Syntheses of, and structural studies on, benzo-fused 1,2,4-thiadiazines

Article abstract of DOI:10.1039/c3ce42205d

The syntheses of nine benzo-fused-1,2,4-thiadizines are reported. The use of microwave synthesis has been shown to afford high yields and short reaction times in several key reaction steps. The molecular geometries of these heterocycles are discussed and

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Table of Contents
Syntheses of and Structural Studies on Benzo-fused 1,2,4-thiadiazines
Ewan R. Clark, John J. Hayward, Bryce J. Leontowicz, Dana J. Eisler and Jeremy M. Rawson
CrystEngComm, 2013, xxx
DOI: 10.1039/xxxxxxxx
Strucutral characterisation of a series of benzothiadiazines reveal a propensity for the N-H group
to act as a hydrogen bond donor. The hydrogen bond acceptor strength of the remaining
heterocyclic N is probed by adjusting the hydrogen-bond acceptor strength of the R-substituent.

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PAPER
Syntheses of, and Structural Studies on, Benzo-fused 1,2,4-thiadiazines
Ewan R. Clark,a John J. Hayward,b Bryce J. Leontowicz,b Dana J. Eislera and Jeremy M. Rawson*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
The syntheses of nine benzoꢀfusedꢀ1,2,4ꢀthiadizines are reported. The use of microwave synthesis has
been shown to afford high yields and short reaction times in several key reaction steps. The molecular
geometries of these heterocycles are discussed and their solid state packing motifs reveal a strong
tendency for the NꢀH group to form hydrogen bonded chains.
The family of 1,2,4ꢀbenzothiadiazines in various oxidation states
10 (Fig. 1, A – C) have attracted attention for both materials and
is varied to include thienyl, pyridyl and functionalised phenyl
rings, as well as a further derivative in which the fused benzoꢀ
pharmaceuticals applications. One electron oxidation of the S(II) 45 ring has been functionalised (Fig. 3, 1 – 9).
variant A leads to stable free radicals,1 some of which exhibit
liquid
crystalline
properties.2
Resonanceꢀstabilized
bis(thiadiazines) and related species have also attracted attention
15 as conducting materials.3 Whilst there are limited examples of
the S(IV) derivative B,4 the S(VI) system has been widely studied
and the framework C lies at the core of a range of commercially
available pharmaceuticals, classified as thiazides, which have
applications in the treatment of hypertension and osteoporosis
20 inter alia.5
Fig. 3 Derivatives of A prepared in this paper.
Experimental
All chemicals were purchased from commercial suppliers and
50 were used without further purification unless otherwise indicated.
Sodium nꢀpropylthiolate was prepared by treatment of nPrSH
with NaH in THF. Solvents used were distilled prior to use.
Glassware was dried for a minimum 1 h at 120 °C before use; airꢀ
and moistureꢀsensitive reagents were manipulated in a Saffron
55 Scientific Ltd Beta Range Glove Box or MBraun Labmaster
under an atmosphere of dry N2. Analytical thin layer
chromatography (TLC) was performed on glassꢀbacked plates
coated with 0.25mm thick Merck 5715 silica gel. Compounds
were visualized using UV light (254 nm). NMR spectra were
60 recorded on a Bruker AMꢀ400 MHz, a Bruker Avance 300US or
a Bruker 500 MHz Avance III with a BBFO probe with residual
solvent peaks used as internal standards; coupling constants were
taken directly from the spectra and are not averaged. Electron
Impact mass spectrometry was performed on a Kratos MS890ꢀEI
65 mass spectrometer; Electrospray Mass Spectrometry was
performed using a Waters LTC machine or Waters Micromass
LCT Classic (ESIꢀTOF) Mass Spectrometer. Elemental analyses
were recorded on an Exeter CEꢀ440 or a PerkinElmer 2400 Series
II Elemental Analyzer. Melting points were determined using a
70 Stanford Research Systems MPA120 EZꢀMelt Automated
Melting Point Apparatus. FTꢀIR spectra were measured as nujol
Fig. 1 Benzothiadiazines containing SII (A), SIV (B) and SVI (C) centres.
Whilst there are a number of synthetic methodologies1 to
access specific derivatives of A depending on the fused
25 substituent (e.g. A1 – A3), a more generic method was
established by Kaszynski to access a range of longꢀchain alkyl
etherꢀfunctionalised derivatives of A4 as liquid crystalline
materials (Fig 2).2
F
30
35
40
H
N
H
N
F
F
Ph
Ph
N
N
S
N
S
F
A1
A2
H
H
N
N
Ph
N
Ph
N
N
S
N
S
A3
A4
Fig. 2 Previously synthesised benzoꢀ1,2,4ꢀthiadiazines
In this current paper we extend this methodology to access a
range of derivatives of A in which the group at the C(3) position
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5
10
Scheme 1 Synthesis of 1 – 9
15 mulls between NaCl plates using a Perkin Elmer Paragon 1000
spectrometer or as thin films on a Bruker Alpha FTꢀIR equipped
recrystallized from hexane to yield 9a as orange needles (8.49 g,
o
64%) mp 63.3 °C (lit. 69ꢀ70 C).13 1H NMR (300 MHz, CDCl3):
with a Platinum single reflection diamond ATR module. Crystals 55 δH = 8.47 (1H, s, C3H), 7.75 (1H, dd, J = 8.5, 1.5 Hz C5H), 7.53
for single crystal Xꢀray diffraction were mounted in
fluoropolymer on a glass fibre or in paratone oil on a cryoloop
20 and measured on a NoniusꢀKappa CCD, Bruker APEX or Bruker
APEXꢀII diffractometer using MoꢀKα radiation (λ = 0.71073 Å)
(1H, d, J = 8.6 Hz, C6H), 2.98 (2H, t, J = 7.3 Hz, SC7H2), 1.80
(2H, sextet, J = 7.4 Hz, SCH2C8H2), 1.12 (3H, t, J = 7.4 Hz,
C9H3) ppm. 13C NMR (300 MHz, CDCl3) δC = 145.23 (C2),
143.48 (C1), 129.41 (q, J = 3.2 Hz, C5), 126.97 (C6), 126.57 (q, J
at temperatures in the range 100ꢀ200 K using a Oxford 60 = 34.4 Hz, C4), 123.24 (q, J = 3.9 Hz, C3), 122.97 (q, J = 271.9
Cryostream cooler. Data collected6 on Nonius Kappa instruments
were processed7 using the HKL package with unitꢀcell parameters
25 refined against all data. Data measured on the Bruker APEX or
APEXꢀII were processed using the SAINTPLUS program8 or
Hz, C10), 34.27 (C7), 21.09 (C8), 13.63 (C9) ppm; IR (solid/cmꢀ1):
νmax = 3119w, 3099w, 2975w, 2937w, 2879w (aliphatic CH),
1619w, 1521m, 1325m (NO2), 1118s, 1089s (CF3), 913m, 825m;
Elemental Analysis calc. for C10H10F3NO2S: C 45.3, H 3.8, N
APEXꢀII software9 with an empirical absorption correction 65 5.3%; found
C 45.0, H 3.6, N 5.4%. Crystallography:
applied (SADABS).10 Structures were solved by direct methods
and refined using fullꢀmatrix least squares within SHELXTL.11
30 All nonꢀH atoms were refined anisotropically and H atoms added
at calculated positions and refined using a riding model. Graphics
Orthorhombic P212121 a = 4.3006(12), b = 12.286(4), c =
21.406(6) Å (structure available as ESI).
Synthesis of 9b
for publication were prepared in Mercury.12 Structural data for 1 70 Ethanol (15 mL), 9a (2.65 g, 10 mmol), H2O (0.5 mL) and glacial
– 9 as well as selected intermediates are available in cif format as
ESI and are available from the CSD (deposit codes CCDC
35 969012 ꢀ 969022).
acetic acid (1 mL) were combined and stirred to form a
homogenous mixture (< 2 min). Powdered iron (2.79 g, 50 mmol)
was added slowly and the reaction mixture was stirred at 150 °C
for 105 min under microwave irradiation. This process was
The synthesis of 9 is described in detail here and is
representative of the general methodology employed. The 75 repeated a further three times for a total of 40 mmol and the
experimental protocols and analytical data for all other
compounds are reported in the ESI.
combined reaction mixture was diluted with CH2Cl2 (150 mL)
and filtered through a silica gel plug. The silica was washed with
CH2Cl2 (100 mL) and the solvents removed in vacuo. The residue
was washed with 100 mL of saturated NaHCO3(aq) and extracted
40
Synthesis of 9a
4ꢀchloroꢀ3ꢀnitroꢀtrifluoromethylꢀbenzene (1.47 mL, 10 mmol) 80 into CH2Cl2 (150 mL); the organic phase was washed with
was added to a solution of sodium propaneꢀ1ꢀthiolate (1.08 g, 11
mmol) in dry DMF (20 mL). The reaction mixture was stirred at
saturated NaHCO3(aq), brine, and then dried over MgSO4. The
CH2Cl2 was removed in vacuo to yield 9b as an orange oil (8.76
g, 37.2 mmol, 93%). 1H NMR (500 MHz, CDCl3) δH = 7.42 (1H,
dd, J = 8.55, 0.65 Hz, C6H), 6.93ꢀ6.92 (2H, m, C5H, C3H), 4.47
45 130 °C for 25 min under microwave irradiation, and this process
repeated a further four times for a total of 50 mmol. The
combined reaction mixtures were added to water (250 mL) and 85 (2H, bs, NH), 2.78 (2H, t, J = 7.2 Hz, SC7H2), 1.60 (2H, sextet, J
the product extracted into Et2O (3 x 100 mL); the organic layer
was washed with water (150 mL), saturated Na2CO3(aq) (200 mL)
50 and then dried over MgSO4. The solvent was removed in vacuo to
reveal a waxy orange solid which was repeatedly extracted with
= 7.3 Hz, SCH2C8H2), 1.00 (3H, t, J = 7.4 Hz, C9H3) ppm; 13C
NMR (300 MHz, CDCl3) δC = 147.73 (C2), 134.61 (C6), 130.94
(q, J = 32.2 Hz, C4), 124.17 (q, J = 272.4 Hz, C10), 122.84 (C1),
114.72 (q, J = 3.1 Hz, C5), 111.10 (q, J = 3.2 Hz, C3), 36.40 (C7),
hot hexane to remove an intractable brownꢀred oil and then 90 22.93 (C8), 13.33 (C9) ppm; IR (thin film/ cmꢀ1): νmax = 3464w
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and 3378w (NH2), 2962m and 2904w (aliphatic CH), 1613w,
C14H9F3N2S: C 57.1, H 3.1, N 9.5%, found C 57.1, H 3.2, N
1258m, 1079m and 1012s (CF3), 793s; HRMS ES(+) m/z [M + 60 9.4%.
H]+ calc. for C10H13F3NS: 236.0721, found 236.0720.
Results
5
Synthesis of 9c
The syntheses of the benzothiadiazines 1 – 9 were achieved using
a modification of the methodology described1b by Kaszynski et
al. (Scheme 1) utilising the appropriate 2ꢀnitroꢀchlorobenzene
65 and aryl nitrile as the major building blocks for construction of
the benzoꢀfused ring and the substituent at the C(3) position
respectively. The first step of the reaction sequence is the
nucleophilic aromatic substitution reaction of nꢀpropylthiolate on
the 2ꢀnitrochlorobenzene. Whilst the reported synthetic method1b
70 afforded intermediate 1a in 94% yield over 2 h, in our hands the
reaction required extended reaction times (up to 2 days) and a
Kugelruhr distillation to achieve 1a in acceptable purity.
However, the ionic nature of the nucleophile made this reaction
an ideal candidate for microwave enhancement14 and permitted
75 us to prepare multiꢀgram amounts of the sulphides 1a and 9a in
high yield without the need for distillation or column
chromatography. Whilst recrystallisation of 9a resulted in a drop
in isolated yield, it is otherwise obtained in excellent purity.
The reported reduction of the nitro group to the amine using
80 iron powder according to the literature method2 again proved
problematic in our hands (reaction times varying between 18 h
and in excess of 1 week for the reaction to go to completion and
was sometimes accompanied by formation of a brown intractable
tar during work up) but again appeared amenable to microwave
85 methods permitting the products to be isolated in high yield and
purity after ca. 90 minutes. Subsequent benzamidine formation
via baseꢀpromoted coupling of the amine to the aromatic nitrile
proceeded under modified conditions using LiHMDS, NaHMDS
or NaOMe (rather than NaH). Thus the inclusion of functionality
90 at C(3) using this methodology requires a lack of (acidic) H
atoms α to the nitrile on the substrate. Despite this restriction, this
approach offers access to a potentially large range of aryl and
heterocyclic derivatives and we have successfully generated arylꢀ,
pyridylꢀ and thienylꢀfunctionalised benzoꢀthiadiazines (1 – 9).
95 This approach should also afford access to selected alkyl variants
derived from tBuCN or Cl3CCN inter alia. The subsequent
cyclisation and pericyclic elimination reactions followed the
procedures reported by Kaszynski,1b,2 affording the target
9b (9.88 g, 42 mmol) in dry THF (15 mL) was added dropwise to
a stirred solution of lithium bis(trimethylsilyl)amide (7.69 g, 46
mmol) in dry THF (40 mL) at 0 °C under N2. The reaction
mixture was allowed to warm to room temperature and stirred for
10 18 h. A solution of benzonitrile (4.3 mL, 42 mmol) in dry THF
(15 mL) then added dropwise to the reaction mixture and stirred
for a further 18 h. The volume of solvent was reduced to approx.
10 mL and the reaction mixture treated with 100 mL of
NaHCO3(aq.) on ice and extracted into CH2Cl2 (150 mL). The
15 organic phase was washed with NaHCO3(aq.) and brine, dried over
MgSO4 and the solvent was removed in vacuo to yield the crude
product as a dark brown/red oil. Pure product was obtained by
repeated extractions with a hot tolueneꢀhexane mixture (70:30) to
remove a granular brown solid and recrystallized from this
20 solvent mixture to yield 9c as white crystals (8.81 g, 62%) mp
108.1 °C. 1H NMR (500 MHz, CDCl3) δH = 7.94 (2H, d, J = 7.0
Hz, C9,13H), 7.53ꢀ7.46 (3H, m, C10,12H, C11H), 7.32ꢀ7.27 (2H, m,
C6H, C5H), 7.16 (1H, s, C3H), 4.83 (2H, bs, NH2), 2.90 (2H, t, J
= 7.4 Hz, SC14H2), 1.73 (2H, sextet, J = 7.4 Hz, SCH2C15H2),
25 1.06 (3H, t, J = 7.4 Hz, C16H3) ppm. 13C NMR (300 MHz,
CDCl3) δC = 155.35 (C7), 147.00 (C2) 135.81 (C8), 135.17 (C1),
131.04 (C11), 128.68 (C10,12), 127.53 (q, J = 32.0 Hz, C4), 127.06
(C9,13), 125.74 (C6), 124.43 (q, J = 271.9 Hz, C17), 120.20 (C5),
117.12 (q, J = 2.77 Hz, C3), 33.19 (C14), 22.11 (C15), 13.81 (C16)
30 ppm; IR (solid/cmꢀ1): νmax = 3457w (NH), 3287w, 3319br,
2967w, 2868w, 1634m, 1611m, 1408m, 1238m, 1118m, 1073m,
897m, 701m, 475m; HRMS ES(+) m/z [M + H]+ calcd for
C17H18F3N2S: 339.1143, found 339.1144; Elemental Analysis
calc. for C17H17F3N2S: C 60.3, H 5.1, N 8.3%; found C 60.4, H
35 5.0, N 8.2%. Crystallography: Orthorhombic Pbcn, a = 9.359(3),
b = 19.512(6), c = 18.547(6) (structure available as ESI).
Synthesis of 9
Nꢀchlorosuccinimide (3.67 g, 27.5 mmol) in CH2Cl2 (70 mL) was
40 added dropwise to a solution of 9c (8.8 g, 26 mmol) in CH2Cl2
(45 mL) at ꢀ78 °C, allowed to warm to room temperature and
stirred for 18 h. The reaction mixture was then washed with 0.1
M NaOH(aq), water and brine, and dried over MgSO4. The solvent
was removed in vacuo and the oily residue reꢀdissolved in toluene
45 (30 mL) and refluxed for 12 h. The solvent was removed in vacuo
and the solid recrystallised from hexaneꢀtoluene (70:30) at ꢀ18 °C
benzothiadiazines
1 – 9. Full experimental details and
100 characterisation data are available as ESI.
Structural Studies on Benzothiadiazines
There are few structural studies of simple benzothiadiazines (A1
,A3, A4, fig 2)1b,c and the main focus of this work was to
elucidate the structural parameters associated with the
105 benzothiadiazine ring and also factors which dictate their solid
state structures. In particular the potential of the NꢀH group in the
4ꢀposition to act as a hydrogen bond donor and the N atom at the
2ꢀposition to act as a hydrogen bond acceptor offers opportunities
for the construction of hydrogenꢀbonded networks. Here we
110 report structural studies on the benzoꢀfused thiadiazines, 1 – 9
and compare them with A1 and A3.
1
to yield 9 as small orange crystals (6.12 g, 80%) mp 118 °C. H
NMR (500 MHz, CDCl3) δH = 7.59 (2H, d, J = 7.1 Hz, C9,13H),
7.46ꢀ7.37 (3H, m, C11H, C10,12H), 7.12 (1H, d, J = 7.3 Hz, C5H),
50 6.83 (1H, bs, NH), 6.73 (1H, d, J = 7.6 Hz, C6H), 6.61 (1H, s,
C3H) ppm; 13C NMR (300 MHz, CDCl3) δC = 156.53 (C7),
137.15 (C2), 133.49 (C8), 131.42 (C11), 129.75 (q, J = 32.9 Hz,
C4), 128.95 (C10,12), 126.925 (q, J = 271.5 Hz, C14), 126.62 (C1),
126.00 (C9,13), 122.92 (C6), 122.49 (q, J = 3.69 Hz, C5), 110.65
55 (C3) ppm; IR (solid/cmꢀ1): νmax = 3230w, 3195w, 3166w, 3050w,
2972w, 1456m, 1324m, 1311m, 1136m, 1122s, 878m, 690m,
662m, 457w; HRMS ES(+) m/z [M + H]+ calcd for C14H10F3N2S
295.0512, found 295.0507; Elemental Analysis calc. for
Molecular geometry:- In order to maintain consistency, the atom
labelling scheme implemented for a discussion of the molecular
geometry (see bond lengths and angles in Table 1) reflects the
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Table 1 Geometric parameters for Compounds 1 – 9.
Compound
Bond length/Å
S(1)ꢀN(2)
1
2
3
4
5
1.7200(13)
1.2925(19)
1.3786(19)
1.4157(19)
1.392(2)
1.7077(14)
1.7010(14)
1.287(2)
1.686(2)
1.291(3)
1.367(3)
1.403(4)
1.393(3)
1.764(2)
1.6984(13)
1.7019(13)
1.2898(19)
1.2844(19)
1.3782(19)
1.374(2)
1.4195(19)
1.409(2)
1.397(2)
1.713(2)
1.299(2)
1.368(2)
1.417(2)
1.392(2)
1.752(2)
N(2)ꢀC(3)
C(3)ꢀN(4)
N(4)ꢀC(5)
C(5)ꢀC(6)
C(6)ꢀS(1)
1.288(2)
1.3746(19)
1.3683(19)
1.400(2)
1.4071(19)
1.399(2)
1.398(2)
1.7700(15)
1.7640(17)
1.396(2)
1.7642(15)
1.7665(17)
1.7582(16)
Bond Angle/°
C(6)S(1)N(2)
102.03(7)
117.33(11)
125.00(14)
121.34(13)
118.70(13)
117.52(12)
35.84
103.94(7)
104.17(7)
105.19(11)
122.52(18)
126.1(2)
125.0(2)
121.0(2)
120.1(2)
0.52
103.46(7)
104.31(7)
101.08(8)
117.4(1)
125.5(2)
120.8(1)
119.1(2)
118.0(1)
35.97
S(1)N(2)C(3)
N(2)C(3)N(4)
C(3)N(4)C(5)
N(4)C(5)C(6)
C(5)C(6)S(1)
Fold/°
118.54(11)
118.34(11)
126.54(15)
126.61(14)
122.63(13)
122.54(13)
119.57(13)
119.24(14)
118.36(12)
118.43(12)
27.53, 27.27
119.95(11)
119.58(12)
126.38(14)
126.71(14)
121.52(12)
123.16(13)
119.93(13)
119.72(15)
119.08(11)
119.03(12)
23.27, 26.54
Compound
Bond length/Å
S(1)ꢀN(2)
6
7
8
9
1.692(3)
1.287(4)
1.365(4)
1.412(4)
1.389(5)
1.768(4)
1.7005(15)
1.286(2)
1.372(2)
1.408(2)
1.390(3)
1.7767(19)
1.719(3)
1.290(4)
1.385(4)
1.407(4)
1.394(5)
1.763(3)
1.73(1), 1.71(1),
1.71(1), 1.72(1)
1.30(1), 1.29(1),
1.30(1), 1.29(1)
1.37(1), 1.37(1),
1.37(1), 1.37(1)
1.42(2), 1.43(2),
1.41(2), 1.43(1)
1.41(1), 1.39(2),
1.40(1), 1.39(2)
1.75(1), 1.75(1),
1.75(1), 1.74(1)
N(2)ꢀC(3)
C(3)ꢀN(4)
N(4)ꢀC(5)
C(5)ꢀC(6)
C(6)ꢀS(1)
Bond Angle/°
C(6)S(1)N(2)
105.50(16)
121.0(3)
125.8(3)
125.5(3)
119.9(3)
119.4(3)
14.18
103.77(8)
120.44(12)
126.10(16)
123.79(15)
120.38(16)
119.18(14)
21.42
101.26(14)
116.3(2)
123.7(3)
120.0(3)
118.1(3)
116.2(2)
41.18
103.3(6), 103.6(6),
103.2(6), 101.6(6)
117.2(8), 117.3(9),
117.3(8), 118.4(9)
124(1), 125(1),
126(1), 126(1)
123(1), 123(1),
123(1), 121(1)
118(1), 118(1),
118(1), 119(1)
S(1)N(2)C(3)
N(2)C(3)N(4)
C(3)N(4)C(5)
N(4)C(5)C(6)
C(5)C(6)S(1)
Fold, θ/°
116.9(9), 117.9(9)
119.1(9), 119.3(9)
34.46, 32.61,
31.07, 32.34
a The fold angle was defined as the angle between the S(1)N(2)C(3)N(4) and N(4)C(5)C(6)S(1) mean planes.
IUPAC numbering scheme (Fig. 4) and not the
a
atom numbering for individual structures). The geometry of the
benzothiadiazine ring is consistent with the resonance form
shown in Figure 4 with C(3)−N(2) distances in the range 1.286(2)
– 1.299(2) Å (Table 1) consistent with predominantly double
5
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bond character (dC=N = 1.2 Å)15 and C(3)ꢀN(4) distances in the
range 1.365(4) – 1.384(4) Å more consistent with a conjugated Cꢀ
N single bond (dC−N = 1.35 Å for phenylamine).15 The S−N bond
CꢀH bonds (dNꢁꢁꢁN = 3.094(3) Å). With each molecule offering
hydrogen bond donor and acceptor character this leads to a oneꢀ
dimensional chain topology (Fig. 6) in the form of helical chains
lengths (1.686(2) – 1.722(3) Å)are comparable with other S−N 60 parallel to the crystallographic a axis. The overall structure
5
single bonds (1.62 – 1.74 Å for isomers of S8ꢀx(NH)x).16 The most
marked feature in the geometry of the benzothiadiazine ring is the
folding (θ) of the molecule about the transꢀannular S(1)ꢁꢁꢁN(4)
vector. For the majority of benzothiadiazines, θ falls in the range
adopts the chiral space group P212121. The nearꢀplanarity of the
thiadiazine framework in 3 is unexpected for a formally 8π antiꢀ
aromatic system but may be due to the opportunity to optimise
the slipped πꢀstack motif parallel to the crystallographic aꢀaxis
21° < θ < 42°; however in both 3 and 6 the angles are less than 65 which offers a mean interꢀmolecular distance of 3.435Å.
10 20o and in 3, in particular, the ring is essentially planar. These
data are consistent with the thiadiazine framework possessing a
formally 8π antiꢀaromatic electron count. A study of the
energetics of deformation of the molecule from planarity is
discussed later but reveals that there is a shallow energy
15 minimum around 30o, consistent with the experimental
observations. Moreover the shallowness of the energy landscape
suggests that optimisation of other packing forces (discussed in
more detail below) may modify this fold angle at minimal
energetic expense.
70
20
1
S
8
9
N2
7
75 Fig. 6 Molecular packing of 3 illustrating the propagation of trifurcated
4
3
6
10
N
hydrogen bonding interactions to form chains.
5
H
The structure of 4 also utilises the paraꢀpyridyl substituent as a
hydrogen bond acceptor forming a polymeric chain parallel to the
25 Fig. 4 IUPAC numbering scheme for the heterocyclic component of the
4Hꢀbenzoꢀ1,2,4ꢀthiadiazine ring.
crystallographic cꢀaxis (Fig. 7). In
80 crystallographically independent molecules which are linked via
NꢀHꢁꢁꢁN contacts (dNꢁꢁꢁN = 2.959(2) and 3.198(2) Å).
4
there are two
Molecular Packing:- The structures of 1 – 9 all exhibit
hydrogenꢀbonding between the N(4)ꢀH hydrogen bond donor and
a hydrogen bond acceptor. Whilst this may be the N(2) atom of a
30 neighbouring heterocyclic ring, there is potential for other
functional groups to be involved, e.g. when pyridyl and
nitrophenyl derivatives are present. The parent phenyl derivative
1 has been reported previously1b and crystallises in the space
group P21/c, with molecules linked via N(4)ꢀHꢁꢁꢁN(2) hydrogen
35 bonds parallel to c (dNꢁꢁꢁN = 3.024(2) Å) to form chains.
In the case of 2, the prevalence for hydrogenꢀbonding is
reflected in an intraꢀmolecular hydrogen bond to the orthoꢀ
pyridyl substituent rather than N(2) (Fig.5). This brings the
pyridyl and benzothiadiazine rings near to coplanarity (7.07° and
40 12.35° for the two crystallographically independent molecules)
which should be contrasted with 1 where the torsion angle is
43.60°.
85
90
95
Fig. 7 Molecular packing of 4 illustrating the propagation of NꢀHꢁꢁꢁN
hydrogen bonding interactions parallel to the crystallographic cꢀaxis.
The structure of the 2ꢀthienyl derivative 5 also exhibits N(4)ꢀ
H…N(2) contacts (dNꢁꢁꢁN = 3.125(2) Å). The structure of 5, like 1
therefore adopts a chainꢀlike motif (Fig. 8). In this case the Nꢀ
45
100 H…N contacts propagate parallel to the crystallographic bꢀaxis.
The structure of 6 utilises the pꢀnitro group to similarly direct a
hydrogen bonding motif (Fig. 9). In 6, as for 3, the hydrogen
bond acceptor forms a trifurcated contact to two CꢀH bonds and
the NꢀH bond (dNꢁꢁꢁO = 3.159(4) Å). These hydrogen bonds
105 propagate parallel to the crystallographic bꢀaxis. Notably 6, like
3, is also close to coplanar and this appears to optimise πꢀstacking
in a headꢀtoꢀtail fashion (parallel to the crystallographic a axis)
with mean interꢀlayer separations of 3.438 Å (cf 3 at 3.435 Å).
50
Fig. 5 Molecular structure of 2 illustrating the coplanarity of the pyridyl
and benzothiadiazine rings in one of the two crystallographically
independent molecules.
The propensity for the pyridyl group to be involved in hydrogen
55 bonding is also reflected in the structure of 3 where the metaꢀ
pyridyl group forms a trifurcated interaction to the NꢀH and two
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30 methoxy interactions are relatively common and are reflected in
2015 reports of this motif in the CSD.18
35
40
45
50
Fig. 8 Molecular packing of 5 illustrating the propagation of NꢀHꢁꢁꢁN
hydrogen bonding interactions parallel to the crystallographic bꢀaxis.
Fig. 11 Molecular packing of 8 illustrating the propagation of NꢀHꢁꢁꢁN
hydrogen bonding interactions parallel to the crystallographic bꢀaxis and
CꢀHꢁꢁꢁO contacts which act as rungs to the Hꢀbonded ladder structure.
5
Fig. 9 Molecular packing of 6 illustrating the propagation of NꢀHꢁꢁꢁO
hydrogen bonding interactions parallel to the crystallographic bꢀaxis.
55
The structure of 9 proved persistently problematic with clear
evidence of twinning in many samples. The best crystal of many
examined still proved twinned (with Fo > Fc for many of the most
disagreeable reflections) but provided adequate data to determine
60 the atomic connectivity and crystal packing features. The CF3
group is not considered a hydrogenꢀbond acceptor and, whilst the
structure of 9 is more complex due to the presence of 4 molecules
in the asymmetric unit, the structure again comprises an
N(4)HꢁꢁꢁN(2) hydrogenꢀbonding network. In this case there are
65 two similar but crystallographically independent chains (with two
crystallographically independent molecules per chain) with each
chain linked parallel to the crystallographic aꢀaxis (Fig. 12).
In the case of 7, one of the two metaꢀnitro groups exhibits a
similar trifurcated interaction to the NꢀH (dNꢁꢁꢁO = 3.214(2) Å)
group, again generating a molecular chain motif (Fig. 10), this
10 time running parallel to the ac diagonal. 7 also adopts a slipped πꢀ
stack (parallel to b) with interꢀlayer separation of 3.397 Å.
70
75
80
Fig. 10 Molecular packing of 7 illustrating the propagation of NꢀHꢁꢁꢁO
hydrogen bonding interactions.
15
The structure of 8 offers the potential for the methoxy group to
act as a hydrogenꢀbond acceptor but the benzothiadiazine N(2)
atom appears to act as a better hydrogen bond acceptor than the
methoxy group with N(4)ꢀHꢁꢁꢁN(2) hydrogen bonds (dNꢁꢁꢁN
3.145(4) Å) forming a chain parallel to the crystallographic bꢀ
20 axis (Fig. 11). The methoxy groups themselves form weak pairs
of centrosymmetric dimers linked via pairs of CꢀHꢁꢁꢁO contacts
[dCꢁꢁꢁO = 3.483(5) Å] which link the NꢀHꢁꢁꢁN bonded chains into a
ladder motif.
=
Whilst CꢀH groups are typically considered weak Hꢀbond donors,
25 the ether functionality is a known hydrogenꢀbond acceptor (ꢀ0.53
< pKHB < 1.98)17 although the less pꢀcharacter associated with the
the O lone pair for arylalkyl ethers of sp2ꢀcharacter (compared to
the sp3ꢀO of a dialkyl ether) make such arylꢀethers less basic.17
Nevertheless such centrosymmetric pairs of CꢀHꢁꢁꢁO methoxyꢀ
85 Fig. 12 Molecular packing of 9 illustrating the propagation of NꢀHꢁꢁꢁN
hydrogen bonding interactions parallel to the crystallographic aꢀaxis. One
of the two crystallographically independent chains coloured grey.
6
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Computational Studies
relation to the Nꢀheterocyclic rings such as pyrazine and pyridine.
Notably the benzoꢀthiadiazine NꢀH bond is involved in Hꢀ
60 bonding to both pyridyl substituents and nitrophenyl derivatives
but prefers the benzothiadiazine N(2) centre in relation to the
weaker methoxyꢀphenyl or thiophenyl Hꢀbond acceptors in 8 and
At the molecular level the geometries of 1 – 9 all appear broadly
similar, with the major variation between them associated with
the folding of the thiadiazine ring. Geometryꢀoptimised
B3LYP/6ꢀ311G* DFT studies on 1 were undertaken to probe the
energetics of the ring system, varying the fold angle of the
thiadiazine ring [torsion C(3)N(4)S(1)C(6)] between planar (θ =
180°) and 90° whilst permitting the rest of the molecule to
optimise. These calculations reveal an energy minimum at θ =
5
5, thus placing the benzothiadiazine heterocyclic ring
N
intermediate between methoxybenzene and nitrobenzene as a
65 hydrogen bond acceptor, i.e. ꢀ0.08 < pKHB < +0.48. Whilst pKHB
values for S/Nꢀcontaining heterocycles have not been extensively
reported, benzothiadiazole20b has
a pKHB value of +0.79.
10 150o i.e. around 30o from planarity but with a range of fold angles
accessible at little energetic cost, e.g. conformations with the
range 130° < θ < 180° fall within 8.5 kJ/mol (Fig. 13). Thus the
experimentally determined range (179.48° – 138.42°) appear in
agreement with a shallow energy minimum to folding such that
15 the small energy offset to deform the heterocyclic ring may be
offset by gains in optimised intermolecular contacts such as the
hydrogenꢀbonding motifs described previously. Notably the most
planar molecular structures also favour the adoption of πꢀstacked
motifs with 3, 6 and 7 exhibiting small fold angles (in the range
20 0.52 – 21.42o) and interꢀplanar separations along the stacking
directions in the range 3.397 – 3.438 Å.
Moreover it is known that hydrogenꢀbond acceptors in 6ꢀ
membered rings have smaller pKHB values than the corresponding
70 5ꢀmembered rings,13b,23 potentially placing benzothiadiazines in
this region.
Notably the pyrazinyl–fused thiadiazine reported1 by
Kaszynski also exhibits NꢀHꢁꢁꢁN donor acceptor interactions to
the strong Hꢀbond acceptor of the pyrazine ring to afford a dimer
75 motif. Curiously the NꢀH group in the tetrafluorobenzo
derivative1 appears not to be involved in any NꢀHꢁꢁꢁE hydrogen
bond, indicating a prevalence for an alternative structureꢀ
directing synthon which dictates the structure. Notably in this
latter case the structure adopts a πꢀstacked structure with
80 alternating fluoroꢀaryl/aryl rings somewhat akin to the C6F6ꢁC6H6
cocrystal.24
120
100
25
Conclusions
80
60
40
The syntheses of a series of benzoꢀ1,2,4ꢀthiadiazines have been
reported. The implementation of microwave techniques
85 substantially decreased reaction times and led to improved yields
for the first two steps in the synthetic pathway. Crystallographic
studies on 1 – 9 reveal a propensity for N(4)ꢀH to exhibit
hydrogen bonding motifs. In the absence of other hydrogen bond
acceptors this occurs to N(2) but both pyridyl and nitro groups
90 are sufficiently strong hydrogen bond acceptors to disrupt the
N(4)ꢀHꢁꢁꢁN(2) hydrogen bond, suggesting both pyridyl and nitro
groups are superior hydrogen bond acceptors than N(2).
Conversely N(2) appears a better hydrogen bond acceptor than
either thiophene or methoxy groups. In addition, the shallow
95 energy minimum for ring deformation permits some flexibility in
the thiadiazine backbone with the 8π heterocycle moving closer
to planarity in those structures which adopt πꢀstacked motifs. The
coordination chemistry of 2 which offers the potential to act as an
N,N′ꢀchelate ligand will be the subject of future publications.
30
20
0
-20
100 120 140 160 180 200 220 240 260
35
Fold angle (o)
Fig. 13. B3LYP/6ꢀ311G* computed energies of 1 with the fold angle
varied between 180° (planar) and 90°.
Discussion
40 The structures of 1 – 9 reveal that the secondary aminoꢀnitrogen
N(4)ꢀH of the benzothiadiazine ring has a strong affinity to be
involved in hydrogen bonding. In the absence of other strong Hꢀ
bond acceptors, the benzothiadiazine N(2) atom is sufficiently
basic to act as the Hꢀbond acceptor, as in 1, 5, 8 and 9 suggesting
45 that N(2) is a stronger acceptor than a thienylꢀS atom or methoxyꢀ
O atom. However the pyridyl substituents present in 2 – 4 and the
nitro groups in 6 and 7 both act as stronger H–bond acceptors
[than the benzothiadiazinylꢀN(2) atom]. These observations are
consistent with previous studies on hydrogenꢀbond acceptor
50 character of different functional groups pioneered by Taft19 and
extended by Abraham20 and Berthelot21 inter alia. The pKHB
scale developed by Taft focuses on equilibrium constants for Hꢀ
bonded donorꢀacceptor complexes in solution. On this scale the
Hꢀbond acceptors relevant to this work have the following values;
55 thiophene (ꢀ0.37),20a methoxybenzene (ꢀ0.08),22 nitrobenzene
(+0.48), pyrazine (+1.22) and pyridine (+1.86).20a This indicates
that thiophene and methoxybenzene are poor Hꢀbond acceptors in
100 Acknowledgements
We would like to thank EPSRC (ERC) and NSERC, CFI/ORF
and the Canada Research Chair program for financial support
(JMR). We gratefully acknowledge Prof. M. Pilkington (Brock
University) for diffractometer time to collect Xꢀray data on both 5
105 and 9 and Dr J.E. Davies (University of Cambridge) for
collecting Xꢀray data on compounds 1 – 4. In addition we would
like to thank the referees for their constructive comments.
Notes and references
a Department of Chemistry, The University of Cambridge, Lensfield
110 Road, Cambridge UK CB2 1EW.
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b Department of Chemistry and Biochemistry, The University of Windsor,
401 Sunset Avenue, Windsor, Ontario, Canada N9B 3P4. Eꢀmail:
jmrawson@uwindsor.ca
22 “Hꢀbonded complexes of phenols” C. Laurence, M. Berthelot and J.
Gratain in The Chemistry of Phenols (Ed. Z. Rappaport), J. Wiley,
2003.
† Electronic Supplementary Information (ESI) available: full
experimental details and analytical data for 1–9; a cif file containing the
crystal structures of 1–9 and selected intermediates. See
DOI: 10.1039/b000000x/
23 A. Mukhopadhyay, M. Mukherjee, P. Pandey, A. K. Samanta, B.
Bandyopadhyay and T. Chakraborty, J. Phys. Chem. A, 2009, 113,
3078.
24 C. R. Patrick and G. S. Prosser, Nature, 1960, 187, 1021; G. W.
Coates, A. R. Dunn, L. M. Henling, J. W. Ziller, E. B. Lobkovsky
and R. H. Grubbs, J. Am. Chem. Soc., 1998, 120, 3641; D. G. Naae,
Acta Crystallogr. Sect. B, 1979, 35, 2765; C. Dai, P. Nguyen, T. B.
Marder, A. J. Scott, W. Clegg and C. Viney, Chem. Commun., 1999,
2493.
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21 “Observations on the Strength of Hydrogen Bonding” C. Laurence
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8
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