A comparative study between para-aminophenyl and ortho-aminophenyl benzothiazoles using NMR and DFT calculations

Article abstract of DOI:10.1002/mrc.4088

Ortho-substituted and para-substituted aminophenyl benzothiazoles were synthesised and characterised using NMR spectroscopy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for the NH

Full text of DOI:10.1002/mrc.4088

Research article
Received: 26 March 2014
Revised: 11 May 2014
Accepted: 15 May 2014
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/mrc.4088
A comparative study between para-
aminophenyl and ortho-aminophenyl
benzothiazoles using NMR and
DFT calculations
G. K. Pierens,* T. K. Venkatachalam and D. Reutens
Ortho-substituted and para-substituted aminophenyl benzothiazoles were synthesised and characterised using NMR spectros-
copy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for
the NH protons indicating the presence of a hydrogen bond in all ortho-substituted compounds as compared to the para
compounds. The presence of intramolecular hydrogen bond in the ortho amino substituted aminophenyl benzothiazole forces
the molecule to be planar which may be an additional advantage in developing these compounds as Alzheimer’s imaging agent
because the binding to amyloid fibrils prefers planar compounds. The splitting pattern of the methylene proton next to the
amino group also showed significant coupling to the amino proton consistent with the notion of the existence of slow exchange
and hydrogen bond in the ortho-substituted compounds. This is further verified by density functional theory calculations which
yielded a near planar low energy conformer for all the o-aminophenyl benzothiazoles and displayed a hydrogen bond from the
1
amine proton to the nitrogen of the thiazole ring. A detailed analysis of the H, 13C and 15N NMR chemical shifts and density
functional theory calculated structures of the compounds are described. Copyright © 2014 John Wiley & Sons, Ltd.
1
Keywords: aminophenyl benzothiazoles; hydrogen bond; H NMR; 13C NMR; 15N NMR; DFT calculations
The [11C]-6-Me-benzothiazole has been prepared by methylation
Introduction
of 4-(6-methyl-2-benzothiazolyl) aniline using [11C] methyl
iodide.[11] Additional modification by removing the 6-methyl
Aminophenyl benzothiazoles are a unique class of compounds
possessing extraordinary biological activity. In recent years, atten-
group in the structure gave [11C] BTA ((N-methyl-[11]C)-2-(4′-
tion has been focused on the development of novel derivatives
of aminophenyl benzothiazoles to utilise them as biologically
useful compounds.[1,2] Stevens et al.[3–5] have extensively studied
these compounds for their anticancer properties. The cytotoxicity
profiles of polyhydroxylated 2-phenyl benzothiazoles against hu-
man tumour cell lines compared well with Genistein and the
benzothiazoles acted as tyrosine kinase inhibitors similar to
Genistein and other known flavones. Several aminophenyl
benzothiazole derivatives have been reported.[6] Interestingly,
introduction of groups at the 3′ position of the phenyl moiety
enhanced the potency of the compounds and derivatives with
methyl, chloro, bromo and iodo groups in that position showed
unprecedented activity against several tumour cell lines. In light
of the biological activity of benzothiazole derivatives, other appli-
cations have been explored including possible application as a
diagnostic agent in Alzheimer’s disease. The progressive neuro-
nal loss associated with this disease is believed to occur because
of the formation of senile plaques and neurofibrillary tangles
within the brain. Several studies have implicated a short peptide
containing 39–43 amino acids as the main constituent of amyloid
plaques.[7,8] These are produced by the proteolytic cleavage of a
precursor protein by secretases[9] to form insoluble fibrils that
deposit in the brain. Todd et al.[10] has reported a comprehensive
review on the development and application of various
compounds for amyloid imaging. Aminophenyl benzothiazoles
have been highlighted as ideal candidates for brain imaging.
(methylaminophenyl)-benzothiazole)) which showed improved
uptake and washout characteristics in normal mice. It also
showed vivo specificity towards amyloid fibrils in the brain of
transgenic mouse models of Alzheimer’s disease and human AD
brain homogenates.[11,12] The 6-hydroxy substituted amino
methyl benzothiazole derivative is also known as Pittsburgh
Compound
B
(PIB)[13–17] and has received Federal Drug
Administration approval as an imaging contrast agent for
Alzheimer’s disease. Although the 4-aminophenyl benzothiazoles
have been studied extensively, the synthesis and characterisation
of the o-aminophenyl benzothiazole derivatives have not been
extensively described and is the subject of this paper. The
compounds we studied were 2-(4′-aminophenyl)benzothiazole
(4′-(benzo[d]thiazole-2yl)aniline) (1) and 2-(2′-aminophenyl)
benzothiazole (2′-(benzo[d]thiazole-2yl)aniline) (8) analogues
(Table 1). The compounds throughout this manuscript will be
referred to as aminophenyl benzothiazoles. We include analysis
of the structure using density functional theory (DFT)
calculations. The aim for studying the structural feature of
*
Correspondence to: G. K. Pierens, Centre for Advanced Imaging, The University
of Queensland, St. Lucia, Brisbane 4072, Australia.
E-mail: g.pierens@uq.edu.au
Centre for Advanced Imaging, The University of Queensland, St.Lucia,
Brisbane 4072, Australia
Magn. Reson. Chem. (2014)
Copyright © 2014 John Wiley & Sons, Ltd.

G. K. Pierens, T. K. Venkatachalam and D. Reutens
Compound number (IUPAC name)
Table 1. Structure numbering scheme and IUPAC names for the synthesised compounds
Compound number
(IUPAC name)
R group
1 (4-(benzo[d]thiazole-2′-yl)aniline)
ÀH
8 (2-(benzo[d]thiazole-2′-yl)aniline)
2 (4-(benzo[d]thiazole-2′-yl)-N-methylaniline)
3 (4-(benzo[d]thiazole-2′-yl)-N-ethylaniline)
4 (4-(benzo[d]thiazole-2′-yl)-N-propylaniline)
5 (4-(benzo[d]thiazole-2′-yl)-N-butylaniline)
6 (4-(benzo[d]thiazole-2′-yl)-N-isoropylaniline)
7 (4-(benzo[d]thiazole-2′-yl)-N-(but-2″-en-1″-yl)aniline)
ÀCH3
9 (2-(benzo[d]thiazole-2′-yl)-N-methylaniline)
10 (2-(benzo[d]thiazole-2′-yl)-N-ethylaniline)
11 (2-(benzo[d]thiazole-2′-yl)-N-propylaniline)
12 (2-(benzo[d]thiazole-2′-yl)-N-butylaniline)
13 (2-(benzo[d]thiazole-2′-yl)-N-isoropylaniline)
14 (2-(benzo[d]thiazole-2′-yl)-N-(but-2″-en-1″-yl)aniline)
ÀCH2CH3
ÀCH2CH2CH3
ÀCH2CH2CH2CH3
ÀCH(CH3)2
ÀCH2CH = CHCH3
ortho-aminophenyl substituted benzothiazole is to investigate
whether the hydrogen bond formation helps to further stabilise
the molecule due to planarity. This aspect is important in terms
of utility of these compounds as Alzheimer’s imaging agents, be-
cause all the known imaging agents (thioflavin T derivatives) are
planar which aids the binding of these molecules to amyloid
fibrils.[18–20] Recently, Petric et al.[21] reported the binding
affinities of two planar molecules of dicyanovinyl naphthalenes
for neuroimaging of amyloid and came to the conclusion that
the most planar analogues showed the highest binding affinities
towards amyloid while the least planar analogue showed lowest
binding affinity.
Figure 1. Scheme illustrating the synthesis of p-aminophenyl and o-
aminophenyl alkyl substituted compounds.
4-aminobenzoic acid instead of o-aminobenzoic acid. Several
mono alkylated amino derivatives were prepared, and their melting
points (°C) are (1):156–157;(2):166–167; (3):127–128; (5):119–120;
(6):137–138; (7):126–127; (8):128–130; (9):11–112; (10):61–62;
(11):81–82; (12):71–72; (13):93–94; (14):128–130.
Experimental
All the chemicals were obtained from Sigma Aldrich and were
used without further purification. NMR spectra were recorded in
deuterated chloroform, and the chemical shifts for protons are re-
ported relative to the residual chloroform signal at 7.25 ppm. The
NMR data were acquired on a Bruker 900 MHz NMR spectrometer
equipped with a cryoprobe. The proton spectra were acquired
with a sweep width of 12 ppm centred at 5 ppm. The carbon
spectra were acquired with a sweep width of 200 ppm centred
at 105 ppm. The residual chloroform peak at 77 ppm was used
as a 13C chemical shift reference. The COSY experiments were ac-
quired with a sweep width of 12 ppm using a 90° pulse of 9 μs
with 128 increments, respectively. The 13C HSQC spectra were ac-
quired with sweep widths of 12 and 200 ppm for proton and car-
bon, respectively, and the carbon centred at 100 ppm.
Additionally, HMBC spectral data were also acquired to establish
the structures of the compounds (13C sweep width of 200 ppm).
The 15N spectra were acquired using a sweep width of 400 ppm
and urea was used as external standard at 73.4 ppm.
The synthesis of the o-substituted aminophenyl benzothiazole
was accomplished by following the synthetic scheme in Fig. 1.
In brief, o-amino thiophenol was condensed with o-
aminobenzoic acid in polyphosphoric acid at 220 °C to furnish
the o-aminophenyl benzothiazole. This was further alkylated
using alkyl bromide/iodide in the presence of potassium carbon-
ate and acetonitrile to yield the desired products. A detailed
description of synthesis and isolation of the products will be
reported elsewhere.[22] The para-substituted aminophenyl
Molecular Modelling
Monte Carlo conformational searching was performed using
Macromodel V10.1 (Schrodinger, LLC, New York).[23] Torsional
sampling (MCMM) was performed with 1000 steps per rotatable
bond. Each step was minimised with the OPLS-2005 force field
using the TNCG method with maximum iterations of 50 000 and
energy convergence threshold of 0.02. All other parameters were
left as the default values. All low energy conformations (<5 kcal/mol
from global minimum) were further optimised using DFT cal-
culations in Jaguar V8.1 (Schrödinger, LLC, New York)
B3LYP/6-311++G(d,p) with chloroform solvent).
[24]
using
Results and Discussion
Tables 2 and 3 show the 1H NMR chemical shifts observed for the
para-substituted and ortho-substituted aminophenyl benzo-
thiazoles in deuterated chloroform at room temperature, respec-
tively. Compound 1 which is the parent para amino substituted
derivative showed a broad singlet at 4.0 ppm corresponding to
the free amino group in the structure. The NMR spectrum further
showed four doublets and two triplets associated with the aro-
matic protons. Compound 2 showed the methyl resonance at
2.90 ppm as a singlet and the NH protons appeared at 4.12 ppm
as a broad singlet and all other proton signals were consistent
benzothiazoles were prepared in
a similar fashion using
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Aminophenyl benzothiazoles, hydrogen bond, NMR and DFT calculations
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G. K. Pierens, T. K. Venkatachalam and D. Reutens
with the structure. The comparison of the 1H NMR chemical shifts
of all the p-aminophenyl substituted derivatives showed that the
aromatic signals were almost identical. This is expected because
there is no significant change in the main structural frame of
the compounds. As expected, the methyl signal from compound
2 appeared as a singlet and the methylene signal of other
compounds in the series showed the expected splitting patterns
due to coupling to the adjacent protonated carbons (Fig. 2).
The 1H NMR chemical shifts for the o-aminophenyl substituted
benzothiazole (compound 8) showed the NH2 proton as a broad
singlet at 6.4 ppm. Comparing this NH2 proton with compound
1 described in the previous paragraph, it is evident that the
o-aminophenyl substituted compound showed a downfield shift
of nearly 2.40 ppm compared to p-aminophenyl substituted
compound 1, indicating that this proton is in slow exchange
and is possibly involved in a hydrogen bond with the thiazole
moiety. There are two positions in the thiazole ring that contain
heterocyclic atoms such as nitrogen or sulfur which could be
involved in the hydrogen bond. On the basis of electronegativity
differences among them, the most preferred is likely to be the
nitrogen atom of the thiazole ring. The hydrogen bonded
structure should yield a stable six membered ring.
The formation of such intramolecular hydrogen bond has been
proposed previously by Dey et al.[25] in dealing with the
solvatochromism of aminophenyl benzothiazole derivatives. It
was proposed that the lone pair of electrons associated with
the nitrogen group is being forced to be parallel with the π-cloud,
thereby altering the resonance characteristics. The formation of
such an intramolecular hydrogen bond is expected to shift the
resonance downfield, and this was confirmed experimentally.
Comparing the other chemical shift values between the aromatic
proton resonances, we found that there was only a marginal
change in the chemical shift values between the o-aminophenyl
and the p-aminophenyl benzothiazole derivatives.
coupling with the amino proton. The amino proton showed a
significant change from 4.12 to 8.79 ppm and from a very broad
resonance to a broad peak with some structure resembling a
quartet. This splitting pattern is expected because this proton is
coupled to the methyl proton and further confirms that the
amino proton is involved in a hydrogen bond with the proton
in slow exchange. All other aromatic proton signals in the
benzothiazole fragment were unchanged.
The other substituted aminophenyl compounds showed a
similar chemical shift change for the amino group from 3.90–4.12
to 8.86–9.10 ppm for the para-substituted and ortho-substituted
compounds, respectively. All other aromatic proton signals in the
benzothiazole fragment are very similar. All the para-compounds
showed the expected splitting pattern, but the ortho-substituted
derivatives showed the extra splitting in the methylene multiplet
adjacent to the amino group. Again, this is due to the coupling to
the amino proton which is in slow exchange due to being
involved in a hydrogen bond. Examples of the observed splitting
pattern for the methylene proton for the para-substituted and
ortho-substituted compounds are shown in Fig. 2. The coupling
constant to the amino proton in the methyl, ethyl, propyl and
butyl substituted compounds is 4.8Hz; however, it increases to
6.2 Hz in the isopropyl-substituted compound. The amino peak in
the ortho-substituted compounds showed splitting associated with
the coupling to the adjacent protons in the alkyl group (Fig. 3)
We then examined the carbon NMR chemical shifts of the
compounds in chloroform solution (Tables 4 and 5). Most of the
carbon chemical shift values were very similar with no significant
change in the chemical shift values with different alkyl groups.
Additionally, there was no significant change in the chemical shift
values of the benzothiazole carbons for the para-substituted and
ortho-substituted compounds. In summary, introduction of various
alkyl groups in the amine functionality of the compounds had no
significant effect on the carbon chemical shift values.
Comparison of the chemical shift values between the N-methyl
substituted derivatives (compounds 2 and 9) showed small
changes in the methyl proton’s chemical shift value from 2.90
to 3.04 ppm, respectively. However, there was a significant
change in the splitting pattern which changed from a singlet to
a doublet (Fig. 2). The doublet arises in compound 9 due to the
The effect of various alkyl groups on 15N chemical shift values
were examined (Table 6). Chemical shifts were determined by
acquiring a 15N HMBC experiment. The 15N chemical shift for
the thiazole ring nitrogen appeared at approximately 290 ppm
in all compounds and was usually much less intense than for
the amine nitrogen. This was expected as changes in the
Figure 2. Expansion of the methylene multiplet adjacent to the amino
group for the para-substituted and ortho-substituted compounds (the
spectra are referenced so that all the peaks are aligned and slight resolu-
tion enhancement has been applied before FT).
Figure 3. Expansion of the amino multiplet of the ortho compounds
showing the splitting pattern (the spectra are referenced so that all the
peaks are aligned and slight resolution enhancement has been applied
before FT).
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Aminophenyl benzothiazoles, hydrogen bond, NMR and DFT calculations
Table 4. 13C NMR chemical shifts for p-aminophenyl benzothiazoles (1–7) in CDCl3
Carbon
1[28,29]
2
3
4
5
6
7
1
149.2
114.7
129.6
123.8
129.6
114.7
168.5
154.2
122.4
126.0
124.4
121.4
134.5
—
151.6
112.0
129.1
122.4
129.1
112.0
168.4
154.2
122.3
126.0
124.2
121.3
134.4
30.3
150.7
112.3
129.2
122.4
129.2
112.3
168.8
154.1
122.3
126.0
124.3
121.4
134.4
38.1
150.8
112.2
129.1
122.4
129.1
112.2
168.8
154.4
122.3
126.0
124.2
121.3
134.5
45.3
150.8
112.2
129.1
122.8
129.1
112.2
168.8
154.3
122.3
126.0
124.2
121.3
134.5
43.2
149.8
112.6
129.2
122.2
129.2
112.6
168.7
154.3
122.3
125.9
124.2
121.3
134.5
44.0
150.6
112.5
129.1
122.8
129.1
112.5
168.9
154.5
122.3
126.0
124.3
121.4
134.6
45.5
2
3
4
5
6
2′
3a′
4′
5′
6′
7′
7a′
2″
3″
4″
5″
—
—
14.7
29.7
31.5
22.8
127.1
128.6
17.8
—
—
—
11.6
20.2
22.8
—
—
—
—
13.9
—
Table 5. 13C NMR chemical shifts for o-aminophenyl benzothiazoles (8–14) in CDCl3
carbon
8[29]
9
10
11
12
13
14
1
146.1
115.3
130.3
116.9
131.5
116.8
169.2
153.7
122.4
126.0
124.8
121.2
137.2
—
148.0
114.8
130.6
115.0
132.1
110.9
169.6
153.6
122.2
125.9
124.7
121.1
133.0
30.4
147.5
114.5
130.7
114.9
132.1
111.3
169.6
153.6
122.2
125.9
124.7
121.1
133.1
37.8
147.7
114.5
130.7
114.8
132.1
111.3
169.6
153.6
122.2
125.9
124.7
121.1
133.1
44.8
147.7
146.1
147.4
114.0
130.6
115.2
132.0
111.8
169.5
153.5
122.3
126.0
125.0
121.1
133.2
44.8
2
114.5
130.7
114.8
132.1
111.3
169.6
153.6
122.2
125.9
124.7
121.1
133.2
42.7
114.4
130.9
114.6
131.9
111.8
169.5
153.6
122.2
125.9
124.7
121.0
133.1
43.6
3
4
5
6
2′
3a′
4′
5′
6′
7′
7a′
2″
3″
4″
5″
—
—
14.6
22.4
31.3
22.9
127.6
127.2
17.8
—
—
—
11.8
20.5
22.9
—
—
—
—
14.0
—
Table 6. 15N NMR chemical shifts for p and o-aminophenyl benzothiazoles in CDCl3
Compound
Para-substituted
NH–R
Ortho-substituted
NH–R
#
ring N
#
ring N
NH2
1
2
3
4
5
6
7
58.9
57.6
76.3
73.2
73.5
90.8
72.5
293.3
289.6
*
8
9
65.2
61.7
79.8
77.2
77.7
95.0
74.9
295.3
291.7
293.3
291.5
292.0
291.2
292.6
NHCH3
NHCH2CH3
10
11
12
13
14
NHCH2CH2CH3
NHCH2CH2CH2CH3
CH(CH3)2
*
290.6
291.3
291.5
CH2CH = CHCH3 (trans)
* Not observable using the similar experimental conditions.
structural characteristics of the benzothiazole moiety did not
affect proton or carbon chemical shifts, as discussed previously.
The 15N chemical shift of the amino group in the molecule was
significantly affected by the alkyl substituent. For example, in
the case of para-aminophenyl benzothiazole derivatives,
compound 1 showed a chemical shift value of 58.9 ppm for the
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G. K. Pierens, T. K. Venkatachalam and D. Reutens
amino group. Increasing length of the alkyl side chain caused a
deshielding of the NH chemical shifts. The chemical shift value
was 57.6 ppm for the methyl-substituted derivative and ethyl, propyl
and butyl and crotyl substitution showed a significant shift in the
chemical shift values (73–76 ppm). The isopropyl-substituted deriva-
tive showed the highest chemical shift value of 90.8 ppm perhaps
owing to the dimethyl group in the structure of the compound.
The 15N chemical shift values of the alkyl substituted
o-aminophenyl benzothiazole revealed the following trend;
compound 8 showed a chemical shift value of 65.2 ppm as com-
pared to 58.9 ppm for the para amino substituted compound 1.
The other compounds in the ortho series showed similar trend
in chemical shift values (Table 6) to that observed for the
p-aminophenyl analogues. The isopropyl-substituted compound
again showed the highest chemical shift value of 95 ppm akin
distribution between these two conformers was almost 50 : 50.
The o-methylamino substituted compound
9
had five
conformers, the lowest of which was near planar with an angle
between the benzothiazole and phenyl rings of 0.5° and an
N–H bond that was only 0.1° out of plane with the phenyl ring.
This conformer also resulted in a hydrogen bond between the
NH proton and the thiazole nitrogen. The other four conformers
where not in a planar arrangement and did not form the
hydrogen bond. From the energies, the Boltzmann population
distribution of the lowest energy conformer versus the four other
conformations was 99.98 : 0.02. The results are in keeping with
observed NMR chemical shift values for the amino proton which
provide evidence of hydrogen bonding. Figure 4 shows the DFT
optimised structures of the o-methylaminophenyl benzothiazole
9. For the p-ethylamino, compound
3 resulted in four
to that obtained for the para-substituted compound
6
conformations due to rotamers within the ethyl chain. The lowest en-
ergy conformation represented 42.6% of the Boltzmann population.
The lowest three energy conformation had a near planar aromatic
substructure (<1.10) and the N–H bond of the amino group was
planar with the phenyl ring in the top two structures.
(90.0 ppm). Duthaler et al.[26] have reported the effects of N-alkyl
substituents upon the 15N chemical shifts of the aminic nitrogen.
The increments on the chemical shift values satisfactorily apply to
the effects observed in the present study. The chemical shift
values did not follow a systematic trend as larger alkyl groups
were introduced into the structure of aminophenyl benzothiazole
compounds[27–29]. Ortho-substituted derivatives had higher chemical
shift values than the corresponding para-substituted derivatives.
We then proceeded to investigate the structures of the com-
pounds using molecular modelling. Firstly, the conformational
space was investigated by performing a Monte Carlo conforma-
tional search using the MacroModel software (Schrodinger,
LLC),[23] and then, each conformation was further optimised by
Jaguar (Schrodinger, LLC)[24] with the inclusion of chloroform
solvent. The final structures were compared to eliminate any
duplicate structures. After the macromodel conformational
search, all the para-substituted derivatives showed the two
aromatic ring being in a planar arrangement and the N–H bond
being in-plane to the phenyl ring. On the other hand, the
ortho-substituted derivatives had a non-planar arrangement of
the aromatic rings from 40° to 80° and none of the compounds
showed a hydrogen bond to the nitrogen or the sulfur. From the
DFT calculations, the p-aminophenyl benzothiazole (compound 1)
showed one planar conformer due to the symmetry of the mole-
cule. The angle between the thiazole and phenyl ring was 1.3°,
and the amine had a planar arrangement with respect to the
phenyl ring due to delocalisation of the nitrogen lone pair.
The o-ethylamino compound 10 resulted in 16 conformers, of
which five were hydrogen bonded to the nitrogen atom in the
thiazole ring. These five conformers comprised 99.98% of the
Boltzmann population, the lowest energy conformer contributing
41.3% of the room temperature population. The latter was a
planar structure with the N–H bond being out of plane by only
0.5°. The other four structures had benzothiazole to phenyl ring an-
gles of 0.3°–2.3° with the N–H bond being out of plane by 2.8°–3.7°.
The p-propylamino compound 4 resulted in 10 conformers
due to the rotation of the propyl side chain. Of the rotamers, five
showed the N–H bond parallel to the phenyl ring while the
remainder showed the N–H bond antiparallel (i.e. 180o in the
opposite direction) due to rotation about the C–N bond.
Optimization of the structure of the o-propylamino compound
11 using Jaguar resulted in 28 conformations. The six lowest
energy conformers showed a hydrogen bond between the NH
group and the nitrogen atom of the thiazole. These conformers
contributed 99.97% of the Boltzmann population. In the lowest
energy conformers, the benzothiazole ring and the phenyl ring
were out of plane slightly by 0.7o. The N–H bond for the amino
group was 0.5o out of plane with the phenyl ring. This resulted
in a planar conformation due to the formation of the hydrogen
bond and is consistent with the NMR data.
The o-aminophenyl benzothiazole derivative (compound 8)
resulted in two conformers. The lowest energy conformer had an
angle between the benzothiazole and the phenyl ring of 1.6°, which
was significantly different to that predicted by the molecular me-
chanics calculation. The N–H bond was almost coplanar with the
phenyl ring at 8.9°. The conformation resulted in a hydrogen bond
between the NH proton and the nitrogen atoms of the thiazole ring,
in agreement with proton NMR results. The second conformer was
found to have an angle between the benzothiazole ring and the
phenyl ring of 34.1°, and the N–H bond was 16.8° out of the plane
of the phenyl ring. The Boltzmann population distribution of
these two conformers was calculated to be 99.92 : 0.08 indicating that
the hydrogen bonded conformer was almost exclusively preferred.
For compound 9 (NHMe), conformational searching and
further optimization with Jaguar yielded similar results. The
p-methylamino compound 2 had two conformers due to
rotation around the C–N bond. The benzothiazole to phenyl ring
angle of 1.3° was very close to a planar configuration. The NH
bond was out of plane by only 0.4°. The Boltzmann population
Figure 4. Density functional theory optimised structures of (o-
methylamino phenyl) benzothiazole (9). a. Lowest energy planar structure
and b. higher energy non-planar structure.
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Aminophenyl benzothiazoles, hydrogen bond, NMR and DFT calculations
[7] S. F. Lichtenthaler, N. Ida, G. Multhaup, C. L. Masters, K. Beyreuther.
Conclusions
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chemical shift in the para and ortho series of compounds.
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