Crystal structures and reactivity of 3a,5a,8a,10a-tetraazaperhydropyrene derivatives. An alternative approach to selective nitrogen alkylation of 1,4,8,11-tetraazacyclotetradecane (cyclam)

Article abstract of DOI:10.1135/cccc20000243

1-Alkyl and 1,8-dialkyl-1,4,8,11-tetraazacyclotetradecanes (alkyl = benzyl or methyl) were synthesised through cis-aminal of cyclam which was obtained by reaction of glyoxal and cyclam. The corresponding trans-aminal was synthesised from the respective li

Full text of DOI:10.1135/cccc20000243

1,4,8,11-Tetraazacyclotetradecane
243
CRYSTAL STRUCTURES AND REACTIVITY OF
3a,5a,8a,10a-TETRAAZAPERHYDROPYRENE DERIVATIVES.
AN ALTERNATIVE APPROACH TO SELECTIVE NITROGEN
ALKYLATION OF 1,4,8,11-TETRAAZACYCLOTETRADECANE (CYCLAM)
1
2,
3
4
5
Jan KOTEK , Petr HERMANN *, Pavel VOJTÍŠEK , Jan ROHOVEC and Ivan LUKEŠ
Department of Inorganic Chemistry, Charles University, Hlavova 2030, 128 40 Prague 2,
1
2
Czech Republic; e-mail: modrej@prfdec.natur.cuni.cz, petrh@prfdec.natur.cuni.cz,
3
4
5
pavojt@prfdec.natur.cuni.cz, rohov@prfdec.natur.cuni.cz, lukes@prfdec.natur.cuni.cz
Received Decem ber 10, 1999
Accepted Jan uary 20, 2000
1-Alkyl an d 1,8-dialkyl-1,4,8,11-tetraazacyclotetradecan es (alkyl = ben zyl or m eth yl) were
syn th esised th rough cis-am in al of cyclam wh ich was obtain ed by reaction of glyoxal an d
cyclam . Th e correspon din g trans-am in al was syn th esised from th e respective lin ear
tetraam in e an d glyoxal followed by cyclisation usin g 1,2-dibrom oeth an e. Th e trans-am in al
derivatives can n ot be used for preparation of cyclam or its derivatives due to exception al
stability of th e am in al bridge. Th e differen t reactivity of both cis- an d trans-am in als is dis-
cussed on th e basis of th e X-ray structures determ in ed for a series of th e cyclam derivatives
an d could be explain ed by steric h in dran ce in th e trans-am in als.
Key w ord s: Azacrown com poun ds; N-Ligan ds; Am in es; cis-Tetraazaperh ydropyren e;
trans-Tetraazaperh ydropyren e; Selective protection ; Cyclam ; Crystal structure; NMR spec-
troscopy 13C; X-Ray diffraction .
Ch em istry of com plexes of m acrocyclic ligan ds, in particular polyaza-
m acrocycles, is a vital part of in organ ic ch em istry1. For th e polyaza-
m acrocycles with pen dan t arm s, th e research h as been focused m ain ly on
ligan ds con tain in g th e sam e kin d of substituen ts. Of th em , th e m ost com -
m on pen dan ts are acetates2, ph osph on ates3, ph osph in ates3,4, am ides5 an d
alkoxy derivatives5b,6. Som e of th e ligan ds com plexes h ave foun d exten sive
use as m agn etic reson an ce im agin g (MRI) con trast agen ts7 or an tibody con -
jugates con tain in g m etal radion uclides7c,8
.
To ch an ge properties (e.g., selectivity, th erm odyn am ic or kin etic stability
of com plexes) of th is type of ligan ds, m eth ods for preparation of less or dif-
feren tly substituted polyazam acrocycles h ave been sough t1. An effort h as
been focused on developin g m eth ods for selective protection of two m ost
com m on tetraazam acrocycles, 1,4,7,10-tetraazacyclododecan e (cyclen ) an d
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
1,4,8,11-tetraazacyclotetradecan e (cyclam , 1). Con sequen tly, un sym m etri-
cally or partially substituted m acrocycles were syn th esised. At an early
stage, th e sim plest but in effective an d/or costly strategy was used. Th e par-
tially substituted ligan ds were syn th esised by th e reaction of a large excess
of m acrocycle with a reactive precursor of a pen dan t arm 9 or usin g appro-
priately protected/substituted open -ch ain precursors10. Th e procedures suf-
fer from a n eed of large am oun ts of expen sive m acrocyclic am in es, tedious
purification of reaction m ixtures an d/or a m ultistep reaction sequen ce.
Lately, several groups h ave been suggested for direct protection of
tetraazam acrocycles, m ain ly for cyclen . Th ey in clude tosyl11,12, ph osph o-
rus12,13, boron 14 or silicon 15 am ides, an d m etal carbon yls16. Th e m eth ods
h ave been widely used in spite of expen sive reagen ts, problem s with
deprotection or use of in ert atm osph ere tech n iques. More recen tly, a m ore
soph isticated m eth ods h ave appeared for cyclen derivatives like
m eth ylsulfon ic acid17 (>N–CH2SO3H) or carbam ate18 protection based on
large differen ces in basicity of n itrogen atom s in th e am in e. For cyclam , a
sim ilar approach was less successful, e.g. for carbam ates19. Orth oform ate
am in al protection followed by alkylation with ben zyl group was em ployed
in th e syn th esis of th e com m ercial cyclen -based MRI con trast agen ts20.
We focused on syn th esis of m acrocycles con tain in g m eth ylen e-
ph osph on ic or m eth ylen eph osph in ic pen dan t arm s an d on in vestigation of
th eir com plexin g properties21. In addition to th e fully substituted cyclam
derivatives we wan ted to prepare 1,8-disubstituted cyclam s with th e two
ph osph orus acid pen dan t groups. However, syn th esis of th e target ligan ds
requires a suitable protection or substitution of two opposite n itrogen atom s
of cyclam rin g. Based on literature suggestion s, we decided to develop pro-
tection th rough an am in al derived from glyoxal (structures I an d II). We
also tested th e syn th esis of cyclam itself th rough an am in al “carbon tem -
plate” m eth od sim ilar to th e procedure used for syn th esis of cyclen 22,23
.
However, in th e course of our work, procedures for “carbon tem plate” syn -
th esis of tetraazacycles appeared24 as well as sim ilar approach es to syn th esis
of m on o- an d disubstituted derivatives th rough protection of cyclen usin g
orth ocarbon ate am in al25a (structure III) or glyoxal am in al25b or of cyclam
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Structure II
Structure I
Structure III
Structure IV
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1,4,8,11-Tetraazacyclotetradecane
245
th rough form aldeh yde am in al26 (structure IV). Syn th eses of 1,4- an d
1,8-dim eth ylated cyclam 27 h ave been publish ed as well as routes to “cis”
(1,11- or 1,4-) protection /substitution of cyclam 28. In th e presen t paper,
syn th esis of partially substituted cyclam derivatives as well as crystal struc-
tures of a series of tetraazaperh ydropyren e derivatives with cis an d trans ori-
en tation of h ydrogen atom s of th e cen tral bridge are described an d th eir
differen t reactivity is discussed.
EXPERIMENTAL
General
Cyclam 1 (ref.29) an d cis-3a,5a,8a,10a-tetraazaperh ydropyren e 2 (ref.30) were syn th esised fol-
lowin g literature procedures. Hydroxylam in e (2 M solution in an h ydrous EtOH) was pre-
pared by reaction of NH2OH·HCl with an equivalen t am oun t of NaOEt in dry EtOH. Oth er
ch em icals available from com m ercial sources (Fluka, Aldrich , Avocado, an d Lach em a) were
used as obtain ed. Solven ts were purified an d dried by th e establish ed procedures31. TLC was
perform ed on “Silufol” silica gel sh eets (Kavalier, Votice, Czech Republic) in th e m ixtures
propan -2-ol–25% aqueous NH3–water 7 : 3 : 3 (A) an d EtOH–25% aqueous NH3 20 : 1 (B);
n in h ydrin detection was used.
Elem en tal an alyses were don e in th e In stitute of Macrom olecular Ch em istry, Academ y of
Scien ces of th e Czech Republic. Meltin g poin ts were determ in ated usin g a Kofler h ot-stage
apparatus (Boetius) an d are un corrected. NMR spectra were recorded on a Varian Un ity Plus
at 400 MHz for 1H an d 100 MHz for 13C (in tern al referen ces for both n uclei: TMS for CDCl3
solution s an d t-BuOH for D2O solution s). Assign m en ts of NMR spectra was based on
2D-correlation experim en ts. For th e n um berin g sch em e of th e 3a,5a,8a,10a-tetraazaperh ydro-
pyren e skeleton for NMR assign m en ts an d X-ray studies, see structure V. All sam ples in D2O
were m easured just after dissolvin g. 13C NMR spectra of 2 an d 9 were also run in H2O at pH
0.7 an d 12.7; coaxial capillary with D2O was used for lock an d t-BuOH as in tern al referen ce.
H13a
H12b
H13b
H14a
C13
C12 C14
H12a
H10b
H14b
H2a
H15
N11
N1
H10a
H9b
H2b
C10
C15
C2
C3
H3a
C9
C16
N8
C7
N4
H9a
H7b
H3b
H5a
H16
C5
C6
H7a
H5b
H6b H6a
Structure V
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
X-Ray Structure Determination
Th e diffraction -quality crystals of com poun ds 5b, 10·1.5H2O, 3a·2H2O, 9·2HBr·H2O, an d
4a·4HCl·4H2O were grown from aqueous solution s (by slow evaporation ), with exception of
5b wh ich were obtain ed by coolin g its h ot eth an olic solution . Th e ch osen crystals were
m oun ted on glass fibres in ran dom orien tation usin g an epoxy glue. Diffraction data (λ =
0.71073 n m ) were collected at 293(1) K usin g a CAD4 diffractom eter (En raf–Non ius). Th e
lattice param eters of th e studied com poun ds were always determ in ed from 25 reflection s
(θ-in tervals: for 5b 13.0–14.0°; for 10·1.5H2O 14.5–15.0°; for 3a ·2H2O 14.0–15.0°; for
9·2HBr·H2O 12.5–14.0°; 4a·4HCl·4H2O 13.5–14.5°). Th e in ten sities were collected by ω–2θ
scan ; th ree stan dard reflection s were always m easured after 1 h (m ean variation s 3% for 5b,
7% for 10·1.5H2O, 3% for 3a ·2H2O, 4% for 9·2HBr·H2O, an d 3% for 4a ·4HCl·4H2O).
Loren zian -polarisation correction s were applied for all com poun ds usin g program JANA 98
(ref.32); absorption correction s were applied to com poun ds 10·1.5H2O (Tm in = 0.383, Tm ax
0.633) an d 9·2HBr·H2O (Tm in = 0.0754, Tm ax = 0.1838) usin g program JANA 98.
=
Th e structures were solved by th e Patterson an d Fourier m eth od or by direct m eth ods,
an d refin ed by full-m atrix least-squares tech n iques (SHELXS86 an d SHELXL97, refs33,34). th e
scatterin g factors used for n eutral atom s were in cluded in th e program SHELXL97. Th e h y-
drogen atom s were foun d in all structures (with exception of on e h ydrogen atom of th e h y-
drate water m olecule in th e structure of 9·2HBr·H2O) on differen ce m aps an d refin ed
isotropically. Crystallograph ic param eters of th e structures determ in ed are given in Table I.
Crystallograph ic data of th e structures reported in th is paper h ave been deposited with th e
Cam bridge Crystallograph ic Data Cen tre as supplem en tary publication n um bers
CCDC-138284 (5b), CCDC-138280 (10·1.5H2O), CCDC-138281 (3a·2H2O), CCDC-138282
(9·2HBr·H2O) an d CCDC-138283 (4a·4HCl·4H2O). Copies of th e data can be obtain ed free of
ch arge on application to CCDC, e-m ail: deposit@ccdc.cam .ac.uk.
Syntheses
3a,8a-Diben zyl-10b,10c-cis-3a,5a,8a,10a-tetraazaperh ydropyren -3a,8a-diium
Dibrom ide35 (3a)
cis-Am in al 2 (2.00 g, 9 m m ol) in 250 m l roun d-bottom flask equipped with a m agn etic stir-
rin g bar was dissolved in 20 m l of dry aceton itrile. Ben zyl brom ide (9.25 g, 54 m m ol) was
quickly added an d th e m ixture was stirred at room tem perature. After 20 m in , m on oben zyl
derivative alm ost quan titatively crystallised out as a wh ite precipitate. After 1 h , th e reaction
m ixture was diluted with an oth er 250 m l of dry aceton itrile an d th e suspen sion was stirred
at room tem perature. After two days, th e solid dissolved an d th e m ixture was left stan din g
for th ree weeks. Diben zylated product slowly deposited. Sligh tly yellow product (3.15 g) was
filtered off an d wash ed with eth er. A secon d crop was obtain ed on addition of eth er to th e
filtrate (0.80 g). Th e overall yield of 3a·2H2O was 3.95 g (73%). Crystals suitable for X-ray
an alysis were o b t ain ed by cryst allisat io n fro m wat er at ro o m t em p erat u re. TLC (A):
RF 0.05–0.1; m .p. 175–177 °C, dec. 1H NMR (D2O): 1.80 m , 2 H (H6a=H13a); 2.20 m , 2 H
(H6b=H13b); 2.87 m , 2 H (H5a=H12a); 3.22 m , 4 H (H3a=H10a + H5b=H12b); 3.45 m , 2 H
(H7a=H14a); 3.50 m , 2 H (H2a=H9a); 3.58 m , 2 H (H2b=H9b); 3.77 m , 2 H (H7b=H14b);
4.75 d, 2 H, J = 12.4 (C(H)H-Ph ); 5.20 s, 2 H (H15=H16); 5.30 d, 2 H, J = 12.4 (C(H)H-Ph );
7.60 m , 10 H (Ph ). 13C NMR (D2O): 21.07 (C6=C13); 49.10 (C3=C10); 49.86 (C2=C9); 54.29
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
(C5=C12); 63.55 (C7=C14); 65.45 (N-CH2-Ph ); 79.88 (C15=C16); 127.77, 132.57, 134.50, an d
136.32 (Ph ).
1,8-Diben zyl-1,4,8,11-tetraazacyclotetradecan e (4a)
Crude brom ide 3a·2H2O (3.90 g, 6.5 m m ol) was dissolved in 75 m l of water, solid NaOH (6.0 g,
150 m m ol) was added an d th e solution was left stan din g un der stirrin g for 1 h an d th en ex-
tracted with ch loroform (5 × 40 m l). Organ ic ph ases were collected an d evaporated on a ro-
tary evaporator to give a yellow oil. Th e oil was dissolved in 20 m l of eth an ol an d 5 m l of
con cen trated HCl was added dropwise with coolin g an d stirrin g. A wh ite precipitate was fil-
tered off an d wash ed with aceton e. Th e crude product was dissolved in 20 m l of boilin g wa-
ter an d 25 m l of con cen trated HCl was added. Th e suspen sion was left in a refrigerator
overn igh t; th e product was filtered off, wash ed with EtOH an d aceton e an d dried in vacuum
over P2O5. Slow evaporation of a water solution of 4a at room tem perature gave sin gle crys-
tals of 4a ·4HCl·4H2O suitable for X-ray an alysis. Th e yield of 4a tetrah ydroch loride
tetrah ydrate was 3.72 g (95%). TLC (A): RF 0.9; TLC (B): RF 0.3; m .p. 240–241 °C, dec.
1H NMR (D2O): 2.08 m , 4 H (H6=H13); 3.27 m , 8 H (H5=H12 + H7=H14); 3.53 m , 8 H
(H2=H9 + H3=H10); 4.32 s, 4 H (N-CH2-Ph ); 7.43 m , 10 H (Ph ). Elem en tal an alysis of several
batch es gave differen t results due to th e presen ce of n on stech iom etric am oun ts of water an d
h ydrogen ch loride, but with th e correct C : N (6 : 1) ratio in all cases.
Free am in e 4a was obtain ed from a stron g alkalin e water solution of th e h ydroch loride h y-
drate after extraction with ch loroform , dryin g (an h ydrous Na2SO4) an d evaporation of th e or-
gan ic ph ase as a colourless slowly crystallisin g oil in alm ost quan titative yield; m .p. 67–68 °C.
3a,8a-Dim eth yl-10b,10c-cis-3a,5a,8a,10a-tetraazaperh ydropyren -3a,8a-diium
Diiodide36 (3b)
cis-Am in al 2 (1.00 g, 4.5 m m ol) was dissolved in 50 m l of dry aceton itrile, m eth yl iodide
(5 g, 35 m m ol) was added to th e solution an d th e m ixture was stirred for 3 days. Th e wh ite
solid was filtered off and washed with ether. The yield of 3b was 1.48 g (65%). TLC (A): RF 0.05;
m .p. 218–219 °C, dec. 1H NMR (D2O): 1.93 m , 2 H (H6a=H13a); 2.42 m , 2 H (H6b=H13b);
2.75 m , 2 H (H5a=H12a); 3.20 m , 6 H (H2a=H9a + H3a=H10a + H5b=H12b); 3.31 m , 2 H
(H3b=H10b); 3.37 s, 3 H (N-CH3); 3.65–3.85 m , 4 H (H7a=H14a + H7b=H14b); 4.50 m , 2 H
(H2b=H9b); 4.71 s, 2 H (H15=H16). 13C NMR (D2O): 21.41 (C6=C13); 49.25 (C3=C10); 51.28
(N-CH3); 52.77 (C2=C9); 54.17 (C5=C12); 68.19 (C7=C14); 79.81 (C15=C16).
1,8-Dim eth yl-1,4,8,11-tetraazacyclotetradecan e (4b)
Iodide 3b (1.00 g, 2 m m ol) was dissolved in 20 m l of water, NaOH pellets (2.0 g, 50 m m ol)
were added an d th e m ixture was stirred for 2 h . Th e product was extracted with ch loroform
(5 × 10 m l), th e extracts were com bin ed an d evaporated to dryn ess. Th e product was iso-
lated as h ydroch loride by precipitation from acidified (HCl) solution with aceton e. Th e yield
of 4b·4HCl·4H2O was 0.71 g (80%). TLC (A): RF 0.3; m .p. 233–235 °C, dec. For C12H40Cl4N4O4
(446.3) calculated: 32.30% C, 9.03% H, 31.78% Cl, 12.55% N; foun d: 32.76% C, 8.74% H,
31.47% Cl, 12.89% N. 1H NMR (D2O): 2.28 m , 4 H (H6=H13); 3.11 s, 6 H (N-CH3); 3.52 m , 8 H
(H5=H12 + H7=H14); 3.75 m , 8 H (H2=H9 + H3=H10).
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1,4,8,11-Tetraazacyclotetradecane
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3a-Ben zyl-10b,10c-cis-3a,5a,8a,10a-tetraazaperh ydropyren -3a-ium Brom ide (5a)
cis-Am in al 2 (1.00 g, 4.5 m m ol) in a 25 m l roun d-bottom flask equipped with a m agn etic
stirrin g bar was covered with 5.5 m l of dry aceton itrile an d alm ost dissolved on stirrin g.
Ben zyl brom ide (1.54 g, 9 m m ol) was quickly added an d th e m ixture was stirred at room
tem perature. After 15 m in , a wh ite crystallin e product precipitated quan titatively. After 2 h ,
th e precipitate was filtered off, wash ed with eth er (2 × 10 m l) an d dried in vacuum over
KOH. Th e yield of 5a·2H2O was 1.70 g (90%). TLC (A): RF 0.1; m .p. 139–141 °C, dec. (ref.37
159–161 °C). 1H NMR (D2O): 1.48 m , 1 H (H13a); 1.80 m , 1 H (H6a); 2.21 m , 2 H (H6b +
H13b); 2.25 m , 1 H (H5a); 2.28 m , 1 H (H12a); 2.47 m , 2 H (H3a + H7a); 2.63 m , 1 H
(H14a); 3.03 m , 1 H (H9a); 3.05 m , 2 H (H3b + H5b); 3.12 m , 3 H (H10a + H12b + H14b);
3.26 m , 2 H (H2a + H9b); 3.51 m , 2 H (H2b + H7b); 3.68 s, 1 H (H15); 4.20 m , 1 H (H10b);
4.36 s, 1 H (H16); 4.78 d, 1 H, J = 13.2 (N-C(H)H-Ph ); 5.07 d, 1 H, J = 13.2 (N-C(H)H-Ph );
7.60 m , 5 H (Ph ). 13C NMR (D2O): 21.06 (C6); 21.44 (C13); 45.03 (C7); 49.67 (C9); 51.68
(C10); 54.40 (C12); 55.04 (C5); 56.36 (C3); 57.02 (C14); 62.86 (C2); 65.67 (N-CH2-Ph ); 72.63
(C16); 84.91 (C15); 128.75, 132.40, 134.14 an d 136.33 (Ph ).
1-Ben zyl-1,4,8,11-tetraazacyclotetradecan e (6a)
A solution of 2 M h ydroxylam in e in an h ydrous EtOH (25 m l, 50 m m ol) was added to crude
5a·2H2O (2.00 g, 4.7 m m ol), th e m ixture was refluxed in dry atm osph ere for 3 h (TLC m on itor-
in g; m ixture A). After coolin g, aqueous NaOH (25 m l, 10%) was added an d th e product was
extracted with ch loroform (3 × 50 m l). Th e com bin ed organ ic ph ases were evaporated on ro-
tary evaporator. Th e resultin g oil was dissolved in 15% aqueous HCl (15 m l) an d h eated to
reflux tem perature in a h eatin g m an tle, 70 m l of EtOH was added an d m ixture was left to
cool slowly in th e m an tle. Th e cooled m ixture was left in refrigerator overn igh t. Th e prod-
uct was filtered off, wash ed with EtOH an d eth er an d dried in vacuum over P2O5. Th e yield
of 6a·4HCl·2H2O was 2.40 g (90%). TLC (A): RF 0.2; m .p. 214–216 °C dec. 1H NMR (D2O):
2.07 m , 4 H (H16 + H13); 3.29 br m , 8 H (H5, H7, H12 an d H14); 3.51 m , 8 H (H2, H3, H9
an d H10); 4.35 s, 2 H (N-CH2-Ph ); 7.43 m , 5 H (Ph ). Elem en tal an alysis of several batch es
gave differen t results due to th e presen ce of n on stech iom etric am oun t of water an d h ydro-
gen ch loride, but with th e correct C : N (17 : 4) ratio in all cases.
Extraction of a stron gly alkalin e solution of th e h ydrated h ydroch loride with ch loroform ,
dryin g of th e organ ic ph ase (Na2SO4) an d evaporation gave a free base as an oil wh ich solid-
ified on stan din g in vacuum desiccator over KOH givin g an off-wh ite solid of 6a as
m on oh ydrate.
3a-Meth yl-10b,10c-cis-3a,5a,8a,10a-tetraazaperh ydropyren -3a-ium Iodide (5b)
Th e com poun d was syn th esised accordin g to literature procedure37,38 with yield 85%. TLC
(A): RF 0.1; m .p. 232–233 °C, dec. (ref.37 233–235 °C). 13C NMR (D2O): 21.04 (C6); 21.79
(C13); 45.12 (C9); 49.42 (C3); 51.78 (N1-CH3); 54.23 (C2 + C10); 55.08 (C12); 56.00 (C7);
56.87 (C5); 67.63 (C14); 72.43 (C16); 85.80 (C15). Crystals suitable for X-ray an alysis were
obtain ed by crystallisation from h ot eth an ol.
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
1-Meth yl-1,4,8,11-tetraazacyclotetradecan e (6b)
Quatern ary salt 5b (0.70 g, 1.9 m m ol) was dissolved in solution of h ydroxylam in e in an h y-
drous EtOH (2 M, 10 m l, 20 m m ol) an d th e m ixture was refluxed in dry atm osph ere for 4 h
(TLC m on itorin g, m ixture A). Aqueous NaOH (25%, 10 m l) was added an d eth an ol was
evaporated in vacuum . Th e m ixture was extracted with ch loroform (8 × 15 m l). Th e com -
bin ed organ ic ph ases were dried (Na2SO4) an d evaporated on a rotary evaporator. Th e result-
in g oil was dissolved in 10 m l of EtOH an d 5 m l of con cen trated HCl were added. Th e
product was precipitated with aceton e added dropwise. After stan din g in a refrigerator over-
n igh t, sm all wh ite leaves were filtered off, wash ed with aceton e, an d dried in air. Th e yield
of 6b ·4HCl·3H2O was 0.47 g (60%). TLC (A): RF ≈ 0.05; m .p. 224–226 °C, dec. For
C
11H36Cl4N4O3 (414.3) calculated: 31.89% C, 8.76% H, 34.23% Cl, 13.53% N; foun d:
32.63% C, 8.52% H, 33.42% Cl, 13.66% N. 1H NMR (D2O): 2.04 m , 4 H (H6=H13); 2.84 s,
3 H (N-CH3); 3.26 m , 8 H (H5=H12 + H7=H14); 3.45 m , 8 H (H2=H9 + H3=H10).
3a-Ben zyl-8a-m eth yl-10b,10c-cis-3a,5a,8a,10a-tetraazaperh ydropyren -3a,8a-diium
Diiodide (3c)
Com poun d 5a (1.00 g, 2.3 m m ol) was suspen ded in 40 m l of dry aceton itrile an d m eth yl io-
dide (2.50 g, 17.6 m m ol) was added with stirrin g. Th e solid slowly dissolved an d crystal-
lisation of sligh tly yellow product was fin ish ed after th ree days stan din g at room tem pera-
ture. Th e solid was filtered off, wash ed with eth er an d dried in air. Yield 1.22 g (82%). TLC
(A): RF ≈ 0.05; m .p. 142–143 °C, dec. For C20H32I2N4 (582.3) calculated: 41.25% C, 5.54% H,
0% Br, 43.59% I, 9.62% N; foun d: 42.32% C, 5.77% H, 2.28% Br, 39.32% I, 10.70% N.
1H NMR (D2O): 1.82 (H13a); 1.98 (H6a); 2.23 (H13b); 2.46 (H6b); 2.71 (H12a); 2.92 (H5a);
3.14 (H12b); 3.19 (H9a); 3.21 (H2a); 3.23 (H5b); 3.32 (H9a); 3.40 (H14a); 3.42 (H3a); 3.45 s,
3 H (N8-CH3); 3.48 (H9b); 3.51 (H2b); 3.68 (H14b); 3.78 (H7a); 3.82 (H7b); 4.38 (H3b); 4.52
(H9b); 4.72 d, 1 H, J = 13.1 (N1-C(H)H–Ph ); 4.84 (H15); 5.03 (H16); 5.21 d, 1 H, J = 13.1
(N1-C(H)H–Ph ); 7.52–7.70 (Ph ). 13C NMR (D2O): 21.06 (C13); 21.46 (C6); 49.48 (N8-CH3);
49.55 (C3 + C10); 51.29 (C2); 52.65 (C9); 54.16 (C12); 54.26 (C5); 63.42 (C14); 65.55
(N1-CH2–Ph ); 68.28 (C7); 79.64 (C15); 79.85 (C16); 127.76, 132.58, 134.51 an d 136.33 (Ph ).
1-Ben zyl-8-m eth yl-1,4,8,11-tetraazacyclotetradecan e (4c)
Quatern ary salt 3c (0.50 g, 0.86 m m ol) was dissolved in 10 m l of water, aqueous NaOH
(10%, 10 m l) was added an d th e m ixture was stirred at room tem perature for 6 h . Free
am in e was extracted with ch loroform (5 × 10 m l). Th e com bin ed organ ic ph ases were evapo-
rated on a rotary evaporator. Th e resultin g oil was dissolved in 5 m l EtOH, 5 m l con cen -
trated HCl was added dropwise an d th e product was precipitated with aceton e added
dropwise. After stan din g in a refrigerator overn igh t, wh ite solid was filtered off, wash ed with
aceton e an d dried in air. Th e yield of 4c·4HCl·H2O was 0.38 g (95%). TLC (A): RF ≈ 0.3; m .p.
200–202 °C, dec. For C18H38Cl4N4O (468.3) calculated: 46.16% C, 8.18% H, 30.28% Cl,
11.96% N; foun d: 45.68% C, 7.63% H, 31.81% Cl, 11.22% N. 1H NMR (D2O): 2.22 m , 4 H
(H6 + H13); 3.02 s, 3 H (N-CH3); 3.45 m , 8 H (H5 + H7 + H12 + H14); 3.69 m , 8 H (H2 + H3 +
H9 + H10); 4.48 s, 2 H (N-CH2-Ph ); 7.55 m , 5 H (Ph ).
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10b,10c-trans-4,5,8a,10a-Tetraazaperh ydroph en an th ren e (8)
Am in e 7 (5.00 g, 29 m m ol) was dissolved in 100 m l of EtOH. Glyoxal (5.90 g of 30% aque-
ous solution , 31 m m ol) was added dropwise durin g 5 m in an d th e m ixture was h eated to re-
flux overn igh t. Th e solven t was evaporated in vacuum an d th e resultin g brown oil was
refluxed with 1 g of an h ydrous sodium sulfate in 100 m l of petroleum eth er. Th e extract
was filtered an d th e solven t was evaporated. Wh ite n eedles of product crystallised durin g
evaporation . Th e yield of 8 was 5.08 g (90%). TLC (A): RF ≈ 0.6; m .p. 97 °C, sublim . (ref.39
103–105 °C). 1H NMR (D2O; tertiary am in e = N1 an d N4, secon dary am in e = N8 an d N11,
n o C9 an d C10): 1.63 m , 4 H (H6a=H13a + H6b=H13b); 2.27 m , 2 H (H5a=H14a); 2.38 m , 2 H
(H2a=H3a); 2.57 m , 2 H (H7a=H12a); 2.68 m , 2 H (H2b=H3b); 2.92 m , 2 H (H5b=H14b);
3.06 m , 2 H (H7b=H12b). 13C NMR (D2O): 27.37 (C6=C13); 44.71 (C7=C12); 54.49 (C2=C3),
56.57 (C5=C14); 80.51 (C15=C16).
10b,10c-trans-3a,5a,8a,10a-Tetraazaperh ydropyren e (9)
Am in al 8 (2.00 g, 10 m m ol) was dissolved in 15 m l of dry DMF an d dry K2CO3 (5.00 g,
36 m m ol) togeth er with 1,2-dibrom om eth an e (2.30 g, 12.2 m m ol) was added to th e solu-
tion . Th e m ixture was stirred at room tem perature for 10 days. Volatiles were rem oved on a
rotary evaporator, th e residue was extracted 4 × 30 m l of petroleum eth er (b.p. 40–60 °C)
an d th e com bin ed extracts were evaporated. Th e residual oil con tain ed som e startin g com -
poun d 8 (TLC) wh ich was decom posed by dissolvin g th e oil in 15 m l of acetic acid an d
stan din g overn igh t. Acetic acid was evaporated, th e residue was dissolved in 15 m l of 10%
aqueous NaOH an d extracted with ch loroform (4 × 15 m l). Th e organ ic ph ases were evapo-
rated an d th e resultin g oil was refluxed in 50 m l of petroleum eth er togeth er with 1.0 g of
an h ydrous Na2SO4. After filtration , th e filtrate was evaporated. Th e product crystallised from
CH2Cl2 solution by slow evaporation of th e solven t. Th e yield 1.47 g (65%). TLC (A): RF 0.7;
m .p. 120–121 °C (ref.40 129–132 °C). 13C NMR (D2O): 25.98 (C6=C13); 54.23 (C2=C3=C9=C10);
56.12 (C5=C7=C12=C14); 84.90 (C15=C16).
10b,10c-trans-3a,5a,8a,10a-Tetraazaperh ydropyren e Bis(h ydrobrom ide) Hydrate
(9·2HBr·H2O)
trans-Am in al 9 (0.20 g, 0.9 m m ol) was dissolved in 5 m l of aqueous HBr (48% aqueous
HBr–water 1 : 3) an d th e h ydrobrom ide was precipitated on addition of aceton e yieldin g
0.34 g (95%) of brom ide. Slow evaporation of solution of 9 in dilute aqueous HBr at room
tem perature gave crystals of th e dih ydrobrom ide salt suitable for X-ray an alysis; m .p. 246 °C,
dec. For C12H26Br2N4O (400.2) calculated: 35.84% C, 6.52% H, 39.74% Br, 13.93% N; foun d:
36.22% C, 6.39% H, 38.56% Br, 13.99% N. 1H NMR (D2O): 2.02 m , 2 H (H6a=H13a); 2.12 m ,
2 H (H6b=H13b); 2.89 m , 4 H (H5a=H7a=H12a=H14a); 3.12 m , 4 H (H2a=H3a=H9a=H10a);
3.39 m, 4 H (H2b=H3b=H9b=H10b); 3.42 m, 4 H (H5b=H7b=H12b=H14b); 3.75 s, 2 H (H15=H16).
13C NMR (D2O): 24.41 (C6=C13); 52.88 (C2=C3=C9=C10); 55.25 (C5=C7=C12=C14); 81.03
(C15=C16).
3a-Ben zyl-10b,10c-trans-3a,5a,8a,10a-tetraazaperh ydropyren -3a-ium Brom ide (10)
trans-Am in al 9 (0.50 g, 2.3 m m ol) was dissolved in 5 m l of dry aceton itrile an d ben zyl bro-
m ide (0.77 g, 4.5 m m ol) was quickly added un der vigorous stirrin g. After 30 m in stirrin g at
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
room tem perature, th e product crystallised. After 2 h at room tem perature, th e bulky precipitate
was filtered, wash ed with eth er (2 × 10 m l) an d dried in vacuum over KOH. Th e yield 0.84 g
(95%). TLC (A): RF 0.1; m .p. 214–216 °C, dec. For C19H29BrN4 (393.4) calculated: 58.01% C,
7.43% H, 20.31% Br, 14.24% N; foun d: 57.53% C, 7.49% H, 20.69% Br, 14.21% N. 1H NMR
(D2O): 1.77–1.95 m , 4 H (H6 + H13); 2.31–2.69 m , 8 H (H5 + H7 + H12 + H14); 2.80 d, 1 H, J =
8.0 (H16); 2.99–3.60 m , 8 H (H2 + H3 + H9 + H10); 3.78 d, 1 H, J = 8.0 (H15); 4.94 d, 1 H, J =
14.0 (N-C(H)H-Ph ); 5.16 d, 1 H, J = 14.0 (N1-C(H)H–Ph ); 7.56–7.60 m , 5 H (Ph ). 13C NMR
(D2O): 21.97 (C13); 25.89 (C6); 48.96 (C3); 53.36 (C9); 54.39 (C10); 55.33 (C7); 56.04 (C5);
56.18 (C12); 59.02 (C2); 62.24 (C14); 62.34 (N1-C-Ph ); 78.50 (C16); 90.78 (C15); 129.10,
132.58, 134.01 an d 135.65 (Ph ).
RESULTS AND DISCUSSION
Syntheses
3a,5a,8a,10a-Tetraazaperh ydropyren e exists in two isom eric form s with cis
or trans orientation of the hydrogen atom s of the glyoxal bridge. cis-Am inal 2
(Sch em e 1) was syn th esised followin g th e literature procedure30. As th e syn -
th esis required relatively expen sive cyclam , we tried to syn th esise cyclam
protected by th e am in al bridge directly from lin ear 1,5,8,12-tetraaza-
dodecan e an alogously to th e preparation of cyclen 23 (Sch em e 2). Recen tly,
a sim ilar approach usin g butan -2,3-dion e am in al was also em ployed for
syn th esis of cyclen , h om ocyclen (1,4,7,10-tetraazacyclotridecan e) an d
cyclam 24b. However, th e direct reaction of glyoxal an d 1,5,8,12-tetraaza-
dodecan e (7) led to trans-am in al 8; th e yield of th e reaction was sim ilar to
R
R
H
H
H
H
H
NH HN
NH HN
N
N
N
N
N
N
N
N
N
N
N
N
X
glyoxal
MeCN
RX
2X
MeCN
MeCN
H
R
R
X
R
X
1
2
PhCH2 Br
Me
5a
5b
PhCH2 Br
Me
3a
3b
for 5a
MeI
I
I
MeCN
NH2OH/EtOH
NaOH
R
N
R
N
H
NH
N
NH
N
N
N
N
N
N
NH
HN
HN
NH HN
NaOH
H
R
H3C
H3C
R
R
2I
PhCH2
PhCH2
6a
4a
4c
SCHEME 1
3c
6b Me
4b Me
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1,4,8,11-Tetraazacyclotetradecane
253
th e previous syn th eses39,40. trans-Am in al 9 form ed after reaction of 8 with
1,2-dibrom oeth an e in DMF in th e presen ce of an h ydrous K2CO3. Th e use of
DMF obviously suppressed side reaction s leadin g to polym eric products.
Literature procedures for trans-am in al 9 usin g 8, glyoxal an d NaBH4 (ref.40)
an d ben ztriazole m ediated cyclisation 41 proceeded in sim ilar yields. Hervé
et al.24b also tried th e sam e reaction in aceton itrile, wh ich was un successful.
Accordin g to th e Hubin ’s paper38, form ation of cis-am in al 2 from cyclam
an d glyoxal is th erm odyn am ically favoured com pared with form ation of
trans-am in al 9. If th e lin ear tetraam in e 7 is used for th e reaction , our results
in dicate form ation of th e trans orien tation on th e glyoxal bridge of 8.
Am in al 8 seem s to be a rigid m olecule an d its con form ation is n ot in flu-
en ced by addition al reaction with 1,2-dibrom oeth an e.
Our route for derivatisation of cyclam em ployed a kn own double
1,8-quatern isation of cis-3a,5a,8a,10a-tetraazaperh ydropyren e (2) with
ben zyl brom ide35 an d m eth yl iodide36,38 (Sch em e 1) an d m on o-
quatern isation 37,38 with th e sam e reagen ts. We used m odified protocol in
less polar solven t givin g sligh tly h igh er yields m ain ly due to a lower solu-
bility of products in aceton itrile. Accordin g to previous results, we foun d
th at th e process of double quatern isation is clearly separated in to two
stages. Reaction of cis-am in al 2 with th e first equivalen t of ben zyl brom ide
givin g 5a was fast an d quan titative in th e solven t used. Form ation of th e
double ion required excess of ben zyl brom ide an d a lon g reaction tim e at
room tem perature. Optim isation of th e con dition s led to a h igh yield of th e
product, con trolled by crystallisation of th e in soluble brom ide 3a as a driv-
in g force of th e reaction . Heatin g of th e reaction m ixture usually gave a
lower yield of m ore im pure product. Un der th e sam e con dition s, reaction
with m eth yl iodide givin g 5b an d 3b was sim ilar but faster in both steps.
Th e two distin ct steps in th e procedure were also illustrated by syn th esis of
3c (partial replacin g brom ide an ion by iodide an ion from excess of MeI was
observed).
In con trast to th e reaction of cis-am in al 2, trans-am in al 9 reacts with
ben zyl brom ide (Sch em e 2) producin g on ly m on oben zyl derivative 10 an d
th e reaction is slower. Because of un reactivity of trans-am in al bridge (see
below) oth er derivatives were n ot syn th esised. Mon om eth yl derivative h as
already been prepared37 usin g a sim ilar procedure, h owever, dim eth yl de-
rivative was obtain ed41 on ly un der h arsh con dition s (large excess of MeI,
sealed am poule). Diben zyl derivative was n ot possible to obtain even un der
th e h arsh con dition s.
Rem oval of th e glyoxal am in al group was m ore problem atic th an we ex-
pected. Sim ilar problem s were n oted24b in preparation of cyclen usin g th e
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
glyoxal “carbon tem plate” (structure II) an d bein g solved usin g h ydroxyl-
am in e22,24a, aqueous h ydrazin e24c or oxidation of th e bridge followed by
deprotection with stron g alkali h ydroxide36. In addition , we tested com -
m on procedures for th e deprotection such as con cen trated H2SO4, con cen -
trated aqueous HBr–AcOH, 10% aqueous NaOH. Usually, th e procedures led
to m ixtures of com poun ds. Fin ally, differen t procedures for m on o- an d
1,8-disubstituted cyclam s were used. Reflux of 5a, 5b in a h ydroxylam in e
solution in an h ydrous EtOH led to 6a, 6b an d reaction s of 3a–3c with 10%
aqueous NaOH gave 4a–4c.
H
H
H
N
N
NH
NH
N
N
N
N
N
N
N
N
(CH2Br)2
DMF
PhCH2Br
MeCN
H
H
H
Br
8
9
10
(CHO)2
EtOH
NH HN
NH HN
NH
N
NH NH2
NH NH2
NH HN
1
6a
7
SCHEME 2
No successful procedure was foun d for rem oval of th e glyoxal bridge from
th e trans derivatives. Treatm en t of trans-am in als 9 or 10 with an alkali solu-
tion un der reflux (20% aqueous NaOH) or in autoclave42 (180 °C, 20%
aqueous NaOH), or with con cen trated sulfuric acid43 at 100 °C or con cen -
trated aqueous HBr–acetic acid un der reflux led on ly to com plex m ixtures
(10) or to isolation of un ch an ged startin g m aterial (trans-am in al 9). In th e
reaction of HBr with un substituted trans-am in al 9, th e startin g m aterial was
recovered as dih ydrobrom ide (see below for X-ray an alysis). We also at-
tem pted to syn th esise cyclam from 8 by reduction sim ilarly to Weism an ’s
procedure23 used for cyclen . However, reduction (h ydrogen ation on 10%
Pd/C, h ydride reduction usin g LiAlH4–THF or (iBu)2AlH–toluen e un der re-
flux) led on ly to th e un ch an ged startin g m aterial. Kolin ski37 n otised a sim i-
lar un reactivity in NaBH4 reduction of m on om eth yl derivative of 9.
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1,4,8,11-Tetraazacyclotetradecane
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Molecular and Crystal Structures
Th e X-ray structures were determ in ed for 5b, 10·1.5H2O, 3a·2H2O,
9·2HBr·H2O, and 4a·4HCl·4H2O. Selected bon d distan ces an d an gles are listed
in Table II an d th eir m olecular structures are sh own in Figs 1–5. For
com parison , th e selected distan ces for th e com poun ds 2, 9, diproton ated 2
((H2-2)2[Fe2OCl6]Cl2·CH3CN), m on oproton ated am in e of 5b (Me-2·HClO4),
an d 3b from literature X-ray structure data are also listed in Table II. Better
th an in th e figures, orien tation of th e n itrogen atom s an d con form ation of
th e rin gs is sh own in structure VI. From th is sch em e, it is clear th at th e
trans derivatives h ave th e n itrogen atom s an d four cycloh exan e-like rin gs
in a plan e arran gem en t. Orien tation of th e n itrogen atom s an d rin gs in cis
derivatives is differen t an d th e cis isom ers can form two en an tiom ers45.
N
N
N
N
N
N
N
N
N
N
N
N
trans isomer
cis isomer
Structure VI
Th e bon d distan ces in th e glyoxal bridge for cis-am in al 2 an d trans-
am in al 9 are virtually th e sam e, som e differen ces are observed for th e con -
n ection of N11 an d N4 with carbon s of th e azam acrocycle an d, clearly, in
orien tation of bon ds an d an gles. Quatern isation led to th e exten sion of
both N–C(glyoxal) an d N–C(azam acrocycle) bon ds an d th e ch an ges are vir-
tually th e sam e for both trans an d cis isom ers. Th e biggest ch an ges were ob-
served after proton ation . Com parin g N–C(glyoxal) bon d len gth s in for
cis-am in als 2, 3a an d double-proton ated 2, (H2-2)2+ cation , we can follow
exten sion from 1.47 to 1.53 Å after quatern isation an d to 1.54 Å after
proton ation of a n itrogen . Sim ultan eously, th e N–C(glyoxal) bon ds becom e
sh orter for n on -quatern ised or n on -proton ated n itrogen an d th is sh orten -
in g poin ts to th eir partial double ch aracter46. However, th e bon d len gth s
are n ot affected in th e trans-am in als 9, 10 an d 9·2HBr series. Th e
NH+–C(glyoxal) bon d len gth s in 9·2HBr (1.50 Å) is even sh orter th an
N(quatern ised)–C(glyoxal) (1.53 Å) in 10. Th is correspon ds with th e h ydro-
gen bon d form ation between N1–H1···N11 in 9·2HBr. Th e H1···N11 dis-
tan ce is 2.31(7) Å an d th e H1–N1–N11 an gle is on ly 74(5)°. Th ese
differen ces clearly poin t to “structural an om eric effect” observed46 for
proton ated cyclam form aldeh yde am in al (structure IV) an d also for th e
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
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1,4,8,11-Tetraazacyclotetradecane
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Collect. Czech. Chem. Commun. (Vol. 65) (2000)

258
Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
oth er glyoxal am in als derived from tet-b (5,5,7,12,14-h exam eth yl-rac-
1,4,8,11-tetraazacyclotetradecan e) discussed in Hubin ’s paper38
.
Oth er in terestin g features were observed com parin g structure of 5b with
Hubin ’s results38 or double-proton ated 2, (H2-2)2+ cation . Surprisin gly,
proton ation of th e cis-am in als took place on th e in tern al con cave n itrogen
atom s; h owever, m eth yl iodide quatern ised th e con vex n itrogen atom s (see
structure of 3a an d 5b, Figs. 1 an d 3). Th is was explain ed by a h igh er basic-
ity of th e con cave n itrogen s an d a sm all size of proton .
Structure of 4a·4HCl·4H2O is th e first structure determ in ed for 1,8-di-
substituted cyclam (Figure 5 an d Table III). Th e con form ation of th e m acro-
cyclic cation correspon ds to th e m ost com m on con form ation 2 of fully
proton ated cyclam ((H4cyclam )4+) wh ich is den oted as (3,4,3,4-A). Th e con -
form ation , sh owin g all th e four proton ated n itrogen atom s in th e corn ers
of a virtual rectan gle, was proved to be m ost stable by m olecular m ech an ics
calculation s2. Th e bon d distan ces with in th e m acrocyclic ch ain are sim ilar
to th ose in oth er com poun ds with th e (H4cyclam )4+ cation . Th e ben zyl sub-
stituen ts are situated to th e opposite direction s towards th e plan e defin ed
by n itrogen atom s of th e m acrocycle. Th e substitution does n ot in fluen ce
FIG. 1
ORTEP represen tation of m olecular structure of (Me-2)+ in crystal structure of 5b
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1,4,8,11-Tetraazacyclotetradecane
259
th e con form ation of th e m acrocycle. Th e structure is stabilised by a n et-
work of h ydrogen bon ds between proton ated n itrogen atom s an d water
m olecules. Ch loride an ion s also sh ow con tacts with proton ated n itrogen
atom s. Th e m acrocycle m olecules are arran ged in h ydroph obic stacks form -
in g h ydroph ilic tubules filled with water m olecules an d ch loride an ion s
FIG. 2
ORTEP represen tation of m olecular structure of (Bn -9)+ in crystal structure of 10·1.5H2O
FIG. 3
ORTEP represen tation of m olecular structure of (Bn 2-2)2+ in crystal structure of 3a·H2O
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

260
Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
(Fig. 6). On e of th e h ydrate water is partly disordered. Hen ce, we tried to
place th e water m olecule in two position s. In th e best m odel, th e occupan cy
factor refin ed were about 60 an d 40%.
13C NMR Spectra
Table IV con tain s 13C NMR sign als assign ed to th e carbon atom s of
3a,5a,8a,10a-tetraazaperh ydropyren e skeleton based on 2D correlation
spectra. Th e n um berin g sch em e is sh own in structure V. Th e spectra of 9 at
FIG. 4
ORTEP represen tation of m olecular structure of (H2-9)2+ in crystal structure of 9·2HBr·H2O
FIG. 5
ORTEP represen tation of m olecular structure of (H4-4a)4+ in crystal structure of 4a·4HCl·4H2O
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1,4,8,11-Tetraazacyclotetradecane
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TABLE III
Selected bon d len gth s (Å), bon d an gles (°), torsion an gles (°) an d geom etry of h ydrogen bon ds
in crystal structure of 4a·4HCl·4H2O
Param eter
Bon d len gth s
Param eter
An gles
Param eter
Torsion an gle
N1–C2
1.497(2)
1.509(2)
1.517(2)
1.501(2)
1.496(2)
C2–N1–C7i
C2–N1–C8
C7i–N1–C8
C5–N4–C3
115.0(1) C7i–N1–C2–C3
110.4(1) N1–C2–C3–N4
110.6(1) C2–C3–N4–C5
116.9(1) C3–N4–C5–C6
N4–C5–C6–C7
64.9(1)
–172.2(1)
61.1(2)
N1–C7i
N1–C8
N4–C5
N4–C3
56.5(2)
–169.7(1)
175.2(1)
–63.6(2)
C5–C6–C7–N1i
C6–C7–N1i–C2i
Hydrogen bon d
Distan ces
An gles
N1–H11 C12i
N4–H41 C11ii
N4–H42 O1Wiii
3.040(2)
3.099(2)
2.665(3)
2.699(3)
160(1)
164(1)
170(2)
168(2)
O1W–H1W O2WBiv
i
ii
iii
Sym m etry codes: –x – 1; –y; –z + 1; x –1/2; –y + 1/2; z + 1/2;
–x – 1/2; –y – 1/2; z + 3/2;
iv
–x; –y + 1; –z + 1.
FIG. 6
Crystal packin g in structure of 4a·4HCl·4H2O
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pH 12.7 an d at about 7 (after dissolvin g in D2O) are virtually th e sam e an d
it in dicates full deproton ation at pH (pD) correspon din g to solution of free
am in e (Table IV). From th e values observed for 9 an d double-proton ated 9,
(H2-9)2+ cation , it is clear th at both th e m olecules are sym m etric, th e
diproton ation h avin g n o in fluen ce on th e sym m etry. Th us, two proton s are
sh ared by all four n itrogen atom s. After quatern isation of a n itrogen atom
(e.g., in 10), th e sym m etry is lower th an for trans-am in al 9 an d each sign al
correspon ds to on e carbon atom .
To com pare effect of proton ation of cis-am in al 2 with trans-am in al 9,
com poun d 2 was also m easured at pH about 0.7 an d 12.7. Th e m olecule
sh ows lower sym m etry th an trans-am in al 9. Except values for th e glyoxal
bridge C15 an d C16, th e oth er carbon s sh ow differen t sign als. Th e sh ifts are
caused by pH ch an ges but also by ch an ge in con form ation . Com parin g sig-
n als for cis-am in al 2 with th ose for 5a an d 5b on on e h an d an d trans-
am in al 9 with 10 on th e oth er, we can see th at quatern isation in fluen ces
th e adjacen t glyoxal carbon C15 sign al in cis isom ers m uch m ore th an in
trans isom ers. However, th e differen ces observed for C2 an d C14 are sim ilar
for both th e isom ers. Hen ce, quatern isation particularly in fluen ces th e car-
bon s of th e glyoxal bridge in cis isom ers.
CONCLUSIONS
An altern ative route for syn th esis of cyclam m on o- an d disubstituted on n i-
trogen atom s was foun d. For som e of th em , crystal structures were deter-
m in ed (5b, 10·1.5H2O, 3a·2H2O, 9·2HBr·H2O, an d 4a·4HCl·4H2O).
Syn th esis of 2 an d 9 sh owed th at form ation of cis or trans isom ers de-
pen ds on th e syn th etic route used. Th e route startin g from cyclam leads to
th e th erm odyn am ically favoured cis-am in al 2, wh ile th e route from lin ear
tetraam in e 7 leads to th e trans-am in al 9. Th is is caused by form ation of 8,
wh ose trans orien tation is probably m ore th erm odyn am ically favoured. Th e
con form ation does n ot ch an ge even durin g th e reaction with 1,2-dibrom o-
ethane. The different reactivity of cis and trans isomers is caused by the an o-
m eric effect discussed previously for sim ilar com poun ds. In addition , a
com parison of structures of th e am in als 2 an d 9 sh ows th at trans-am in al 9
is n ot fluxion al an d its rin gs are in plan e (see structure VI). Its n itrogen
lon e electron pairs are sun k in h ydrogen atom s of C–H bon ds, an d h en ce,
th e pairs are protected again st reagen t attack. In fluxion al45 cis isom ers, th e
am in al bridge (an d two n itrogen atom s) is exposed to outside of th e cage
rin g atom s an d h en ce is accessible to electroph ilic/n ucleoph ilic attack. Th e
13C NMR spectra also sh ow differen t beh aviour of th e glyoxal bridge with pH
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Kotek, Hermann, Vojtíšek, Rohovec, Lukeš:
change in cis isomers. Thus, different reactivity of the isomers can be explained
by com bin ation of both , an om eric an d structure effects.
Presen ted route for syn th esis of 1,8-disubstituted cyclam derivatives is
sligh tly less con ven ien t th an th e recen tly publish ed syn th esis of Guillard et
al.26 but it can be con sidered an altern ative way. However, m on osubsti-
tuted cyclam derivatives are obtain ed m ore easily th an usin g kn own proce-
dures. Syn th eses of cyclam derivatives with on e or two ph osph orus acid
m oieties in pen dan t arm s, based on th e am in es presen ted h ere, are un der
study an d will be publish ed in due course.
This work was supported by the Ministry of Education of the Czech Republic (grant No. VS96140),
programme EU COST COST D18, and by the Grant Agency of the Charles University (grant No.
243/1999/BCH).
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