Synthesis of a new class of electron rich chiral cyclophanes with large cavities

Article abstract of DOI:10.1016/S0040-4020(03)00686-0

BINOL based electron rich chiral cyclophanes possessing large cavities have been synthesized starting from m-terphenyl dibromide and methyl m-/p-cinnamate. The presence of double bonds in the chiral cyclophanes makes them electron rich as revealed by C-T complexation studies of such cyclophanes donors with guests like TCNE, TCNQ and DDQ.

Full text of DOI:10.1016/S0040-4020(03)00686-0

Tetrahedron 59 (2003) 5373–5376
Synthesis of a new class of electron rich chiral cyclophanes with
large cavities
†
*
Perumal Rajakumar and Muthialu Srisailas
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600 025, India
Received 2 August 2002; revised 19 April 2003; accepted 29 April 2003
Abstract—BINOL based electron rich chiral cyclophanes possessing large cavities have been synthesized starting from m-terphenyl
dibromide and methyl m-/p-cinnamate. The presence of double bonds in the chiral cyclophanes makes them electron rich as revealed by C–T
complexation studies of such cyclophanes donors with guests like TCNE, TCNQ and DDQ. q 2003 Elsevier Science Ltd. All rights reserved.
1
1. Introduction
The chiral cyclophane 5, in its H NMR, signals for the
methylene protons merged to appear as multiplet in the
region d 4.90–5.90, not as in the case of chiral cyclophanes
reported earlier,5a where the methylene protons appear as
clear doublets. The aromatic protons appear in the region
between d 7.37–7.87. In 13C NMR, the cyclophane 5
showed 22 signals for aromatic carbons in addition to
benzylic carbons at d 70.1 and 70.7. The momeric structure
was supported by the FAB-MS spectrum, which showed the
molecular ion peak at m/z 752. The compound had a specific
rotation of -186 (c 0.4, CHCl3). This cyclophane has a large
cavity size and hence may bind bigger guest molecules
when compared with chiral cyclophanes reported earlier.5a
The design of organic molecules possessing functional
groups that can interact with guest molecules in comple-
mentary ways is a challenge in organic chemistry.1 The
synthesis of BINOL based crown ethers was pioneered by
Cram2 and the chiral discriminating properties of BINOL
are being exploited in modern organic synthesis and in
asymmetric catalysis.3 Electron rich cyclophanes bearing
acetylenic units were reported by Whitlock.4 Although
chiral cyclophanes based on BINOL were earlier reported
from our laboratory,5 the synthesis of electron rich chiral
cyclophanes with ethylene units would be more promising
as they could form complexes with electron deficient guest
molecules. Herein, we report the synthesis and CT
complexation studies of electron rich BINOL based chiral
cyclophanes.
In order to further increase the cavity size, methyl m-/p-
hydroxycinnamate were used as spacer units. Treatment of
the dibromide 1 with methyl m-hydroxycinnamate in DMF
at 608C for 48 h gave diester 6a in good yield. Diol 7a
obtained by the reduction of diester 6a using LAH in THF
was converted to dibromide 8a by treatment with PBr3 in
CH2Cl2 at rt for 12 h. Coupling dibromide 8a with (S)-
BINOL in acetone in the presence of K2CO3 gave chiral
cyclophane 9a in 21% yield. When a similar sequence was
applied for methyl p-hydroxycinnamate, cyclophane 9b was
obtained in 16% yield (Scheme 2).
2. Results and discussion
The m-terphenyl bromide 1 was synthesized employing the
Hart reaction.6 The treatment of m-terphenyl dibromide 1
with p-hydroxybenzaldehyde in DMF in the presence of
K2CO3 at 608C for 48 h gave dialdehyde 2 in good yield.
The dialdehyde 2 was reduced to diol 3 using NaBH4 in
methanol and the diol 3 was converted into dibromide 4
using PBr3 in CH2Cl2 at rt for 12 h. Dibromide 4 was then
coupled with (S)-BINOL in acetone in the presence of
K2CO3 under high dilution conditions to afford the chiral
cyclophane 5 in 38% yield (Scheme 1).
Cyclophanes 9a and 9b had optical rotations of -136.4 (c
0.4, CHCl3) and -120.0 (c 0.4, CHCl3) respectively.
Cyclophanes 9a and 9b were characterized by 1H, 13C
NMR and elemental analysis. The monomeric structures of
cyclophanes 9a, b were evidenced by FAB-MS.
2.1. Complexation studies
Keywords: chiral cyclophanes; electron rich; large cavities.
*
Corresponding author. Tel.: þ91-442-351-269x213; fax: þ91-442-353-
The presence of the double bond in cyclophanes 9a and 9b
makes them electron rich hence may act as molecular
receptors for electron deficient guest molecules. In order to
309; e-mail: perumalrajakumar@hotmail.com
Present address: Division of Organic Chemistry (Synthesis), National
Chemical Laboratory, Dr. Homi Baba Road, Pune, 411 008, India.
†
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00686-0

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P. Rajakumar, M. Srisailas / Tetrahedron 59 (2003) 5373–5376
Scheme 1. Reagents and conditions: (i) 2.2 equiv. p-hydroxybenzaldehyde, K2CO3, DMF, 608C, 48 h, 77%; (ii) NaBH4, MeOH, 08C, 6 h, 95%; (iii) PBr3,
CH2Cl2, 08C, 92%; (iv) (S)-BINOL, K2CO3, acetone, rt, 120 h, 38%.
Scheme 2. Reagents and conditions: (i) 2.2 equiv. methyl m-/p-hydroxycinnamate, K2CO3, DMF, 608C, 48 h, 56/46% (m-/p-); (ii) LAH, THF, rt, 6 h, 51/57%
(m-/p-); (iii) PBr3, CH2Cl2, 08C, 46/38% (m-/p-); (iv) (S)-BINOL, K2CO3, acetone, rt, 120 h, 21/16% (m-/p-).
test the formation of charge transfer (CT) complexes,
studies were carried out using the cyclophanes 9a and 9b
with small molecules viz., TCNE, TCNQ, DDQ, DIPY in
CHCl3/CH3CN (4:1).
their complexation studies with chiral guest molecules are
under progress.
3. Experimental
3.1. General
The UV–visible spectra of the CT complex of cyclophanes
9a and 9b with TCNE individually showed two absorbance
maxima at 416 nm and 398 nm. The Ka values were
determined using the Benesi-Hildebrand equation.7 The
association constant (Ka) was found to be 59 and 62 M21 for
CT complexes of cyclophane 9a and 9b with TCNE
respectively. Complexation studies were also attempted
with cyclophanes 9a and 9b and other guest molecules such
as TCNQ, DDQ and DIPY. Appreciable changes were not
observed in the UV–visible spectra of the cyclophanes 9a
and 9b with TCNQ, DDQ and DIPY.
All the melting points are uncorrected. The H and 13C
1
NMR spectra were recorded on a JEOL GSX 400 NMR
spectrometer at 400 and 100.4 MHz respectively and
coupling constants (J) are expressed in Hertz. The mass
spectra were recorded on JEOL JMS-DX 303 HF (EI,
70 eV) and FAB-MS on JEOL SX 102/DA-6000 using
m-nitrobenzyl alcohol (NBA) as matrix. The optical
rotations were recorded on an Autopol-II automatic spectro-
polarimeter with cell length 10 cm using the D-line of
sodium at 258C. The organic extracts of crude products were
Further syntheses of electron rich chiral cyclophanes and

P. Rajakumar, M. Srisailas / Tetrahedron 59 (2003) 5373–5376
5375
dried over anhydrous sodium sulfate. Column chromato-
graphy was carried out with silica gel (ACME, 100–200
mesh). m-Terphenyl dibromide was synthesized following
the literature procedure.6a
70.7, 110.9, 115.5, 120.5, 123.7, 124.8, 124.9, 125.3, 125.5,
125.8, 126.7, 126.8, 127.1, 127.4, 128.1, 128.4, 129.3,
130.8, 133.4, 134.3, 136.6, 140.5, 153.7; m/z (FAB-MS) 752
(Mþ). Anal. Calcd for C54H40O4: C, 86.14; H, 5.36. Found:
C, 86.09; H, 5.38.
3.1.1. Dialdehyde 2. To a solution of m-terphenyl
dibromide (4.16 g, 10 mmol) in DMF was added p-hydroxy-
benzaldehyde (2.564 g, 21 mmol) and anhydrous K2CO3
(14.0 g) and the reaction mixture was stirred at 608C for
48 h. Then, the reaction mixture was added to a large
amount of water (1 L) and digested over a water bath for
30 min. The residue obtained was extracted with CHCl3
(4£100 mL) and the extracts were washed with water
(3£100 mL); with brine (200 mL) and dried. Evaporation of
the organic layer gave the dialdehyde 2, which was purified
over silica gel using hexane/CHCl3 (1:1). Colourless solid;
yield 77%; mp 2058C; IR (KBr, cm21) 3050, 1682 (CvO),
3.1.5. Diester 6a. m-Terphenyl dibromide (4.16 g,
10 mmol) and methyl m-hydroxycinnamate (3.76 g,
21 mmol) in dry DMF (40 mL) was treated with anhydrous
K2CO3 (14 g) at 608C for 48 h. Then, the reaction mixture
was worked up as described for dialdehyde 4. The crude
product was purified over silica using hexane/CHCl3 (1:2)
to afford the diester 6a as a colourless solid. Yield 56%; mp
192–1948C; IR (KBr, cm21) 3050, 1704 (CvO), 1600; 1H
NMR d 3.79 (s, 6H); 5.12 (s, 4H); 6.42 (d, 2H, J¼16.1 Hz);
7.02 (d, 2H, J¼4 Hz); 7.13 (d, 4H, J¼4 Hz); 7.23 (s, 1H);
7.30 (t, 2H, J¼4 Hz); 7.52 (d, 4H, J¼7.8 Hz); 7.58 (d, 2H,
J¼6.8 Hz); 7.63 (s, 1H); 7.66 (d, 4H, J¼7.8 Hz); 7.80 (s,
2H); 13C NMR d 51.7, 69.7, 114.0, 116.9, 118.1, 121.0,
125.9, 126.2, 127.5, 127.9, 129.2, 129.9, 135.8, 140.9,
141.3, 144.7, 158.9, 167.3, 196.4; m/z (EI, 70 eV) 610 (Mþ,
6), 562 (15), 537 (14), 471 (20), 467 (100), 386 (11), 366
(70), 271 (56), 257 (72), 236 (36), 184 (74), 149 (84), 158
(46). Anal. Calcd for C40H34O6: C, 78.67; H, 5.61. Found:
C, 78.62; H, 5.58.
1
1605; H NMR (400 MHz, CDCl3) d 5.18 (s, 4H); 7.09 (d,
4H, J¼8.8 Hz); 7.52 (d, 4H, J¼8.3 Hz); 7.57 (d, 2H,
J¼4 Hz); 7.59 (t, 1H, J¼4 Hz); 7.67 (d, 4H, J¼8.3 Hz);
7.79 (s, 1H); 7.84 (d, 4H, J¼8.8 Hz); 9.88 (s, 2H); 13C NMR
(100.4 MHz, CDCl3) d 69.9, 115.1, 125.9, 126.3, 127.5,
128.0, 129.3, 130.1, 131.9, 135.1, 141.1, 141.2, 163.6,
190.7; m/z (EI, 70 eV) 498 (Mþ, 5), 369 (17), 302 (5), 271
(100), 200 (9), 165 (17), 87 (27). Anal. Calcd for
C34H26O4:C, 81.91; H, 5.26. Found: C, 81.85; H, 5.27.
3.1.6. Diester 6b. m-Terphenyl dibromide (4.16 g,
0.01 mol) and methyl p-hydroxycinnamate (3.76 g,
0.021 mol) was treated as described above. The crude
product was chromatographed over silica using hexane/
CHCl3 (1:2) to afford the diester 6b as a colourless solid.
Yield 43%; mp 1778C; IR (KBr, cm21) 3050, 1690 (CvO),
3.1.2. Diol 3. To a solution of the dialdehyde 2 (3.984 g,
8 mmol) in methanol (70 mL) was added in portions NaBH4
(0.151 g, 4 mmol) at 08C. The reaction mixture was stirred
at rt for 6 h, after which conc. HCl (10 drops) was added.
The residue obtained was filtered off. Evaporation of the
solvent in vacuo gave the diol 3, which was recrystallized
from CHCl3/MeOH (5:1). Yield 95%; mp 2088C (lit.6b
2088C).
1
1600; H NMR d 3.52 (s, 6H); 5.07 (s, 4H); 6.24 (d, 2H,
J¼15.6 Hz); 6.72–6.93 (m, 4H), 7.17–7.92 (m, 18H); 13C
NMR d 59.6, 69.8, 115.2, 117.5, 126.3, 127.1, 127.5, 127.9,
128.3, 128.9, 129.3, 130.3, 135.6, 141.3, 144.4, 160.5,
193.3. m/z (EI, 70 eV) 610 (Mþ, 8), 562 (12), 551 (7), 525
(24), 492 (41), 386 (17), 288 (62), 243 (24), 184 (76), 153
(36). Anal. Calcd for C40H34O6/C, 78.67; H, 5.61. Found: C,
78.63; H, 5.59.
3.1.3. Dibromide 4. To a stirred suspension of diol 4
(3.012 g, 6 mmol) in CH2Cl2 (120 mL), PBr3 (0.3 mL,
3 mmol) was added and the reaction mixture was stirred at
08C for 12 h. The reaction was poured into water (500 mL)
and the organic layer was washed with water (3£150 mL);
with brine (200 mL) and dried. The solvent was evaporated
in vacuo to give dibromide 4, which was recrystallized from
hexane/CH2Cl2 (1:5). Colourless solid; yield 92%; mp
3.1.7. Diol 7a. To a solution of diester 6a (8.418 g,
13.8 mmol) in dry THF (300 mL) was added in portions
lithium aluminium hydride (0.656 g, 17.3 mmol) at 08C.
The reaction mixture was stirred at rt for 6 h and then run
into Na2SO4.10H2O (20 g) and stirred. The mixture was
then digested on a steam bath (20 min) and filtered. The
inorganic residue was further extracted (Soxhlet) with THF
(200 mL). The combined THF fractions, on evaporation,
gave the corresponding alcohol, which was purified by
recrystallization from a minimum volume of THF/MeOH
(4:1). Colourless solid; yield 51%; mp 2128C; IR
1
1428C; IR (KBr, cm21) 3050, 1605; H NMR (400 MHz,
CDCl3) d 4.57 (s, 4H); 5.01 (s, 4H); 6.70–6.81 (m, 4H);
7.02–7.48 (m, 16H); m/z (FAB-MS) 632 (Mþþ 4); 630
(Mþþ2); 628 (Mþ). Anal. Calcd for C34H28O2Br2: C,
64.99; H, 4.49. Found: C, 65.12; H, 4.62.
3.1.4. Cyclophane 5. Dibromide 4 (0.314 g, 0.5 mmol) and
(S)-BINOL (0.143 g, 0.5 mmol) were stirred with K2CO3
(20 mmol) in acetone (400 mL) at room temperature for
120 h, after which the reaction mixture was acidified and
evaporated to dryness. The residue obtained was extracted
with CH2Cl2 (3£100 mL), washed with 10% NaOH
(2£50 mL); with water (3£100 mL) and dried (MgSO4).
Evaporation of the organic layer gave a residue, which was
chromatographed over SiO2 using hexane/CHCl3 (1:1) to
afford the chiral cyclophane 5 as a colourless solid. Yield
38%; mp 1788C; [a]2D5¼-186 (c 0.4, CHCl3); IR
1
(KBr, cm21) 3300, 3050, 1626, 1600; H NMR (DMSO-
d6) d 5.08 (s, 4H); 5.37–5.41 (m, 4H); 6.72 (bs, 2H,
exchangeable with D2O); 6.92–8.01 (m, 24H); m/z (EI,
70 eV) 554 (Mþ, 11), 499 (6), 478 (14), 445 (4), 413 (23),
384 (62), 308 (18), 288 (41), 229 (100), 184 (36), 153 (42).
Anal. Calcd For C38H34O4: C, 82.28; H, 6.18. Found: C,
82.14; H, 6.07.
3.1.8. Diol 7b. Following the procedure as above, the
treatment of diester 6b with lithium aluminium
hydride gave the diol 7b as a colourless solid. Yield 57%;
1
(KBr, cm21) 3050, 1605; H NMR d 4.90–5.90 (m, 8H);
6.86–7.38 (m, 20H); 7.77–7.87 (m, 12H); 13C NMR d 70.1,

5376
P. Rajakumar, M. Srisailas / Tetrahedron 59 (2003) 5373–5376
mp 165–1678C; IR (KBr, cm21) 3300, 3050, 1626, 1600;
1H NMR (DMSO-d6) d 5.24 (s, 4H); 5.28–5.39 (m, 4H);
6.68 (bs, 2H, exchangeable with D2O); 7.03–8.12 (m, 24H);
m/z (EI, 70 eV) 554 (Mþ, 11), 478 (14), 445 (4), 412 (23),
386 (62), 308 (18), 289 (41), 229 (100), 184 (36), 153 (42).
Anal. Calcd For C38H34O4: C, 82.28; H, 6.18. Found: C,
82.14; H, 6.07.
125.8, 125.9, 126.4, 127.0, 127.1, 127.4, 127.9, 128.1,
129.4, 129.6, 129.8, 130.9, 134.1, 141.2, 153.3; m/z (FAB-
MS) 804 (Mþ). Anal. Calcd for C58H44O4: C, 86.54; H,
5.51. Found: C, 86.50; H, 5.48.
3.2. UV–visible studies
Complexation studies have been carried out with cyclo-
phane 9a in (1.83£1023 M) with TCNE (1.99£1023 M)
using CHCl3/CH3CN (4:1) as solvent. Different solutions
were prepared with varying concentrations of TCNE for the
same concentration of cyclophane 9a. The two absorption
maxima observed at 416 nm and 398 nm was found to
increase with increasing TCNE concentration. Using the
Benesi-Hildebrand equation,7 the association constant (Ka)
was found to be 59 M21 from the plot of D0/[A] against
1/[A]. Similar experiments with cyclophane 9b and TCNE
3.1.9. Dibromide 8a. Treatment of diol 7a (3.324 g,
6 mmol) in CH2Cl2 with PBr3 (0.3 mL, 3 mmol) at 08C
for 6 h followed by usual workup gave the dibromide 8a as a
pale yellow solid. Yield 46%; mp 1098C; IR (KBr, cm21
)
1
3050, 1626, 1600; H NMR d 4.47 (m, 4H); 5.02 (s, 4H);
6.22–7.78 (m, 24H); m/z (FAB-MS) 684 (Mþþ 4); 682
(Mþþ2); 680 (Mþ). Anal. Calcd For C38H32O2Br2: C,
67.07; H, 4.74. Found: C, 66.89; H, 4.55.
3.1.10. Dibromide 8b. Treatment of diol 8b (3.324 g,
6 mmol) in CH2Cl2 with PBr3 (0.3 mL, 3 mmol) at 08C for
6 h followed by usual workup gave the dibromide 8b as a
gave the association constant Ka as 62 M21
.
pale yellow solid. Yield 38%; mp 1248C; IR (KBr, cm21
)
Acknowledgements
1
3050, 1626, 1600; H NMR d 4.56 (m, 4H); 5.13 (s, 4H);
6.18–7.90 (m, 24H); m/z (FAB-MS) 684 (Mþþ 4); 682
(Mþþ2); 680 (Mþ). Anal. Calcd For C38H32O2Br2: C,
67.07; H, 4.74. Found: C, 66.76; H, 4.49.
M. S. thanks CSIR, New Delhi for financial support. The
authors thank UGC, New Delhi for the financial assistance
(SAP-III) to the department and also RSIC, IIT and Dr
Geetha Gopalakrishnan, SPIC Science foundation, Madras
for spectral and optical data.
3.1.11. Cyclophane 9a. Dibromide 8a (0.34 g, 0.5 mmol)
and (S)-BINOL (0.143 g, 0.5 mmol) were stirred with
K2CO3 (20 mmol) in acetone (400 mL) at room temperature
for 120 h after which the reaction mixture was acidified and
evaporated to dryness. The residue obtained was extracted
with CH2Cl2 (3£100 mL), washed with 10% NaOH
(2£50 mL); with water (3£100 mL) and dried (MgSO4).
Evaporation of the organic layer gave a residue which was
chromatographed over SiO2 using hexane/CHCl3 (1:1) to
afford the chiral cyclophane 9a as a colourless solid. Yield
21%; mp 1918C; [a]D25¼-136.4 (c 0.4, CHCl3); IR
References
1. Cram, D. J. In From Design to Discovery; Seeman, J. I., Ed.;
American Chemical Society: Washington, DC, 1990.
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Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236,
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1
(KBr, cm21) 3050, 1632, 1605; H NMR d 4.81–5.59 (m,
8H); 6.70–6.76 (m, 12H); 7.12–7.37 (m, 16H); 7.75–7.88
(m, 8H); 13C NMR d 75.1, 84.2, 115.7, 115.7, 115.8, 115.9,
120.7, 123.6, 125.2, 125.9, 126.2, 126.4, 126.5, 126.7,
126.8, 126.8, 126.9, 127.1, 127.1, 127.8, 127.9, 129.1,
129.2, 129.3, 134.2, 136.4, 142.4, 153.9; m/z (FAB-MS) 804
(Mþ). Anal. Calcd for C58H44O4: C, 86.54; H, 5.51. Found:
C, 86.49; H, 5.49.
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3.1.12. Cyclophane 9b. Coupling of dibromide 8b (0.34 g,
0.5 mmol) with (S)-BINOL (0.143 g, 0.5 mmol) in the
presence of K2CO3 (14 g) in acetone (400 mL) at rt for
120 h followed by work up as described above gave a
residue, which was purified over SiO2 using hexane/CHCl3
(1:1) to give the cyclophane 9b as a colourless solid. Yield
16%; mp 1388C; [a]D25¼-120.0 (c 0.4, CHCl3); IR
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1
(KBr, cm21) 3050, 1632, 1605; H NMR d 5.00–5.06 (m,
8H); 6.64 (d, 2H, J¼8.3 Hz); 6.95 (d, 2H, J¼8.3 Hz); 7.00–
7.56 (m, 24H); 7.76–7.90 (m, 8H); 13C NMR d 70.4, 114.9,
115.3, 115.9, 117.4, 122.4, 123.2, 123.9, 124.4, 124.9,
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