0.7
kcal/mol.
The X-ray analysis of compound 3, as will be shown below, clearly shows that compound 3
exists as the keto form 3b in the solid state and the nitrogen atom from the piperidine unit is
far from the tautomeric backbone, as predicted by the theoretical calculations (Figure 5). The
NMR data show at room temperature very broad H-4 and C-4 resonances and one missing C-
3 resonance. It was found in [27] that the piperidine ring was flipping at ambient temperature
and that the flipping could be stopped by lowering the temperature. Upon cooling the H-4 and
C-4 resonances broaden even further, whereas those of H-2”, H-6” and H-4” each split into
two indicating that the ring flipping has slowed down, whereas the corresponding 13C
resonances do not split either indicating that the piperidine ring is positioned symmetrically
with respect to the naphthalene ring or the piperidine ring is moving with respect to the
piperidine ring. However, the broadening of the resonances at ambient temperature can only
be explained if the piperidine ring is pointing in the direction of H-4 as shown in Scheme 2.
This means that the hydrogen bond is clearly between the substituents at C-1 and C-2 as also
indicated by the very high frequency shift of the XH proton (XH means either OH or NH).
As seen from Figure 5 right, the acid addition is a suitable stimulus for switching the
tautomeric equilibrium to the pure keto form, because the protonated piperidine nitrogen
atom, participates in additional intramolecular hydrogen bond formation, which further
stabilizes the keto form, shifting the equilibrium fully towards the keto form.
The calculated positions of the absorption maxima of the corresponding enol and keto forms
of the neutral compounds collected in Table 1 logically follow the spectral changes in
solution. The calculated absorption maxima of the enol and keto forms respectively in
compounds 1 and 3, coincide, as observed by the experiment. In case of 2, the calculated
absorption maximum of the enol form is slightly red shifted, compared to 1 and 3, and the
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position of the keto form absorbance is not affected. As seen from Table 3, the deprotonation
of 2 leads to red shift in the maxima of both enol and keto tautomers, while the protonation of
3 does not bring substantial effect, which is logical having in mind that the protonated
nitrogen atom from the piperidine unit is not conjugated to the chromophore system.
As seen from Figure S1, in which deprotonation of 1 and 2 is compared, the addition of base
to the solution of 2, leads to decrease of the maximum of the keto form at 500 nm and
appearance of a new band at 600 nm. This additional band, which is not observed in 1, gives
indication that in 2, the additional hydroxyl group is deprotonated as theoretical calculations
suggest.
Addition of one equivalent of tetrabutylammonium hydroxide to 2 led to precipitation so the
NMR results shown in Scheme 5 are for addition of 0.66 equivalent of base. High frequency
shifts are found for C-2, C-5, C-6, C-7 and C-1´, whereas C-3 and C-8a are shifted to low
frequency. The interpretation may be complicated by the fact that two tautomers exist and the
equilibrium constant may change as a function of titration. Titration of the phenol group of 3-
hydroxybenzoic acid led to a high frequency shift for C-3 whereas that of C-6 was shifted to
high frequency [28]. As discussed above, in case of 2 titration may occur either at O-2 or at
the nitrogen depending on the tautomeric form (2-) or at O-6 (2a-/2b-). Looking at the changes
13
in C chemical shifts of Scheme 5 the picture is not immediately clear. However, taking the
calculated nuclear shieldings of Table 2 into account it is obvious that the OH/NH proton at
C-2 or N is not titrating as this would lead to a considerable low frequency shifts of C-2
(remember that the nuclear shieldings and the chemical shifts have opposite signs). The
opposite is found. The change in chemical shifts around C-6 is in agreement with the finding
for 3-hydroxybenzoic acid as mentioned above. Based on these findings the OH proton at C-6
is titrated in DMSO using tetrabutylammonium hydroxide as base. The high frequency shift
of C-1´can due both to titration and to a shift in the equilibrium. However, the low frequency
of the C-4´ could also be due to titration, but the small magnitude indicates that it is most
likely both due to titration (low frequency shift) and a shift in the equilibrium versus the azo-
form (high frequency shift).
As seen from Figure 6, the addition of acid leads to gradual shift of the tautomeric equilibrium
in 3 to the keto form, which can be monitored with the decreasing absorption maxima of the
enol form and raise of the red shifted absorption of 3b. As a result, the pure spectrum of the
keto form can be seen, which approximates very well with the pure spectrum of 1b obtained
by overlapping bands decomposition [8]. The process is reversible upon base addition, which
shows that the tautomerism in 3 can be controlled.
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13
Scheme 5. C titration shifts of 2 after addition of 0.66 equivalents of tetrabutylammonium
hydroxide
Table 3. Predicted values for the neutral forms of 1 – 3 and ionized forms of 2 and 3 (see
Figures 1 and 2).
neutral forms
λmax, f*
ionized forms
λmax, f
keto
λmax, f
λmax, f
keto
compound
enol
enol
-
374; 0.63
390; 0.51
376; 0.64
405; 0.61
405; 0.61
404; 0.62
-
1
537; 0.13
372; 0.63
569; 0.28
418; 0.63
2
3
*f – oscillator strength
Figure 6. Absorption spectra of 3 in ACN upon acid addition: (____without acid addition; ____
final spectrum upon acid addition).
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In the solid state:
The X-ray analysis of compound 3, presented on Figure 7, clearly shows that compound 3
exists as a keto form 3b in the solid state and that the nitrogen atom from the piperidine unit is
far from the tautomeric backbone, as predicted by the theoretical calculations (Figure 5).
Compound 3 crystallizes in the space group P-1 (No. 2) with two independent molecules A
and B per asymmetric unit. Molecule A, around O1, features an angle of 16.2° between the
mean angle comprising the phenyl ring, and the one of the naphthyl ring. Furthermore, the
C8–O1 bond is 1.276(4) Å long, and in the adjacent aromatic ring, the C–C distances are
distributed alternatingly as follows: C8–C9 1.448(5), C9–C10 1.325(5), C10–C11 1.466(6),
C11–C16 1.397(5), C16–C7 1.462(4) and C7–C8 1.426(6) Å. The distances C7–N2 and N2–
N1 are respectively 1.337(5) and 1.328(4) Å long, indicating the trend of distances expected
from the structure of 3b, except for the fact that the N1–N2 bond seems shorter than the
expected N–N single bond of 1.47, but longer than a N=N bond with 1.24 Å (see Figure S2
and S3). The N1…O1 distance is 2.523(5) Å, the distance H1…O1 is 1.748 Å, and a stable 6-
ring is thus stabilized in molecule A via N1–H1–O1 of 133.9°. O1 makes a short contact of
2.510 Å to H18B of a neighbor molecule A’ (3-x, -y, -1-z), which is another confirmation of
the fact that the molecule A is in its keto form.
In molecule B, the phenyl and naphthyl groups form an angle of only 13.3° to each other, and
the O2–C30 distance is even shorter than in molecule A, with 1.269(5) Å. The distances in the
aromatic ring bearing O2 are C30–C31 1.451(4), C31–C32 1.350(5), C32–C33 1.437(5),
C33–C38 1.407(4), C38–C29 1.440(5) and C29–C30 1.453(6) Å, while the distances C29–N5
and N5–N4 are respectively 1.334(4) and 1.310(5) Å long. The N4…O2 distance is 2.501 Å
and H4A is 1.754 Å away from the O2. This H-bond is again stabilized by a stable 6-ring with
an N–H–O angle of 137.8°. O2 also makes a short contact to H44B of another molecule B’
(2-x, -2-y, -z) at 2.449 Å, which is even shorter than for molecule A and A’. Yet, the N–N
distance in molecule B is significantly shorter than in A, which might indicate a more stable
azo-group. Nevertheless, in both molecules A and B, the H-atom involved in tautomerism (H1
or H4A) is completely found linked to the respective nitrogen atom, with the 3b form as
clearly the most stable one. The crystal structure further supports the discussion on the
piperidyl entity, which is turned away from the tautomeric site. Indeed, in molecule A, a short
contact between the N3 atom and H10 is found to be 2.505 Å long (N3–C10 2.872(2) Å),
while in molecule B, the analogue distance between N6 and H32 is 2.580 Å (N6–C32
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2.923(2) Å). Both N-atoms, N3 and N6, are also fixed in their pyramidal conformation with
angle sums of ca. 328.6 ± 0.7° on average.
The partially significant differences between molecules A and B might as well occur from
packing effects. Indeed, there are offset parallel π-π interactions as well as C–H…π
interactions as follows: H25 of a molecule B undergoes C–H…π interactions with C2 and C3
of molecule A at distances of respectively 2.878 and 2.837 Å, with an angle between the two
involved phenyl groups of almost 72°. Further packing involves a pair of two offset molecules
B, arranged head-to-tail which interact twice via C30 of one and C24 of the neighbor
molecule (and vice versa) at a distance of 3.368(6) Å. The molecules of A are also packed in
an antiparallel way with an offset parallel packing of the naphthyl groups, but the average
distances between the aromatic cores is typically longer than 3.55 Å, so only weak
interactions can be considered. Stacks of A and stacks of B lead to a chevron type
arrangement in the three dimensional packing.
Figure 7. X-ray analysis of 3, ellipsoids are represented with 30% of probability, H bonds are
drawn as blue dashed lines.
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4. Conclusions:
Compounds 1, 2 and 3 exist as tautomeric mixtures in solution as shown by UV-VIS, NMR
spectroscopy and quantum chemical calculations. The structural changes in 2 and 3, make
possible to control the tautomerism in solution.
In the case of 2, a shift in the equilibrium can be achieved through deprotonation of the
additional hydroxyl group, while in 3, the protonation of the piperidine nitrogen stimulates
shift to the keto tautomer.
Compound 3 is more suitable as tautomeric switch, because the piperidine unit is not
conjugated to the tautomeric backbone and the protonation process does not influence the
absorption spectra directly.
Acknowledgements:
The
financial
support
by
the
Swiss
National
Science
Foundation
(SupraMedChem@Balkans.Net SCOPES Institutional Partnership) and Bulgarian Science
Fund (Bulgarian Science Fund and DAAD joint research project DNTS01/04 Proton Cranes)
is gratefully acknowledged. In addition, we acknowledge the access to computational
facilities provided by Project MADARA (Project RNF01/0110).
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Highlights:
• Two possible mechanisms for controlling the tautomerism in Sudan I are
discussed.
• The availability of additional OH group changes the tautomeric equilibrium
upon deprotonation.
• The addition of sidearm, which easily protonates, control the tautomeric
process through H-bonding.