A new bis-Troeger's base: Synthesis, spectroscopy, crystal structure and isomerization

Article abstract of DOI:10.1135/cccc20061278

A new bis-Troeger's base was prepared from a tetraamine precursor as a mixture of two diastereoisomers. One of the isomers has a chair-like geometry, and the other possesses a boat-like geometry, embodying molecular tweezers. A one-pot preparation of bis-

Full text of DOI:10.1135/cccc20061278

1278
Valík, Matějka, Herdtweck, Král, Dolenský:
A NEW BIS-TRÖGER’S BASE: SYNTHESIS, SPECTROSCOPY,
CRYSTAL STRUCTURE AND ISOMERIZATION
b
a3
Martin VALÍKa1, Pavel MATĚJKAa2, Eberhardt HERDTWECK , Vladimír KRÁL
a4,
and Bohumil DOLENSKÝ
*
a
Department of Analytical Chemistry, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: valik@vscht.cz,
pavel.matejka@vscht.cz, kralv@vscht.cz, dolenskb@vscht.cz
Department of Inorganic Chemistry, Technische Universität München,
Lichtenbergstraße 4, D-85747 Garching, Germany; e-mail: eberhardt.herdtweck@ch.tum.de
1
2
3
4
b
Received August 2, 2006
Accepted August 14, 2006
A n ew bis-Tröger’s base was prepared from a tetraam in e precursor as a m ixture of two dia-
stereoisom ers. On e of th e isom ers h as a ch air-like geom etry, an d th e oth er possesses a boat-
like geom etry, em bodyin g m olecular tweezers. A on e-pot preparation of bis-TB isom ers an d
th eir in tercon version un der acid con dition s was also studied. Structures of both isom ers
were con firm ed by sin gle-crystal X-ray diffraction . Exten sive spectroscopic data, in cludin g
1H an d 13C NMR, IR an d Ram an spectra of th e isom ers, are given .
Keyw ord s: Molecular tweezers; Tröger’s bases; Ch iral receptors; Isom erization ; IR/Ram an
spectroscopy; NMR spectroscopy; X-ray diffraction .
In 1887, Tröger described1 th e con den sation of p-toluidin e with form alde-
h yde to afford an un kn own base. It was n ot un til 1935 th at Spielm an
solved2 its structure. He foun d th at th e base is a un ique com poun d, wh ich
possessed n itrogen s wh ich do n ot un dergou um brella in version . Th e com -
poun d, today kn own as Tröger’s base (TB), becam e sim ply kn own as an
exam ple of a “ch iral n itrogen ” com poun d, wh ich is stable at room tem pera-
ture for lon g periods. In th e late 1990’s supram olecular ch em ists started a
ren aissan ce of TB com poun ds. TB derivatives on ce bein g curiosities in or-
gan ic ch em istry textbooks becom e buildin g blocks for m olecular arch itects.
Th e reason s for th eir rediscovery are th e rigid V-sh ape (85–120°) an d, of
course, th eir in h eren t ch irality. Th us, TB derivatives foun d use in supram o-
lecular ch em istry3, with application s in cludin g th e con struction of recep-
tors for ach iral4 an d ch iral5 an alytes, as well as for drug developm en t6.
A few years ago, TB derivatives of n ew dim en sion ality were discovered
by th e fin din gs7,8 th at m ore th an on e TB system (1,5-diazabicyclo[3.3.1]-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20061278

A New Bis-Tröger’s Base
1279
n on an e) can be attach ed to a sin gle cen tral ben zen e rin g. Th e preparation
of bis-TB derivatives via procedures, in wh ich each TB system is form ed in a
separate reaction , was described7. We h ave publish ed an all-TB-at-on ce pro-
cedure, in wh ich two or even th ree TB fram eworks are form ed in on e step8.
In addition , we h ave recen tly publish ed a on e-pot m ixed con den sation of a
m on oam in e with a diam in e, in wh ich bis-TB derivatives (an d h igh er-order
lin ear oligo-TB derivatives) are form ed with out in term ediate preparation 9.
Th e bis-TB derivatives exist as boat-like (syn-bis-TB) an d ch air-like
(anti-bis-TB) diastereoisom ers, wh ich can be in tercon verted un der acid con -
dition s. Th e syn-bis-TB isom er m im ics ch iral m olecular tweezers. Th us, it is
an in terestin g subject for supram olecular ch em istry. In th is paper we de-
scribed th e preparation of n ew bis-TB derivatives in good yields. We also
describe a first dem on stration of th eir bin din g ability, stability in acid m e-
dia, an d spectral properties useful in distin guish in g between th e syn an d
anti isom ers.
Preparation of Bis-TB
Acylation of 1,4-diam in oben zen e with 4-m eth oxy-2-n itroben zoyl ch loride
produced bisam ide 1. Reduction of th e n itro groups followed by th e am ide
reduction with LiAlH4 afforded tetraam in e 3, th e precursor for th e con com -
itan t form ation of two TB fram eworks8. Th e reaction of 3 with a source of
form aldeh yde in acid m edia can give two possible regioisom ers, 4 an d 5
(Sch em e 1 an d Ch art 1). Neverth eless, we foun d th at regioisom er 4 is form ed
exclusively as a m ixture of two diastereoisom ers (Fig. 1), th e anti dia-
stereoisom er 4a (racem ic m ixture) an d syn diastereoisom er 4b (meso-form ),
in th e 5:3 ratio. Each diastereoisom er was isolated an d th eir structures were
con firm ed by sin gle-crystal X-ray diffraction (Figs 2 an d 3). Th eir regio-
selectivity is surprisin g; h owever, it is in full accordan ce with th e curren t
state-of-th e-art in th is field7–10a. Th e yield of bis-TB 4 was 40% (25% of 4a
an d 15% of 4b, overall yield 35%), wh ich is dram atically better th an we
obtain ed8 with an ilin e derivatives (ca. 5%). Th is is apparen tly due to th e
blockin g of th e position s para to th e NH2 groups with m eth oxy groups,
wh ich preven ts oligom er-form in g side reaction s.
In addition , we tried to prepare bis-TB 4 by th e m ixed con den sation of
4-m eth oxyan ilin e an d 1,4-ph en ylen ediam in e with h exam eth ylen tetram in e
(HMTA) in TFA, i.e. by th e oligom erization reaction we recen tly publish ed9.
Un der th ese con dition s we isolated th e expected isom ers of bis-TB 4 in 7%
yield (4a/4b 2:1). Dim eth oxy-TB derivative 6 (19%) an d its form ylated de-
rivative 7 (2%) were also isolated (Ch art 1).
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1280
Valík, Matějka, Herdtweck, Král, Dolenský:
SCHEME 1
Syn th esis of bis-Tröger’s bases 4a an d 4b
CHART 1
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1281
FIG. 1
Diastereoisom ers 4a an d 4b, n um berin g for NMR assign m en ts
FIG. 2
ORTEP style plot of anti diastereoisom er 4a. Th erm al ellipsoids are drawn at th e 50% probabil-
ity level (crystal m eth an ol is om itted)
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1282
Valík, Matějka, Herdtweck, Král, Dolenský:
Next, we tried th e oligom erization of 4-m eth oxyan ilin e an d 1,4-
ph en ylen ediam in e with paraform aldeh yde in th e m elt con tain in g TsOH.
We observed n o form ation of bis-TB 4, an d even n o form ation of TB 6. Th e
on ly isolated product was quin azolin e 8 (20% yield). Quin azolin e 8 is also
form ed in a sim ilar yield (22%) wh en on ly 4-m eth oxyan ilin e an d para-
form aldeh yde were m elted with TsOH (i.e. with out 1,4-ph en ylen ediam in e).
Note th at quin azolin e 8 is described11 as th e product of reaction 4-m eth oxy-
an ilin e with form aldeh yde in aqueous acids (yield 22%).
Nuclear Magnetic Resonance
For m an y studies it would be useful to h ave th e un am biguous assign m en t
of th e ch em ical sh ifts of atom s of 4a an d 4b, an d also a un iversal an d fast
m eth od to distin guish between anti diastereoisom er 4a an d syn dia-
stereoisom er 4b with out X-ray an alysis. Th e ch em ical sh ifts were assign ed
an alysis of 1D an d 2D NMR spectra. Structural param eters were also ob-
tain ed from com puter m odels of th e isom ers of 4. Th e geom etries were op-
FIG. 3
ORTEP style plot of syn diastereoisom er 4b in th e solid state. Th erm al ellipsoids are drawn at
th e 50% probability level. Selected con tact distan ces: O1···O2 8.166(2) Å; Cg1···Cg2 7.038 Å.
Cg defin es th e cen ter of gravity of th e periph ery arom atic rin gs
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1283
tim ized by PM3 sem iem pirical m eth od usin g HyperCh em 6.03 software.
Th us, th e distan ces between h ydrogen atom s from com puter m odels an d
from th e sin gle-crystal X-ray structures aided to explain th e observed NOEs
(Table I). Sim ilarly, th e dih edral an gles were used to calculate th e couplin g
3
con stan ts from th e Karplus relation sh ip JCH = 3.6 cos 2θ – cos θ + 4.3 for a
better un derstan din g of HMBC spectra, wh ere th e in ten sity of th e correla-
tion peak is proportion al to th e value of in teraction con stan t (Table II). Th e
1
assign m en t of m an y of th e sign als in th e 13C an d H NMR spectra was rela-
tively straigh tforward. However, th e assign m en t of certain specific TB
fram ework proton s, n am ely H7a, H7b, H8a, H8b, H9a, H9b (Fig. 1), was ch al-
len gin g. Th e followin g fin din gs h old for both isom ers of 4 as well as for
previously publish ed TB derivatives7–9,12
.
Due to th e sh orter distan ce of H7a–H6 com pared to H7b–H6, a sign ifican tly
stron ger NOE at H7a com pared to H7b was observed wh en H6 was irradiated
in th e NOESY experim en t. Sim ilarly, th e NOE was observed on ly at H7a
wh en H12 was irradiated. In addition , th e assign m en t was in accord with
3
th e expected value of JCH of C8–H7a an d C8–H7b, wh erein stron g correlation
of C8 was observed with H7a but n o correlation with H7b in th e HMBC spec-
TABLE I
Selected atom distan ces (in Å) in 4a an d 4b, an d th e in ten sity of observed NOE
anti Diastereoisom er 4a
syn Diastereoisom er 4b
Distan ce
m odela
X-ray
NOEb
m odela
X-ray
NOEb
H6–H7a
H6–H7b
H8a–H7b
H8b–H7b
H8b–H9b
H8a–H9b
H3–H9a
H3–H9b
H12–H7a
H12–H7b
2.63
2.81
2.61
3.75
2.61
3.75
2.73
3.71
2.70
3.68
2.55(2)
2.83(2)
2.39(2)
3.48(2)
2.39(2)
3.48(2)
2.58(2)
3.65(2)
2.51(2)
3.60(2)
m
w
2.61
2.79
2.61
3.75
2.62
3.76
2.73
3.71
2.71
3.69
2.53(3)
3.00(3)
2.33(3)
3.52(3)
2.36(3)
3.52(3)
2.50(3)
3.65(3)
2.51(3)
3.68(3)
m
w
w
w
n ull
w
n ull
w
n ull
m
n ull
m
n ull
m
n ull
m
n ull
n ull
a
b
PM3 optim ized structure (vide in fra).
m edium > weak > n ull.
NOE in ten sity is given in th e scale stron g >
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1284
Valík, Matějka, Herdtweck, Král, Dolenský:
tra. Next, in th e HMBC spectrum , C11 h as a stron g correlation on ly with
H7b. Note th at a stron ger correlation peak is observed between H6 an d H7b
th an between H6 an d H7a in th e COSY spectrum . By an alogy to proton s H7,
irradiation of H3 gives rise to a NOE on ly on H9a an d n ot on H9b. A stron g
correlation was observed for C8–H9a an d n ull correlation for C8–H9b in th e
HMBC spectrum . C4 sh ows a stron g correlation in th e HMBC spectrum on ly
with H9b. Irradiatin g H8a gives a NOE at H7b, wh ile irradiation of H8b affords
a NOE at H9b. It is also very h elpful th at in th e HMBC spectrum , both C4
an d C7 h ave stron ger correlation s with H8b th an with H8a, wh ereas both
carbon s C11 an d C9 sh ow stron ger correlation s with H8a th an with H8b, in
TABLE II
Selected dih edral an gles (in °) an d th e in ten sity of observed HMBC cross-peaks
anti Diastereoisom er 4a
syn Diastereoisom er 4b
An gle
m odela
X-ray
3JCH
HMBCb
m odela
X-ray
3JCH
HMBCb
C8–N–C7–H7a
C8–N–C7–H7b
C8–N–C9–H9a
C8–N–C9–H9b
C4–N–C8–H8a
C4–N–C8–H8b
C4–C5–C7–H7a
C4–C5–C7–H7b
C4–N–C9–H9a
C4–N–C9–H9b
C7–N–C8–H8a
C7–N–C8–H8b
C9–N–C8–H8a
C9–N–C8–H8b
C11–N–C8–H8a
C11–N–C8–H8b
C11–N–C7–H7a
C11–N–C7–H7b
163.8
–80.9
163.5
–81.5
–62.5
178.8
169.8(9)
–72.4(10)
170.1(10)
–73.8(9)
–66.8(10)
174.5(9)
8.3
0.7
8.3
0.7
1.8
8.9
4.2
2.2
4.2
7.5
2.7
8.8
8.8
2.6
8.9
1.8
4.2
7.5
4.2
2.2
s
163.6
–81.1
163.3
–81.7
–62.5
178.8
–129.3
113.1
39.5
171.5(11)
–70.8(11)
168.7(12)
–73.6(12)
–68.8(12)
169.3(11)
–139.7(12)
101.2(12)
46.8(12)
8.3
0.7
8.3
0.7
1.8
8.9
4.2
2.2
4.2
7.5
2.6
8.8
8.8
2.6
8.9
1.8
4.2
7.5
4.1
2.3
s
n ull
s
n ull
s
n ull
n ull
w
s
w
s
129.4 –135.3(9)
covered
w
w
w
s
113.0
39.8
106.1(10)
47.3(10)
163.4(9)
51.5(10)
169.1(9)
169.0(10)
50.3(9)
w
w
s
154.8
53.5
154.5
53.7
164.5(12)
50.7(12)
w
m
m
w
s
w
m
m
w
s
172.2
172.6
53.9
172.3
172.6
53.9
171.2(11)
169.8(12)
47.8(11)
178.7
–62.7
39.7
173.3(9)
–69.0(9)
48.5(9)
178.8
–62.5
39.6
173.9(12)
–65.6(11)
49.5(12)
w
w
s
w
w
s
155.0
164.5(10)
154.8
167.2(11)
C11–C10–C9–H9a 129.0 –133.9(9)
C11–C10–C9–H9b 113.5
106.8(9)
m
m
–128.6 –131.1(12)
114.1 111.7(11)
m
m
a
b
PM3 optim ized structure (vide in fra).
HMBC in ten sity is given in th e scale stron g >
3
m edium > weak > n ull. Karplus relation sh ip JCH = 3.6 cos 2θ – cos θ + 4.3.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1285
3
good agreem en t with th e expected JCH values (Table II). In addition , th ere
are sm all couplin g con stan ts between proton s H8 an d H9, an d between pro-
ton s H8 an d H7; h owever, th ese rarely observed in teraction s were foun d to
be useless for ch em ical sh ift assign m en t.
Th e distin guish in g of anti diastereoisom er 4a an d syn diastereoisom er 4b
of un sym m etrical bis-TB derivatives based on NMR is well described10a,12
.
However, for distin guish in g th e isom ers of sym m etrical bis-TB derivatives
on ly an em pirical rule was described7b, an d applied10b also to tris-TB deriva-
tives. Accordin g to th e rule, th e absolute differen ces between th e ch em ical
sh ifts of th e gem in al proton s of all m eth ylen e bridges are larger for syn
diastereoisom ers th an for anti diastereoisom ers. Differen t an isotropy effects
in th e isom ers are th e explan ation . We foun d th at th e differen ces are very
sm all (<0.1 ppm ) an d th e rule h olds for isom ers of 4 on ly in CDCl3; h ow-
ever, it failed in oth er solven ts (Table III). We believe th at th e an isotropy
effects could be less im portan t th an th e effects of solven t, especially wh en
even very weak h ost-guest com plexes are form ed. On th e oth er h an d, th e
ch em ical sh ifts differen ces for H8 proton s (ca. –0.2 ppm ) an d also th e differ-
en ces for atom s H2 (∆δ = 0.24–0.32), H6 (∆δ = 0.34–0.50), H8b (∆δ =
0.26–0.30) an d H13 (∆δ = 0.18–0.31) as well as certain ch em ical sh ifts of car-
bon s, in arom atic solven ts (ben zen e-d6, toluen e-d7, n itroben zen e-d5) appear
to be useful. Sum m arizin g, it appears difficult to un am biguously distin -
guish syn an d anti diastereoisom ers of sym m etrical bis-TB derivatives on th e
basis of NMR data on ly.
TABLE III
Ch em ical sh ift differen ces for h ydrogen s of th e m eth ylen e bridge in 4
syn
syn
syn
∆∆δH7 = |δH7a–δH7b
|
∆∆δH8 = |δH8a–δH8b
|
∆∆δH9 = |δH9a–δH9b|
Solven t
anti
anti
anti
– |δH7a–δH7b
|
– |δH8a–δH8b
|
– |δH9a–δH9b|
CDCl3
0.04
0.01
0.10
0.08
0.10
0.02
0.02
0.01
–0.03
–0.21
–0.22
–0.20
–0.07
–0.03
0.07
–0.03
0.09
CD3CN
C6D6
C6D5CD3
C6D5NO2
CD3NO2
CF3COOD
0.09
0.07
–0.04
–0.13
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1286
Infrared and Raman Spectroscopy
Valík, Matějka, Herdtweck, Král, Dolenský:
We attem pted to distin guish th e anti diastereoisom er 4a an d syn diastereo-
isom er 4b isom ers by IR an d Ram an spectra. In gen eral, wh ile th e in ten sity
of an IR absorption ban d depen ds on th e ch an ge in th e dipole m om en t
durin g th e correspon din g vibration al m otion , th e in ten sity of a Ram an ac-
tive ban d depen ds on th e ch an ge in th e polarizability durin g th at vibra-
tion . Th us, vibration al spectra are sen sitive to th e sym m etry of m olecular
vibration s, wh ich are related to th e sym m etry of m olecules. In addition , th e
rule of m utual exclusion states for m olecules with a cen ter of sym m etry;
m olecular vibration s sym m etric with regard to th e cen ter of sym m etry are
forbidden in th e IR, wh ereas m olecular vibration s, wh ich are an tisym m etric
to th e cen tre of sym m etry, are forbidden in th e Ram an spectrum . Th is rule
is easy to apply to sm all m olecules with a lim ited n um ber of vibration al
m odes, but it is n ot as straigh tforward in th e case of large m olecules with
m an y vibration al m odes of sim ilar frequen cies. Furth erm ore, th e forbidden
vibration al tran sition s can be observed as very weak or weak ban ds in th e
correspon din g spectra.
To overcom e th ese problem s an d to con firm th e structural differen ce be-
tween both isom ers, we perform ed a detailed com parison of th e precise
ban d position s an d relative in ten sities for both isom ers in th e com m on
waven um ber ran ge 1700–650 cm –1. We sough t th e closest correspon din g
peak position s in th e Ram an an d IR spectra m easured un der m atch in g con -
dition s (solid-state, solution ) creatin g pairs of peak position s. We foun d
forty such pairs in th e solid-state spectra of both isom ers, an d 35 pairs for
4a (36 for 4b) in th e solution spectra. For each of th e pairs we calculated
th e absolute value of th e waven um ber differen ce an d sum m ed th ese differ-
en ces (Tables IV an d V). Th e h ypoth esis is th at th e sum of differen ces h as
to be bigger for 4a th an for 4b, because with cen trosym m etric 4a th ere are
som e sim ilar, but n ot iden tical m odes observed in IR an d Ram an spectra,
wh ereas th e iden tical m odes can be observed in th e case of 4b. Th e result is
in agreem en t with th e h ypoth esis. Wh ile in th e case of 4a th e sum of dif-
feren ces is 117 an d 108 for solid-state spectrum an d for spectrum in solu-
tion , respectively, in th e case of 4b th e correspon din g values are 85 an d
69 (th e differen ce between 4a an d 4b is m ore th an 30 in both cases;
(Σ diff (IR–Ram )anti – Σ diff (IR–Ram )syn
)
= 32; (Σ diff (IR–Ram )anti
–
solid
Σ diff (IR–Ram )syn
)
= 39). Furth erm ore, in th e case of 4a th ere are bigger
CDCl3
differen ces between th e in ten sities of m an y ban ds in IR an d Ram an spec-
trum com pared to th ose of sim ilar in ten sities in th e IR an d Ram an spectra
of com poun d 4b. Hen ce, we see th at for cen trosym m etric 4a m an y in ten se
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1287
TABLE IV
Th e IR an d Ram an waven um bers (in cm –1) for anti diastereoisom er 4a
IR
Ram an
Diff (IR–Ram )a
solid
CDCl3
solid
CDCl3
solid
CDCl3
1610 m
–
1610 w
–
1612 m
1594 m
1579 m
1498 vw
1612 m
1596 m
1583 m
1497 vw
2
–
4
6
3
1
1
2
8
5
1
1
4
8
6
–
2
1
11
4
3
1
1
–
2
1
2
0
2
2
–
8
3
1
3
0
2
4
7
3
0
1
10
5
–
2
2
8
2
3
2
1
–
0
0
3
1
1
1575 w
1492 vs
1473 vs
1464 sh
1441 sh
1434 m
1427 sh
1361 w
1337 vw
1327 m
1309 m
1291 w
1272 s
–
1575 vw
1494 vs
1474 s
1465 sh
1443 vw
1435 w
1425 sh
1362 w
1338 vw
1328 w
1310 w
1292 vw
1273 m
–
1476 sh –vw 1473 sh –vw
1463 w
1442 sh
1436 s
1462 m
1443 sh
1437 m
1421 sh
1355 s
1419 sh
1356 s
1338 w
1326 w
1313 w
1299 w
1278 m
1263 sh
1259 m
1238 w
1206 m –w
1191 w
1166 w
1150 w
1143 sh –w
1106 w
1092 m
1077 w
1040 w
1022 w
1341 sh
1328 vw
1309 w
1302 sh –vw
1278 m
1264 m
1259 m
1239 w
1209 m –w
1189 w
1167 w
1153 w
1144 sh –w
1105 sh
1093 m
1076 w
1041 w
1021 w
1257 s
1237 s
1217 s
1187 s
1163 sh –w
1151 m
1142 sh
–
1257 m
1237 m
1217 m
1187 s
1164 sh –vw
1151 m
1143 sh
–
1094 m
1076 m
1038 s
1022 sh –w
1013 w
1093 w
1076 m
1038 m
1022 sh –vw
1012 w
1015 sh –vw 1013 sh –vw
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1288
Valík, Matějka, Herdtweck, Král, Dolenský:
TABLE IV
(Continued)
IR
Ram an
Diff (IR–Ram )a
solid
CDCl3
solid
CDCl3
solid
CDCl3
997 vw
972 s
960 s
943 s
920 w
904 s
–
994 sh –vw
972 m
960 m
943 m
924 m
solven t
solven t
863 w
996 w
970 vw
960 w
950 vw
922 m –w
905 vw
896 w
854 w
843 vw–sh
827 m
812 s
997 w
967 vw
958 w
947 vw
923 m –w
903 vw
897 w
858 vw
846 vw
825 m
813 m
–
1
2
0
7
2
1
–
6
4
3
6
1
1
–
0
–
1
3
5
2
4
1
–
–
5
6
1
7
–
–
–
–
–
–
860 sh
839 s
824 m
806 w
749 vs
735 sh
–
840 s
824 m
806 w
solven t
solven t
solven t
solven t
680 m
669 m
750 vw
736 s
734 s
726 m
719 m –w
–
724 sh
719 sh
solven t
solven t
719 sh
681 m
668 m
669 m
Num ber of com pared item s
40
35
ΣDiff (IR–Ram )anti
117
108
a
Diff (IR–Ram ) = absolute values of differen ces between correspon din g peak position s in IR
an d Ram an spectra.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1289
TABLE V
Th e IR an d Ram an waven um bers (in cm –1) for syn diastereoisom er 4b
IR
Ram an
Diff (IR–Ram )a
solid
CDCl3
solid
CDCl3
solid
CDCl3
1611 w
–
1610 w
–
1612 sh
1604 m
1598 m
–
1612 m
–
1
–
–
–
2
0
4
1
1
1
7
3
3
7
4
4
0
1
–
0
–
1
4
2
–
1
1
0
–
2
–
–
–
5
1
1
0
0
1
6
–
5
4
1
0
3
4
–
2
–
5
3
0
–
1
4
1
–
–
–
1597 m
1588 sh
1579 sh
1495 vw
1475 sh –vw
1456 m
1442 sh
1436 m
1421 sh –w
–
–
–
1475 w
1494 vs
1474 s
1460 sh
1440 m
1435 sh
1427 m
1373 vw
1360 sh
1342 w
1326 w–m
1310 w
1291 sh –w
1274 m –s
–
1474 w
1494 vs
1474 s
1456 sh
1442 sh
1435 w
1427 w
–
1473 m –s
1494 vw
1470 w
1459 m –w
1439 m
1434 sh –w
1420 w
1370 m
1357 s
1361 vw
1343 w
1327 w
1310 w
1292 sh –vw
1273 m
–
1356 vs
1347 sh
1328 m
1310 w
1295 sh –vw
1277 m
1265 m
1258 sh
–
1349 sh
1322 m
1306 w
1291 sh –w
1273 m
–
1258 m
–
1256 m
–
1258 m –s
1247 m
1237 sh –w
1209 m
1186 w
1179 w
1167 w
1150 w
1238 m
1213 s
1188 w
–
1237 m
1214 s
1189 w
–
1242 w
1211 m
1189 w
–
1166 m
1149 m
1142 sh
–
1166 m
1150 m
1144 sh
–
1167 w
1154 w
1142 sh –vw 1143 sh
1104 w–m 1105 sh
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1290
Valík, Matějka, Herdtweck, Král, Dolenský:
TABLE V
(Continued)
IR
Ram an
Diff (IR–Ram )a
solid
CDCl3
solid
CDCl3
solid
CDCl3
1092 w–m
1071 m
1039 m
1018 w
989 w
974 sh
968 m
948 m
918 w
902 sh
899 m
870 sh
859 sh
846 sh
833 m –s
–
1093 w
1071 m
1039 m
1018 w
989 w
1092 m
1070 w
1043 w
1020 w
990 vw
974 vw
966 vw
949 vw
916 m
900 w
895 sh –vw
874 w
–
1095 m
1072 w
1040 w
1019 w
990 vw
974 vw
968 sh
0
1
4
2
1
0
2
1
2
2
4
4
–
0
–
–
1
–
–
1
6
2
4
–
2
1
1
1
1
0
0
1
1
–
–
–
2
1
3
1
4
1
–
–
–
–
–
–
974 sh –vw
968 m
950 m
951 sh
925 w–m
solven t
solven t
solven t
863 w
924 m
902 sh –vw
896 vw
874 vw–sh
861 vw–sh
846 vw–sh
837 m
847 w–m
834 s
846 m
–
821 sh –w
809 sh
816 m
807 w
799 m
–
822 w
808 sh
–
805 m
791 sh
792 sh –vw
–
752 s
solven t
solven t
solven t
solven t
681 sh –w
671 m
739 sh
725 sh
714 sh –w
680 sh –w
671 w–m
738 vs
719 sh
712 s
739 s
722 s
715 sh
676 m –s
–
solven t
solven t
Num ber of com pared item s
40
85
36
69
ΣDiff (IR–Ram )anti
a
Diff (IR–Ram ) = absolute values of differen ces between correspon din g peak position s in IR
an d Ram an spectra.
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1291
Ram an ban ds are weak in th e IR an d vice versa, wh ereas such a pron oun ced
effect is n ot observed in th e case of 4b. Th e m ost eviden t case is th e ban d at
ca. 1189 cm –1 attributed to a skeletal m ode with con siderable participation
of stretch in g m odes of C–N in th e cen tral part of th e m olecules13. Th is
ban d (1187 cm –1) of 4a is stron g in th e IR spectrum an d weak in th e Ram an
spectrum (in both solid state an d solution ), wh ile in 4b, a weak in ten sity is
observed in both th e IR an d th e Ram an spectrum . All of th ese fin din gs
sh ow th at th e com bin ation of IR an d Ram an spectroscopy can be a power-
ful tool for th e structure determ in ation of bis-TB isom ers.
Furth erm ore, we foun d a strikin g sim ilarity between th e IR an d Ram an
spectra obtain ed in th e solid state an d in solution for isom er 4a, wh ich
dem on strates a n egligible structural ch an ge in th is m olecule upon dissolu-
tion . On th e oth er h an d, eviden t in ten sity an d peak position differen ces are
observed between Ram an spectra of isom er 4b obtain ed in solid state an d
solution , suggestin g som e sm all con form ation al ch an ges of isom er 4b,
wh ich occur upon dissolution it in CDCl3.
Isomerization of Bis-TB 4
A ch aracteristic property of TB derivatives is racem ization in acid solution .
Th e in stability in acidic m edia is often viewed as a disadvan tage. Th is is
true for m an y com m on TB derivatives, wh ereby th eir m ain application s are
based on th eir ch irality. However, in th e case of bis-TB derivatives, treat-
m en t with acid m ay be used to con trol th e open in g an d closin g of th e m o-
lecular tweezers. Because th e beh avior in acid con dition s is very im portan t
for furth er use of bis-TB, an d because it is little kn own about th e racem iz-
ation of TB 14 (on ly few n otes7,10,15 about oligo-TB), we perform ed th e fol-
lowin g studies (Table VI).
Both isom ers of 4 were foun d to be stable in CF3COOD at room tem pera-
ture. However, above 55 °C, th ey isom erized rapidly. In terestin gly, som e
tris-TB derivatives isom erize in TFA at room tem perature10a, oth er tris-TB
derivatives are stable10b even at 95 °C. Th e ratio 4a/4b was 2:1 at equilib-
rium , i.e. th e sam e ratio in wh ich th e isom ers were isolated (TFA was used
as th e reaction solven t). We foun d th e solven t can affects th e ratio. Th us,
th e racem ization by TFA-d1 in toluen e-d7 gave th e ratio 7:3 wh ile in
n itroben zen e-d5 4:6. Faster isom erization of 4b th an 4a was observed. We
also observed a m ild in fluen ce of th e used acid. Th us, DCl in CD3OD/D2O
led to th e ratio 5:5, wh ile CF3COOD in CD3OD/D2O gave th e ratio 6:4.
Th e isom erization in con cen trated DCl (35% in D2O) was un doubtedly
th e m ost in terestin g. In th at case, th e equilibrium is attain ed in 24 h at
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1292
Valík, Matějka, Herdtweck, Král, Dolenský:
room tem perature an d th e ratio 4a/4b was foun d to be 7:93. In addition ,
1
th e ch em ical sh ifts of isom ers 4 are very differen t. Th e H NMR sign als of
isom er 4a in are sh arp an d th e ch em ical sh ifts are sim ilar to th ose observed
in CF3COOD. In con trast, th e isom er 4b sh ows som e very broad sign als an d
th e ch em ical sh ifts are pretty differen t. Togeth er with th e dram atic ch an ge
in th e ratio (tem plate effect), it is obviously due to th e form ation of a com -
plex of 4b with DCl/D2O, wh ich is observable on NMR tim escale. Th e big-
gest differen ces between ch em ical sh ifts (∆δ = δ4b – δ4a) were observed at
atom s H6 (∆δ = –1.36; very broad sign al), H2 (∆δ = –0.82; broad sign al),
TABLE VI
Isom erization equilibria of 4a an d 4b
Isom erization con dition s
Equilibrium
m m ol l–1
acid
solven t
tem p.
tim e
4a:4b
c0(4a) = 2.34
c0(4b) = 2.16
c0(4a) = 2.34
c0(4b) = 2.16
c0(4a) = 0.55
c0(4b) = 0.55
c0(4a) = 3.02
c0(4b) = 3.06
c0(4a) = 0.51
c0(4b) = 0.52
c0(4a) = 0.48
c0(4b) = 0.47
c0(4a) = 0.64
c0(4b) = 0.64
c0(4a) = 0.64
c0(4b) = 0.64
c0(4a) = 8.65
c0(4b) = 8.71
a
a
b
1
2
TFA-d1
TFA-d1
TFA-d1
TFA-d1
r.t.
∞
60 °C
<18 h
64:36
50:50
CD3OD/D2O
(12:1 v/v)d
3
4
5
6
7
8
200 eq. DClc
13 eq. TFA-d1
r.t.
60 °C
r.t.
~4 d
>10 d
>6 d
69:31e
63:37e
c
CDCl3
c
c
c
c
220 eq. TFA-d1
220 eq. TFA-d1
170 eq. TFA-d1
170 eq. TFA-d1
CD3OD
59:41
57:43
72:28
41:59
CD3OD/D2O
(12:1 v/v)
r.t.
>6 d
C6D5CD3
C6D5NO2
60 °C
60 °C
<18 h
<18 h
9
DCla
DCld
r.t.
~24 h
7:93
a
b
c
Th e acid was used as solven t. No racem ization . eq. m ean s equivalen ts of acid to a m ole
d
e
of 4. DCl was added as 35% (w/w) solution in D2O. Th e ratio at 10th day, i.e. n ot at
equilibrium .
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1293
H13 (∆δ = –0.62), H7a (∆δ = –0.54; broad sign al) an d H3 (∆δ = –0.31). Despite
its poor solubility, th e com plex is stable even in dilute acid (9% DCl in
D2O). On th e oth er h an d, n o com plex form ation was observed in
CF3COOD over NaCl or in CF3COOD/D2O (1:1) over NaCl. Th is could be
explain ed by differen t degrees of proton ation . Th e TB system s were foun d
to be dideuterated14b in solution s of stron g acids such as DCl (35% in D2O);
h owever, based on th e sim ilarity of 13C NMR spectra of 4 in CF3COOD an d
of th e m on oh ydroch loride of th e TB in DMSO-d6, th e TB system s of 4 are
probably on ly m on odeuterated in CF3COOD. Un fortun ately, th e ch em ical
exch an ges in th e system 4a/4b/DCl/D2O (deuteration , isom erization an d
probably also com plexation ) caused im possible to record com plete NOESY,
13C an d 13C correlated NMR spectra to obtain a closer view in to th e system .
Wh atever h appen in g, th e isom erization of bis-TB 4 in 35% DCl in D2O, fol-
lowed by fast n eutralization an d crystallization from m eth an ol is th e easy
way to get pure tweezers-like isom er 4b.
To con vert 4a to th e 4b isom er we also tried to optim ize con dition s of
crystallization -in duced asym m etric tran sform ation (CIAT), th e process we
recen tly used for th e con version of diastereoisom ers of Tröger’s base deriva-
tives15. Even th ough 4b is less soluble (crystallizes from MeOH as th e first)
th an 4a in m ost of th e solven ts we used (e.g. MeOH, toluen e), we did n ot
fin d th e con dition s (solven t, con cen tration s, acid) wh ere th e racem ization
of diastereoisom ers of 4 takes place in th e liquid ph ase togeth er with crys-
tallization of on ly on e diastereoisom er.
A Note to Binding Abilities of Bis-TB 4
Th e sidewalls of th e tweezers 4b are relatively flat, th us, on e m ay n ot ex-
pect h igh bin din g affin ity16. We perform ed titration s with poten tial guest
m olecules. By perform in g titration s m on itored by UV-VIS spectroscopy, we
foun d n o bin din g of fluoran il or fulleren e C60 to eith er isom er of 4. By
NMR m on itorin g, we foun d very weak an d n on specific bin din g of 1,2-, 1,3-
an d 1,4-din itroben zen es an d 1,3,5-trin itroben zen e to both isom ers of 4.
Un fortun ately, due to sm all ch an ges in ch em ical sh ifts (∆δ m ax ~0.07 ppm ,
N-CH2-N h ydrogen s) an d un clear stoich iom etry of th e weak com plexes,
m ean in gful stability con stan ts could n ot be determ in ed. We observed
bigger ch an ges in ch em ical sh ifts for 4b com pared to 4a; h owever, n eith er
th ree equivalen ts of 1,4-din itroben zen e n or 1,3,5-trin itroben zen e h as an y
in fluen ce on th e 4a/4b equilibration ratio of racem ization in TFA-d1.
In con clusion , we in troduced a n ew m em ber of th e n ovel fam ily of m o-
lecular tweezers based on Tröger’s base derivatives, an d sh owed h ow th e ge-
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1294
Valík, Matějka, Herdtweck, Král, Dolenský:
om etry of th e sym m etrical bis-TB isom ers 4 could be distin guish ed on th e
basis of IR an d Ram an spectra. We observed th at th e isom erization of bis-TB
4 in con cen trated DCl (35% in D2O) is driven by th e form ation a stron ger
com plex of 4b th an of 4a, wh ich leads to a h igh er con cen tration of 4b iso-
m er in th e dyn am ic system . It is clear th at th e com plexation is associated
with som e deuteration (positive ch arge on n itrogen ). Th us th e quatern iz-
ation of th e n itrogen s of 4, wh ich im ports a perm an en t ch arge on th e m ol-
ecule, would be a way to “learn ” th e m olecule to bin d in n eutral con dition .
EXPERIMENTAL
Nuclear Magn etic Reson an ce
All NMR experim en ts were recorded in CDCl3 solution s on a Varian Mercury in strum en t.
1H an d 13C NMR spectra were recorded at 300.08 an d 75.46 MHz, respectively. Ch em ical
sh ifts δ (ppm ) are referen ced to th e in tern al stan dard Me4Si for both 1H an d 13C NMR spec-
tra; th e couplin g con stan ts J are given in Hz. Th e correlation tech n iques g-HSQC, g-COSY,
2D NOESY (m ixin g tim e 450 m s) an d 1D NOESY (m ixin g tim e 600 m s) were used un der
1
stan dard con dition s. Th e g-HMBC spectra were recorded with param eters of JCH couplin g
n
180 Hz (param eter j1h x) an d JCH couplin g 8 Hz (param eter jn h x). Th e ch em ical sh ifts of
th e free base of diastereoisom ers 4 an d th eir couplin g con stan ts for H7a, H7b, H8a, H8b,
H9a an d H9b were determ in ed by sim ulation as six-spin s system by MestRe-C 4.4.6
(Mestrelab Research , Spain ).
Ram an Spectroscopy
Ram an spectra (4000–100 cm –1) were collected usin g a Fourier-tran sform n ear-in frared
(FT-NIR) spectrom eter Equin ox 55/S (Bruker) equipped with an FT Ram an m odule FRA 106/S
(Bruker). Th e focused laser beam (150 m W) of a Nd:YAG laser (1064 n m , Coh eren t) was
used to irradiate th e sam ples studied. Both com poun ds VA-4 an d VV-4 were exam in ed in
glass vials both in th e solid state as powdered sam ples an d in CDCl3 solution . Th e glass vial
was placed on a m otor-driven X-Y-Z sam ple stage. Th e scattered ligh t was collected in back-
scatterin g geom etry. In terferogram s were obtain ed usin g a quartz beam splitter an d a Ge
detector (liquid N2 cooled). 512 an d 1024 separate in terferogram s per 2 cm –1 resolved spec-
trum were accum ulated four tim es an d twelve tim es for solid sam ples an d solution s, respec-
tively. Th e data for th e solven t (CDCl3) were m easured in th e sam e way as for solution s. Th e
averaged spectra an d stan dard deviation records were calculated an d saved in th e JCAMP-DX
form at. Th e averaged spectrum of th e solven t was subtracted from th e spectra of solution s
an d th e region s of th e m ost in ten se ban ds of th e solven t (2320–2165, 680–620, 375–350 an d
271–247 cm –1) were blan ked. Th e OPUS 4.0 (Bruker) an d th e OMNIC 4.0 an d 7.1 (Th erm o
Nicolet, U.S.A.) software packages were used to process th e data.
In frared Spectroscopy
IR spectra (4000–650 cm –1) were collected usin g a FTIR spectrom eter Avatar (Th erm o
Nicolet) equipped with sin gle boun ce ATR accessory MIRacle. Th e powdered sam ples were
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1295
placed directly on Zn Se crystal; th en th ey were dissolved in a few droplets of CDCl3 an d
th en th e solven t was left for several m in utes to evaporate. Hen ce, a th in dry film well adh er-
in g to th e ATR crystal was prepared. Afterwards 64 scan s were accum ulated per spectrum at
2-cm –1 resolution . Two repetitive m easurem en ts were perform ed for every sam ple. CDCl3
was used also to clean th e surface of Zn Se crystal. Th e sam e param eters were used to collect
spectra of th e solution s an d of th e solven t except for th e cell, wh ere a capped was used to
preven t evaporation of th e solven t. Th e averaged spectra were calculated an d th e spectrum
of th e solven t was subtracted from spectra of solution s. Th e region s of th e m ost in ten se ab-
sorption ban ds of th e solven t (915–874 an d 753–690 cm –1) were blan ked. Th e OMNIC 4.0
an d 7.1 (Th erm o Nicolet) were used to process th e spectral data.
Sin gle-Crystal X-ray Structure Determ in ation (4a an d 4b)17
Crystal data an d details of th e structure determ in ation are presen ted in Table VII. Suitable
sin gle crystals were grown from m eth an ol. A clear colorless fragm en t (n eedle) was stored un -
der perfluorin ated eth er, tran sferred in to a Lin dem an n capillary, fixed, an d sealed. Prelim i-
n ary exam in ation an d data collection were carried out on an area detectin g system (Non ius,
MACH3, κ-CCD) at th e win dow of a rotatin g an ode (Non ius, FR951) an d with graph ite
m on och rom atic MoKα radiation (λ = 0.71073 Å). Th e un it cell param eters were obtain ed by
full-m atrix least-squares refin em en t of 4091 (4201) reflection s. Data collection were per-
form ed at 173 K (Oxford Cryosystem s) with in a θ-ran ge of 1.92° < θ < 25.37° (1.46° < θ <
25.39°). Nin e data sets were m easured in rotation scan m odus with ∆ϕ/∆Ω = 2.0° (0.70°).
A total n um ber of 24 822 (40 307) in ten sities were in tegrated. Raw data were corrected for
Loren tz polarization , an d for laten t decay an d absorption effects arisin g from th e scalin g
procedure. After m ergin g [Rin t = 0.036 (0.046)] a sum of 4101 (3835) (all data) an d 3503
(3395) [I > 2σ(I)], respectively, rem ain ed an d all data were used. Th e structure was solved by
a com bin ation of direct m eth ods an d differen ce Fourier syn th eses. All n on -h ydrogen atom s
were refin ed with an isotropic displacem en t param eters. All h ydrogen atom position s were
foun d in th e differen ce Fourier m ap calculated from th e m odel con tain in g all n on -h ydrogen
atom s. Th e h ydrogen position s were refin ed with in dividual isotropic displacem en t param e-
ters. Full-m atrix least-squares refin em en ts with 427 (393) param eters were carried out by m in i-
2
2 2
m izin g Σw(Fo – Fc
) with SHELXL97 weigh tin g sch em e an d stopped at sh ift/error < 0.001.
Th e fin al residual electron den sity m aps sh owed n o rem arkable features. 4b: Th e relatively
h igh R-values are caused by th e very low crystal quality as can be seen from th e un usual
h igh m osaicity 1.146(1)°. Neutral atom scatterin g factors for all atom s an d an om alous dis-
persion correction s for th e n on -h ydrogen atom s were taken from International Tables for
Crystallography. All calculation s were perform ed on an In tel Pen tium II PC, with th e Strux-V
system , in cludin g th e program s PLATON, SIR92, an d SHELXL97.
CCDC 297484 (4a) an d 297485 (4b) con tain th e supplem en tary crystallograph ic data
(excludin g structure factors) for th is paper. Th ese data can be obtain ed free of ch arge
via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e Cam bridge Crystallograph ic
Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam .ac.uk).
N,N′-(1,4-Ph en ylen e)bis(5-m eth oxy-2-n itroben zam ide) (1)
2-Nitro-5-m eth oxyben zoic acid (16.0 g, 81.2 m m ol) was treated with th ion yl ch loride
(12 m l) in toluen e (30 m l) at 60 °C for 4 h . Th e resultin g solution was evaporated in vacuo
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1296
Valík, Matějka, Herdtweck, Král, Dolenský:
TABLE VII
Sum m ary of th e crystal data an d details of data collection an d refin em en t for com poun ds 4a
an d 4b
Param eter
4a
4b
Em pirical form ula
C26H26N4O2·CH3OH
458.55
C26H26N4O2
426.51
Form ula m ass
Crystal system
triclin ic
m on oclin ic
P21/n (No. 14)
16.8844(2)
6.3595(1)
19.7900(3)
90
Space group
a, Å
P1 (No. 2)
9.9365(1)
10.6602(1)
11.61557(2)
71.1801(5)
74.8869(5)
89.2167(8)
1120.99(3)
2
b, Å
c, Å
α, °
β, °
100.7536(6)
90
γ, °
V, Å3
2087.66(5)
4
Z
ρ
calcd, g cm –3
1.359
1.357
µ, m m –1
0.090
0.088
T, K
173
173
F(000)
488
904
Crystal size, m m
θ-ran ge, °
0.61 × 0.58 × 0.20
1.92/25.37
h: ±11; k: ±12; l: ±13
24822
0.59 × 0.20 × 0.13
1.46/25.39
h: ±20; k: ±7; l: ±23
40307
In dex ran ges
Reflection s collected
In depen den t reflection s,
Io > 2σ(Io)/all data/Rin t
3503/4101/0.036
3395/3835/0.046
Data/restrain ts/param eters
R1, Io > 2σ(Io)/all data
wR2, Io > 2σ(Io)/all data
GOF
4101/0/427
0.0357/0.0442
0.0858/0.0914
1.025
3835/0/393
0.0501/0.0577
0.1264/0.1307
1.154
Weigh ts a/b
∆ρm ax/m in , e Å–3
0.0452/0.3865
0.21/–0.21
0.0617/0.9483
0.24/–0.22
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1297
to dryn ess, an d th e residue, crude 2-n itro-5-m eth oxyben zoyl ch loride, was dissolved in DMF
(40 m l). A solution of 1,4-diam in oben zen e (3.5 g, 32.4 m m ol) in pyridin e (20 m l) was added
over 10 m in . Th e reaction m ixture was stirred at room tem perature overn igh t an d th en at
45 °C for 3 h . Th e solution was diluted with water (1 l), an d th e precipitated product was fil-
tered off, an d wash ed with water, m eth an ol an d dich lorom eth an e. After dryin g in vacuo
14.9 g (99%) of 1 was obtain ed. M.p. 296–298 °C. 1H NMR (300 MHz, DMSO-d6): 10.58 br s,
3
2 H (NH); 8.18 d, 2 H, JHH = 8.8; 7.23 m , 4 H; 7.65 s, 4 H; 3.94 s, 6 H (OCH3). 13C APT
NMR (75 MHz, DMSO-d6): 163.8 (C), 163.5 (C), 138.7 (C), 135.7 (C), 134.9 (C), 127.0 (CH),
120.0 (2 × CH), 115.4 (CH), 114.2 (CH), 56.6 (OCH3). For C22H18N4O8 (466.4) calculated:
56.66% C, 3.89% H, 12.01% N; foun d: 56.24% C, 3.91% H, 12.07% N. LRMS (FAB+): 467
(100%, MH+), 436 (50%, MH+ – OCH3).
N,N′-(1,4-Ph en ylen e)bis(2-am in o-5-m eth oxyben zam ide) (2)
A flask was ch arged with com poun d 1 (13.6 g, 29.2 m m ol), catalyst (5% Pd/C, 1.3 g), m eth a-
n ol (30 m l) an d DMF (50 m l). Th e reaction m ixture was stirred for 2 days un der h ydrogen .
Th e catalyst was filtered off un der argon an d th e solven t evaporated in vacuo. Th e residue
was wash ed with toluen e (100 m l) to give 2 (10.8 g, 91%). M.p. 214–217 °C. 1H NMR
4
3
(DMSO-d6): 10.00 s, 2 H (NH); 7.66 s, 4 H; 7.18 d, 2 H, JHH = 3.0; 6.91 dd, 2 H, JHH = 8.9,
4JHH = 3.0; 6.72 d, 2 H, JHH = 8.8; 5.75–6.10 m , 4 H (NH2); 3.73 s, 6 H (OCH3). 13C APT
3
NMR (DMSO-d6): 167.3 (CO), 149.4 (C), 143.7 (C), 134.8 (C), 120.9 (2 × CH), 119.7 (CH),
117.9 (CH), 115.8 (C), 112.6 (CH), 55.6 (OCH3). For C22H22N4O4 (406.5) calculated:
65.01% C, 5.46% H, 13.78% N; foun d: 64.64% C, 5.80% H, 13.64% N. LRMS (FAB+): 407
(25%, MH+), 157 (5%, MH+ – C8H8NO2), 150 (100%, C8H8NO2+).
N,N′-Bis(2-am in o-5-m eth oxyben zyl)-1,4-ph en ylen ediam in e (3)
A 3 M toluen e solution of LAH (50 m l, 150 m m ol) was slowly added to a solution of 2
(4.00 __, 9.85 m m ol) in dioxan e (40 m l). Th e reaction m ixture was refluxed for 8 h , cooled
an d carefully quen ch ed with water (12 m l), 15% aqueous solution of NaOH (14 m l) an d
water (14 m l). Th e in soluble part was filtered off an d wash ed with dioxan e (2 × 30 m l) an d
dieth yl eth er (4 × 30 m l). Th e ligh t brown com poun d 3 (3.6 g, 97%) was obtain ed from th e
filtrate by evaporation to dryn ess in vacuo. 1H NMR (DMSO-d6): 6.72 m , 2 H; 6.57 m , 4 H;
3
3
6.46 s, 4 H; 5.14 t, 2 H, JHH = 5.6 (NH); 4.54 s, 4 H (NH2); 3.94 d, 4 H, JHH = 5.5 (CH2);
3.59 s, 6 H (OCH3). 13C APT NMR (DMSO-d6): 150.9 (C), 140.5 (C), 140.0 (C), 125.1 (C),
115.6 (CH), 114.3 (CH), 114.0 (2 × CH), 112.3 (CH), 55.2 (OCH3), 45.2 (CH2).
3,12-Dim eth oxy-16,17-dih ydro-5H,10H-6,18:9,15-dim eth an oben zo[1,2-c:6,5-c′]-
bis[1,5]ben zodiazocin e 4a an d 4b
Com poun d 3 (3.10 g, 8.19 m m ol) an d h exam eth yltetram in e (3.3 g, 23.57 m m ol) were added
to trifluoroacetic acid (130 m l). Th e reaction m ixture was stirred at 60 °C for 12 h , th en di-
luted with water (1 l) an d ice, alkalin ized with con cen trated am m on ia solution , an d ex-
tracted with dich lorom eth an e (3 × 200 m l). Th e organ ic layers were com bin ed, wash ed with
brin e, dried over an h ydrous Na2SO4 an d evaporated in vacuo to dryn ess. Th e residue was
separated by colum n ch rom atograph y (silica, dich lorom eth an e/m eth an ol 95:5). As th e first
isom er 4a (890 m g, 25%) was eluted, followed by isom er 4b (520 m g, 15%).
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

1298
Valík, Matějka, Herdtweck, Král, Dolenský:
(6R*,9R*,15R*,18R*)-3,12-Dimethoxy-16,17-dihydro-5H,10H-6,18:9,15-dimethanobenzo-
3
[1,2-c:6,5-c′]bis[1,5]benzodiazocine (4a). 1H NMR (CDCl3): 6.98 d, 2 H, JHH = 8.8 (H3, H16);
3
4
4
6.90 s, 2 H (H12, H25); 6.67 dd, 2 H, JHH = 8.8, JHH = 2.8 (H2, H15); 6.35 d, 2 H, JHH = 2.8
(H6, H19); 4.54 d, 2 H, JHH = 16.6 (H7b, H20b); 4.22 d, 2 H, JHH = 16.7 (H9b, H22b); 4.13 d,
2
2
2 H, JHH = 12.4 (H8a, H21a); 4.05 d, 2 H, JHH = 12.4 (H8b, H21b); 4.04 d, 2 H, JHH = 16.6
2
2
2
(H7a, H20a); 3.73 d, 2 H, JHH = 16.7 (H9a, H22a); 3.62 s, 6 H (H13, H26). 13C NMR (CDCl3):
2
156.1 (C1, C14), 143.7 (C11, C24), 140.9 (C4, C17), 128.7 (C5, C18), 126.0 (C3, C16), 124.9 (C10
,
C23), 124.2 (C12, C25), 113.9 (C2, C15), 110.8 (C6, C19), 66.3 (C8, C21), 58.4 (C7, C20), 55.8
(C9, C22), 55.3 (C13, C26). For atom n um berin g, see Fig. 1 an d for ch em ical sh ifts in oth er
solven ts, see Tables VIII an d IX. M.p. 254–258 °C with decom position . For C26H26N4O2
(426.5) calculated: 73.22% C, 6.14% H, 13.14% N; foun d: 72.85% C, 6.20% H, 12.90% N.
HRMS (FAB+): for C26H26N4O2 (MH+) calculated: 427.2134; foun d: 427.2124.
(6R*,9S*,15S*,18R*)-3,12-dimethoxy-16,17-dihydro-5H,10H-6,18:9,15-dimetha nobenzo-
3
[1,2-c:6,5-c′]bis[1,5]benzodiazocine (4b). 1H NMR (CDCl3): 6.94 d, 2 H, JHH = 8.8 (H3, H16);
3
4
4
6.91 s, 2 H (H12, H25); 6.61 dd, 2 H, JHH = 8.8, JHH = 2.9 (H2, H15); 6.32 d, 2 H, JHH = 2.9
(H6, H19); 4.56 d, 2 H, JHH = 16.8 (H7b, H20b); 4.28 d, 2 H, JHH = 17.0 (H9b, H22b); 4.11 d,
2
2
2 H, JHH = 12.6 (H8a, H21a); 4.02 d, 2 H, JHH = 16.8 (H7a, H20a); 4.02 d, 2 H, JHH = 12.6
2
2
2
(H8b, H21b); 3.72 d, 2 H, JHH = 17.0 (H9a, H22a); 3.59 s, 6 H (H13, H26). 13C NMR (CDCl3):
2
156.1 (C1, C14), 143.7 (C11, C24), 141.1 (C4, C17), 128.7 (C5, C18), 126.2 (C3, C16), 124.7 (C10
,
C23), 124.1 (C12, C25), 113.9 (C2, C15), 110.7 (C6, C19), 66.4 (C8, C21), 58.1 (C7, C20), 55.8
(C9, C22), 55.3 (C13, C26). For atom n um berin g, see Fig. 1 an d for ch em ical sh ifts in oth er
solven ts, see Tables VIII an d IX. M.p. 271–281 °C with decom position . For C26H26N4O2
(426.5) calculated: 73.22% C, 6.14% H, 13.14% N; foun d: 72.68% C, 6.26% H, 12.96% N.
HRMS (FAB+): for C26H26N4O2 (MH+) calculated: 427.2134; foun d: 427.2124.
On e-Pot Preparation of 4a an d 4b
A vial was ch arged with 1,4-ph en ylen ediam in e (105 m g, 0.97 m m ol), 4-m eth oxyan ilin e
(344 m g, 2.79 m m ol) an d h exam eth ylen etetram in e (260 m g, 1.85 m m ol), an d TFA (4 m l)
was added. Th e m ixture was stirred at 80 °C for 18 h . After coolin g th e m ixture was treated
with m eth ylen e ch loride an d water, an d n eutralized by addin g solid NaHCO3, an d alkalized
by addin g con cen trated aqueous am m on ia. Th e aqueous layer was extracted with CH2Cl2,
th e com bin ed organ ic layers were dried over an h ydrous Na2SO4 an d evaporated to dryn ess
in vacuo. Th e com plex m ixture was separated by repeated colum n ch rom atograph y on silica
usin g a CH2Cl2/m eth an ol m ixture (from 1:0 to 9:1) to obtain 9 m g (2%) of form yl-TB 7,
74 m g (19%) of m on o-TB 6 an d 29 m g (7%) of bis-TB 4 (4a/4b 2:1).
2,8-Dimethoxy-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-4-carbaldehyde (7). 1H NMR
4
3
(CDCl3): 10.57 s, 1 H (H18); 7.22 d, 1 H, JHH = 3.0 (H13); 7.08 d, 1 H, JHH = 8.8 (H3);
6.77 dd, 1 H, JHH = 8.8, JHH = 2.9 (C2); 6.71 d, 1 H, JHH = 3.0 (H15); 6.41 d, 1 H, JHH = 2.9
(H6); 4.80 d, 1 H, JHH = 16.8 (H7b); 4.69 d, 1 H, JHH = 16.8 (H9b); 4.35 d, 1 H, JHH = 12.8
3
4
4
4
2
2
2
(H8); 4.34 d, 1 H, JHH = 12.8 (H8); 4.14 d, 1 H, JHH = 16.8 (H9a); 3.97 d, 1 H, JHH = 16.8
(H7a); 3.75 s, 3 H (H16); 3.70 s, 3 H (H17). 13C NMR (CDCl3): 190.9 (C18), 156.3 (C1), 155.9
(C14), 144.6 (C11), 140.6 (C4), 130.3 (C10), 128.1 (C5), 126.1 (C3), 122.5 (C12), 119.6 (C15),
114.4 (C2), 110.8 (C13), 110.5 (C6), 67.0 (C8), 60.5 (C7), 58.4 (C9), 55.5 (C16), 55.4 (C17). For
atom n um berin g, see Ch art 1. HRMS (FAB+): for C18H19N2O3 (MH+) calculated: 311.1396;
foun d: 311.1396.
2
2
2
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1299
TABLE VIII
13C NMR ch em ical sh ifts (in ppm ) for 4a an d 4b in various solven ts
Carbon
CDCl3
CD3NO2
C6D6
C6D5CD3
C6D5NO2
CF3COOD
C1
4a
156.10
156.06
113.88
113.85
126.00
126.17
140.91
141.13
128.65
128.72
110.79
110.66
58.43
157.48
157.40
115.09
114.91
127.31
127.32
142.71
142.57
130.56
130.54
111.97
111.91
59.54
157.04
156.64
114.62
114.59
126.82
126.36
142.66
142.27
129.77
129.11
111.61
111.24
59.31
156.99
156.71
114.47
114.60
126.76
126.44
142.68
142.36
129.75
~129.30
111.54
111.03
59.34
156.58
156.18
114.24
113.81
126.64
126.57
142.15
141.84
~129.55
~129.25
111.14
110.56
59.12
161.11
160.94
116.57
116.25
125.30
125.41
129.57
129.69
127.50
127.73
113.37
113.07
57.22
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
C2
C3
C4
C5
C6
C7
58.06
59.39
59.06
59.15
59.13
56.77
66.34
67.58
67.08
67.07
67.14
68.23
C8
66.44
67.68
67.45
67.43
67.27
68.36
55.80
56.79
56.64
56.66
56.42
56.10
C9
55.77
56.87
56.88
56.88
56.44
55.95
124.90
124.74
143.67
143.71
124.20
124.10
55.27
126.74
126.53
145.27
145.15
125.34
125.21
56.03
125.88
125.74
144.89
145.07
124.93
124.90
55.31
~125.81
~125.68
144.96
145.07
124.90
124.89
55.17
126.08
126.17
144.88
145.07
124.94
124.90
55.26
120.98
120.80
140.98
141.10
126.98
127.00
55.89
C10
C11
C12
C13
55.25
55.90
54.93
54.83
54.83
55.74
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1300
Valík, Matějka, Herdtweck, Král, Dolenský:
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 9, pp. 1278–1302

A New Bis-Tröger’s Base
1301
Reaction of Am in es in with Paraform aldeh yde in th e Melt
A vial was ch arged with 4-m eth oxyan ilin e (114 m g, 0.93 m m ol), 1,4-ph en ylen ediam in e
(50 m g, 0.46 m m ol), paraform aldeh yde (84 m g) an d TsOH·H2O (257 m g, 1.35 m m ol),
tigh tly closed an d h eated at 80 °C in an oil bath for 17 h . Th e obtain ed m elt was treated
with a m ixture of con cen trated aqueous am m on ia (1 m l), CH2Cl2 (30 m l), an d water
(25 m l). Th e organ ic layer was dried over an h ydrous MgSO4 an d evaporated to dryn ess. Th e
obtain ed solid was separated by preparative TLC (20 × 20 × 0.2 cm , silica, Un iplate,
An alTech , 3% of CH3OH in CH2Cl2) to obtain 25 m g (20%) of 8. Wh en th e experim en t was
repeated with out 1,4-ph en ylen ediam in e, a 22% yield of 8 was obtain ed.
6-Methoxy-3-(4-methoxyphenyl)-3,4-dihydroquinazoline (8). 1H NMR (CDCl3): 7.37 s, 1 H
3
3
3
(H2); 7.13 d, 1 H, JHH = 8.6 (H8); 7.10 d, 2 H, JHH = 9.0 (H13); 6.94 d, 2 H, JHH = 9.0 (H14);
6.78 dd, 1 H, JHH = 8.6, JHH = 2.8 (H7); 6.51 d, 1 H, JHH = 2.8 (H5); 4.87 s, 2 H (H4); 3.82 s,
3 H (H16); 3.78 s, 3 H (H11). 13C NMR (CDCl3): 157.5 (C6), 156.8 (C15), 145.7 (C2), 136.8
(C12), 134.6 (C10), 125.6 (C8), 122.0 (C9), 120.1 (C13), 114.7 (C14), 113.3 (C7), 111.1 (C5),
55.5 (C16), 55.4 (C11), 47.7 (C4). For atom n um berin g, see Ch art 1. HRMS (FAB+): for
3
4
4
C
16H17N2O2 (MH+) calculated: 269.1290; foun d: 269.1290.
This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic
(MSM 6046137307 and LC06077), Grant Agency of the Czech Republic (203/03/D049), and EU
(CIDNA NMP4-CT-2003-505669).
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