Bis(methylphosphonic acid) derivatives of 1,4,8,11-tetraazacyclotetradecane (cyclam). Synthesis, crystal and molecular structures, and solution properties

Article abstract of DOI:10.1135/cccc20001289

Cyclam derivatives with methylphosphonic acid arms in position 1,8 and substituent R = H, Me, CH₂Ph in positions 4 and 11 are synthesised by Mannich reaction of an appropriate cyclam derivative, formaldehyde and phosphonic acid/diethyl phosphite followed by removal of protecting benzyl groups from nitrogen atoms. Mono(methylphosphonic acid) derivative of cyclam can be obtained by a similar route. Crystal structures of four phosphonic acid derivatives show the same ring conformation and orientation pendants due to strong intramolecular hydrogen bonds between phosphonate oxygen atoms and protonated nitrogen atoms adjacent over ethylene chains. The hydrogen bonds are stable even in aqueous solution. Activation parameters for destabilisation of the conformation are estimated from temperature-dependent NMR measurement. The protonation constants determined confirm the expected high basicity of the compounds and its dependence on the nitrogen atom substituents. The enhanced basicity of the nitrogen atoms non-bonded to methylenephosphonic acid moiety, is explained by the presence of the strong hydrogen bonds.

Full text of DOI:10.1135/cccc20001289

Derivatives of Cyclam
1289
BIS(METHYLPHOSPHONIC ACID) DERIVATIVES
OF 1,4,8,11-TETRAAZACYCLOTETRADECANE (CYCLAM).
SYNTHESIS, CRYSTAL AND MOLECULAR STRUCTURES,
AND SOLUTION PROPERTIES
1
2
3
4,
Jan KOTEK , Pavel VOJTÍŠEK , Ivana CÍSAŘOVÁ , Petr HERMANN *,
5
6
7
Petr JUREČKA , Jan ROHOVEC and Ivan LUKEŠ
Department of Inorganic Chemistry, Faculty of Science, Charles University,
1
Hlavova 2030, 128 40 Prague 2, Czech Republic; e-mail: modrej@prfdec.natur.cuni.cz;
2
5
3
4
pavojt@prfdec.natur.cuni.cz; cisarova@prfdec.natur.cuni.cz; petrh@prfdec.natur.cuni.cz;
6
7
jureckap@prfdec.natur.cuni.cz; rohov@prfdec.natur.cuni.cz; lukes@prfdec.natur.cuni.cz
Received April 14, 2000
Accepted Jun e 30, 2000
Dedicated to Professor Josef Loub who established laboratory of X-ray diffraction methods at the
Faculty of Science, on the occasion of his 70th birthday.
Cyclam derivatives with m eth ylph osph on ic acid arm s in position 1,8 an d substituen t R = H,
Me, CH2Ph in position s 4 an d 11 are syn th esised by Man n ich reaction of an appropriate
cyclam derivative, form aldeh yde an d ph osph on ic acid/dieth yl ph osph ite followed by re-
m oval of protectin g ben zyl groups from n itrogen atom s. Mon o(m eth ylph osph on ic acid) de-
rivative of cyclam can be obtain ed by a sim ilar route. Crystal structures of four ph osph on ic
acid derivatives sh ow th e sam e rin g con form ation an d orien tation pen dan ts due to stron g
in tram olecular h ydrogen bon ds between ph osph on ate oxygen atom s an d proton ated n itro-
gen atom s adjacen t over eth ylen e ch ain s. Th e h ydrogen bon ds are stable even in aqueous
solution . Activation param eters for destabilisation of th e con form ation are estim ated from
tem perature-depen den t NMR m easurem en t. Th e proton ation con stan ts determ in ed con firm
th e expected h igh basicity of th e com poun ds an d its depen den ce on th e n itrogen atom sub-
stituen ts. Th e en h an ced basicity of th e n itrogen atom s n on -bon ded to m eth ylen e-
ph osph on ic acid m oiety, is explain ed by th e presen ce of th e stron g h ydrogen bon ds.
Key w ord s: Azacrown com poun ds; Macrocycles; Cyclam ; Tetrazacyclotetradecan e; Ph osph o-
n ic acids; Crystal structure; Con form ation an alysis; Basicity; Poten tiom etry; NMR spectros-
copy; Proton ation con stan ts; Hydrogen bon ds.
Polyazacycles with coordin atin g pen dan t arm s are superior ligan ds for tran -
sition m etal ion s an d lan th an ides1,2. Th ey form th erm odyn am ically very
stable com plexes an d sh ow h igh selectivities to m etal ion s1–3. Polyden tate
ligan ds, such as 1,4,8,11-tetraazacyclotetradecan e-1,4,8,11-tetraacetic acid
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1290
Kotek et al.:
(1a, H4teta) an d 1,4,7,10-tetraazacyclododecan e-1,4,7,10-tetraacetic acid
(2a, H4dota), form th erm odyn am ically an d kin etically very stable com -
plexes even with labile m etal ion s as th e first-row tran sition -m etal divalen t
ion s or trivalen t lan th an ides2. Th e kin etic stability is caused, prim arily, by
con ven ien t steric arran gem en t of th e ligan ds th at can fully wrap a m etal
ion an d protect it from solven t m olecules or oth er reagen ts. On th e oth er
h an d, th e ligan ds sh ow low selectivity to m etal ion s2. Th e selectivity can be
en h an ced by replacin g acetate pen dan ts by with oth er groups such as
h ydroxyalkyl or acetam ide pen dan ts3.
R'
R
R'
R
N
N
N
N
N
N
N
N
R
R'
R
R'
1a, R = R' = CH2CO2H
1b, R = R' = CH2PO3H2
1c, R = R' = CH2P(Ph)O2H H4tetpPh
H4teta
H8tetp
2a, R = R' = CH2CO2H
2b, R = R' = CH2PO3H2
2c, R = R' = CH2P(Ph)O2H H4dotpPh
2d, R = H, R' = CH2CO2H H2do2a
2e, R = H, R' = CH2PO3H2 H4do2p
H4dota
H8dotp
R"
N
R = R' = R" = CH2CO2H,
N
R
CH2P(Me)O2H or
CH2P(Et)O2H
N
R'
Th e properties of m acrocyclic ligan ds h ave been explored wh en design -
in g th e m agn etic reson an ce im agin g (MRI) con trast agen ts4 based on Gd3+
or diagn ostic an d/or th erapeutic radioph arm aceuticals utilisin g m etal
radion uclides5. In search for oth er ligan ds with sim ilar or better properties
th an com m on acetate derivatives, research h as also been focused on syn -
th esis an d in vestigation of azam acrocycles with ph osph on ic or ph osph in ic
acid pen dan t arm s. Com plexes with th e ph osph orus ligan ds exh ibit h igh er
selectivity in com plexation an d sufficien t th erm odyn am ic stability6. Ki-
n etic properties of th e com plexes are com parable with th eir acetate
an alogs7. Th e m ost studied com poun ds were lan th an ide com plexes of
1,4,7,10-tetraazacyclododecan e (cyclen ) derivatives. Th e in vestigation s h as
led to an NMR sh ift reagen t8 for alkali m etal ion s [Tm (dotp)]5–, wh ere
H8dotp = 1,4,7,10-tetraazacyclododecan e-1,4,7,10-tetra(m eth ylph osph on ic
acid) (2b), an d tem perature9 or pH (ref.10) MRI probes based on H8dotp or
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1291
on ph osph in ic acid derivatives of cyclen . Ph osph in ic acid derivatives of
1,4,7-triazacyclon on an e selectively com plex Mg2+ over Ca2+ an d can be
used for determ in ation of Mg2+ con cen tration in vivo11.
Derivatives of cyclam were in vestigated m uch less th an th ose of cyclen .
On ly on e derivative con tain in g four m eth ylen eph osph on ic acid arm s
(H8tetp, 1b) was studied12,13. It was foun d th at th e ligan d con tain s two very
basic rin g n itrogen atom s12,13 sh owin g som e selectivity for larger m etal
ion s6b. It was suggested th at all th e arm s can n ot be coordin ated to th e sam e
tran sition m etal ion s due to th e bulkin ess of th e ph osph on ate m oiety an d,
th erefore, full coordin ation ability of th e ligan d can n ot be utilised. We as-
sum e th at th e lim itation can be overcom e by syn th esis of cyclam -based lig-
an ds with on ly two ph osph on ic acid arm s with four n itrogen an d two
oxygen don or atom s, wh ich sh ould be particularly suitable for
com plexation of octah edral cation s of th e first tran sition -m etal row. Th e
syn th esis an d in vestigation of th e 1,8-disubstituted cyclam ligan ds H4L are
th e subject of th e presen t paper.
EXPERIMENTAL
General
Startin g am in es 3a–3c (for structures, see Sch em e 1) were prepared by th e literature proce-
dures14,15. Reactive paraform aldeh yde was filtered off from an old aqueous form aldeh yde so-
lution an d dried in desiccator over P2O5. Palladium (10%) on active carbon purch ased from
Aldrich (Catalog No. 33,010-8) an d all 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 dried by estab-
lish ed procedures16. Water for determ in ation of proton ation con stan ts was purified usin g
Milli-Q (Millipore) purification system . 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), EtOH–25% aqueous NH3 15 : 1 (B), an d propan -2-ol–25% aqueous NH3–water
15 : 3 : 3 (C) usin g n in h ydrin detection . Silica gel 60 (0.040–0.065 m m , Merck), sulfon ate
(Dowex 50, Fluka) an d carboxylate (Am berlite CG50/N1, Roh m & Haas) cation exch an gers
an d an an ion exch an ge resin (Dowex 1, Fluka) were used for colum n ch rom atograph y.
Elem en tal an alyses were don e in th e In stitute of Macrom olecular Ch em istry of Academ y
of Scien ces of th e Czech Republic (Prague). Meltin g poin ts were determ in ed usin g a Kofler
h ot-stage apparatus (Boetius) an d are un corrected. NMR spectra were recorded on a Varian
1
Un ity Plus at 400 MHz for 1H, 169 MHz for 31P{ H} an d 100 MHz for 13C with in tern al refer-
en ces TMS for CDCl3 solution s an d t-BuOH for D2O solution s an d extern al referen ce 85%
H3PO4. Hydrogen atom assign m en ts were based on 2D NMR experim en ts. For NMR titration
experim en ts, see below. Tem perature was con trolled by a VT-regulator, con tain in g a th erm o-
couple calibrated usin g MeOH an d HOCH2CH2OH accordin g to a literature procedure17
.
Th erm ogravim etric (TG) an alysis was don e at th e Prague In stitute of Ch em ical Tech n ology
on a Stan ton Redcroft apparatus at 25–300 °C in air (10 °C m in –1).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

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Kotek et al.:
Chemicals and Stock Solutions for Potentiometric Titrations
Th e stock solution of n itric acid (≈0.03 m ol dm –3) was prepared by passin g a solution of
recrystallised potassium n itrate th rough a Dowex 50W-8 colum n in th e H+ form because of
traces of NO an d NO2 presen t in th e con cen trated acid. Carbon ate-free KOH solution s (≈0.2
an d ≈0.95 m ol dm –3) were stan dardised again st potassium h ydrogen ph th alate an d HNO3 so-
lution again st th e ≈0.2 M KOH solution . Sam ples of th e ligan ds for preparation of stock solu-
tion s were dried to con stan t weigh t (H4L1·9H2O at 120 °C for 2 h ; H4L2·8H2O at 100 °C for
4 h ; H4L3·6H2O at 110 °C for 2 h ; H4L4·5.5H2O at 110 °C for 1 h ; H4L5·4H2O at 110 °C for
1.5 h ). Ligan d stock solution s were prepared by dissolvin g th e dried solids in water except of
4a (H4L1) wh ich was dissolved in th e stan dard KOH solution (≈1.8 equivalen ts) followed by
addition of water. An alytical con cen tration s of th e ligan ds determ in ed from th e weigh ts of
th e dried ligan ds were in accordan ce with th eir con cen tration s determ in ed togeth er with re-
fin em en t of proton ation con stan ts usin g OPIUM program .
Potentiometric Titrations
Titration s were carried out in a vessel th erm ostatted at 25 ± 0.1 °C, at an ion ic stren gth
I(KNO3) = 0.1 m ol dm –3 an d in th e presen ce of extra HNO3 in th e –log [H+] ran ge 1.8–12.1
(except for th e titration s with 4a (H4L1), wh ich is in soluble below pH about 5) usin g a PHM
240 pH-m eter, a 2-m l ABU 900 autom atic piston burette an d a GK 2401B com bin ed elec-
trode (Radiom eter). Th e in itial volum e was 5 cm 3 an d th e con cen tration of all th e ligan ds
was 0.004 m ol dm –3. Titration for each system was carried out at least four tim es, each titra-
tion con sistin g of about 40 poin ts. An in ert atm osph ere was en sured by con stan t passage of
argon saturated with th e vapor of th e solven t used in m easurem en ts. Water ion product,
pKw = 13.78, was taken from ref.18. Th e proton ation con stan ts βn calculated are con cen tra-
tion con stan ts an d are defin ed by βn = [HnL]/([H]n[L]) (pK1 = log β1; pKn = log βn – log βn–1).
Th e con stan ts (with stan dard deviation s) were calculated with program OPIUM (ref.19). Th e
program m in im ises th e criterion of th e gen eralised least squares m eth od usin g th e calibra-
tion fun ction
E = E0 + S log [H+] + j1[H+] + j2Kw/[H+] ,
wh ere th e additive term E0 con tain s th e stan dard poten tials of th e electrodes used an d con -
tribution s of in ert ion s to th e liquid-jun ction poten tial, S correspon ds to th e Nern stian
slope, th e value of wh ich sh ould be close to th e th eoretical value an d j1[H+] an d j2[OH–]
term s are con tribution s of th e H+ an d OH– ion s to th e liquid-jun ction poten tial. It is clear
th at j1 an d j2 cause deviation from a lin ear depen den ce between E an d –log [H+] on ly in
stron g acid an d stron g alkalin e solution s. Th e calibration param eters were determ in ed from
titration of stan dard HNO3 with stan dard KOH before an y titration of ligan ds to give a cali-
bration -titration pair used for calculation s of th e con stan ts.
NMR Titrations
1H an d 31P NMR titration experim en ts for determ in ation of th e h igh est proton ation con -
stan ts of 4e (H4L5) (–log [H+] ran ge 12.4–13.5, about 30 poin ts) were carried out un der th e
con dition s of poten tiom etric titration s (H2O, 0.1 M KNO3, 25 °C, 0.004 M ligan d), h owever,
with n o con trol of ion ic stren gth at th e last poin ts above –log [H+] 13. A coaxial capillary
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1293
with D2O was used for th e lock an d water sign al was presaturated. Th e 31P NMR spectra
were recorded with n o 1H decouplin g. Proton ation con tan ts were calculated with OPIUM
from δP of ph osph on ic acid group an d δH of th e NCH2P m oiety. NMR titration s over th e
wh ole pH region were don e at 25.0 °C in H2O with presaturation of water sign al, at con cen -
tration of ligan ds 0.03 m ol dm –3 usin g a coaxial capillary with D2O for th e lock. pH (ap-
proxim ate ran ge 0–14) of th e solution s was adjusted with aqueous KOH or aqueous HCl an d
m easured with a pH-m eter calibrated with stan dard buffers20
.
Variable–Temperature NMR Measurements
1H NMR spectra for determ in ation of activation param eters of fluxion al beh avior of th e
cyclam rin g were followed in th e ran ge of 0–90 °C in water with presaturation of water pro-
ton sign al an d with D2O in a coaxial capillary for lock. Com poun d 4e (H4L5) was m easured
at pH 10.97 (100% form ation of (H2L5)2–). Tem perature-depen den t spectra were treated with
software package G-NMR to give th e rate con stan t of th e exch an ge. Th e rate con stan ts were
used for calculation of th e activation param eters.
Crystal Structure Determinations
Th e diffraction -quality crystals of com poun ds 4b·8H2O (H4L2·8H2O), 4c·6H2O (H4L3·6H2O)
an d 4e·4H2O (H4L5·4H2O) were grown from aqueous solution s by slow vapour diffusion of
aceton e; th e crystals of 4a·9H2O (H4L1·9H2O) were obtain ed from a h ot aqueous solution by
slow coolin g. Th e picked-up crystals were m oun ted on glass fibres in ran dom orien tation
with epoxy glue. Usin g a CAD4 diffractom eter (En raf–Non ius, λ = 0.71073 Å) diffraction
data for 4a·9H2O (H4L1·9H2O) an d 4b·8H2O (H4L2·8H2O) were collected at 293(1) K, for
4c·6H2O (H4L3·6H2O) an d 4e·4H2O (H4L5·4H2O) at 150(1) K. 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 4a·9H2O
(H4L1·9H2O) 13.0–14.0°; for 4b ·8H2O (H4L2·8H2O) 14.0–15.1°; for 4c·6H2O (H4L3·6H2O)
13.0–14.0°; for 4e·4H2O (H4L5·4H2O) 11.0–12.5°). Th e in ten sities were collected by th e ω–2θ
scan ; th ree stan dard reflection s were always m easured after 1 h (m ean variation 5.9% for
4a·9H2O (H4L1·9H2O), 2.8% for 4b·8H2O (H4L2·8H2O), 1.6% for 4c·6H2O (H4L3·6H2O) an d
2.5% for 4e·4H2O (H4L5·4H2O). Loren zian -polarisation correction was used for all com -
poun ds usin g program JANA 98 (ref.21); absorption correction s were n ot applied. Th e struc-
tures 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 (ref.22), SHELXL97 (ref.23)). Scatterin g factors
for th e n eutral atom s used were in cluded in th e program SHELXL97 (ref.23). Th e structure of
4b·8H2O (H4L2·8H2O) was refin ed as racem ic twin (SHELXL97, ref.23). Th e h ydrogen atom s
were foun d an d refin ed isotropically in structures of 4b ·8H2O (H4L2·8H2O), 4c·6H2O
(H4L3·6H2O) an d 4e·4H2O (H4L5·4H2O). All H atom s of m acrocyclic rin g, but n o h ydrogen
atom s of solvate water m olecules an d of ph osph on ic acid groups, were foun d an d refin ed in
structure of 4a·9H2O (H4L1·9H2O). Som e H atom s of th e ph en yl group were foun d an d also
refin ed, but th e rem ain in g on es were located in th eoretical position in th e structure of
4a·9H2O (H4L1·9H2O). Table I gives pertin en t crystallograph ic data of all structures. Th e R
value obtain ed for structure of 4a·9H2O (H4L1·9H2O) is rath er h igh due to a poor quality of
th e crystals. Th us, e.s.d. values of bon din g param eters are about th ree tim es h igh er th an for
th e oth er structures, h owever, structure of th e com poun d appears to be correct. Crystallo-
graph ic param eters of th e structures determ in ated are given in Table I. Crystallograph ic data
for th e structures reported in th is paper h ave been deposited with th e Cam bridge Crystallo-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1294
Kotek et al.:
TABLE I
Experim en tal data for th e X-ray difraction studies of com poun ds H4L1·9H2O, H4L2·8H2O,
H4L3·6H2O an d H4L5·4H2O
4a 9Η2Ο
4b 8Η2Ο
4c 6Η2Ο
4e 4Η2Ο
Param eters
(H4L1 9H2O)
(H4L2 8H2O)
(H4L3 6H2O)
(H4L5 4H2O)
a
Form ula
Mw
T, K
C26H60N4O15P2
C20H54N4O14P2
636.61
293(1)
C14H46N4O12O2
524.49
150(1)
C12H38N4O10P2
460.40
150(1)
730.72a
293(1)
Crystal dim en sion ,
0.18 × 0.25 × 0.48 0.18 × 0.42 × 0.50 0.18 × 0.55 × 0.73 0.07 × 0.07 × 0.55
m m
Colour an d sh ape
Crystal system
Space group
a, Å
b, Å
c, Å
colorless irregular
m on oclin ic
C2/c(n o.15)
11.045(9)
21.143(14)
15.897(4)
90
colorless plate
triclin ic
P1(n o.1)
8.8361(7)
10.1124(7)
10.4054(8)
81.002(6)
73.665(6)
66.116(6)
814.9(1)
1
colorless plate
triclin ic
P-1(n o.2)
7.857(2)
8.2558(8)
10.7117(9)
69.471(8)
76.25(1)
71.88(1)
611.7(2)
1
colorless n eedle
orth orh om bic
Pbca(n o.61)
8.030(3)
16.660(5)
16.220(6)
90
90
90
2 170(1)
4
1.409
α, °
β, °
97.98(5)
90
γ, °
U, Å3
3 676.4(5)
4
Z
Dc, g cm –3
λ, Å
1.320a
1.297
0.71073
0.198
1.424
0.71073
0.242
0.71073
0.186
1 488
0.71073
0.255
992
µ, m m –1
F(000)
344
284
θ ran ge of data
collection , °
In dex ran ges
1.93–25.14
2.04–24.97
2.05–24.97
2.44–23.98
–12, 13; –25, 25;
–18, 0
–9, 10; –11, 12;
–11, 12
5 276
–8, 9; 0, 9;
–11, 12
2 144
0, 9; 0, 19; 0, 15
1 988
Num ber of reflection s 6 356
m easured
Rσ
0.1815
2 361
0.015
4 811
0.011
2 021
0.029
1 340
Num ber of refletion s
observed [I > 2σ(I)]
Num ber of in depen d- 3 271
en t reflection s
5 128
2 144
1 701
Rin t
0.2112
–
–
–
Coefficien ts A, B in
weigh tin g sch em eb
Data, restrain ts,
param eters
0.1919, 47.3939
0.0429, 0.0833
0.0397, 0.2763
0.0438, 1.4830
3 271, 0, 271
5 1128, 0, 575
2 144, 0, 238
1 701, 0, 204
Goodn ess-of-fit on F2 1.152
1.028
1.078
1.087
Fin al R, R′ in dices
[I ≥ 2σ(I)]c
0.1701, 0.4376
0.0244, 0.0633
0.0263, 0.0708
0.0326, 0.0794
Maxim um sh ift/e.s.d. 0.244
0.128
0.000
0.001
Largest differen ce
1.13, –0.97
0.217, –0.214
0.330, –0.321
0.356, –0.333
peak an d h ole, e Å3
Th eoretical values, som e H-atom s were n ot foun d. w = 1/[σ2(Fo2) + (A·P)2 + B·P], wh ere P =
a
b
(Fo + 2Fc2)/3 (SHELXL97, ref.23). R = Σ Fo – Fc /Σ Fc ; R′ = [Σw(Fo – Fc
) ) ]
2/Σw(Fo
2
c
2
2
2
2 1/2
(SHELXL97, ref.23).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1295
graph ic Data Cen tre as supplem en tary publication n um ber CCDC-143863 (4a ·9H2O;
H4L1·9H2O), -143865 (4b·8H2O; H4L2·8H2O), -143866 (4c·6H2O; H4L3·6H2O) an d -143864
(4e·4H2O; H4L5·4H2O). 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
Ca u tion ! Mixture of aqueous HCl and formaldehyde can produce highly carcinogenic (ClCH2)2O!
1,8-Diben zyl-1,4,8,11-tetraazacyclotetradecan e-4,11-di(m eth ylph osph on ic Acid) (4a, H4L1)
Hydrated h ydroch loride of 3a (2.00 g, ≈3.5 m m ol) was dissolved in water (40 m l),
alkalin ised with 15% aqueous NaOH (20 m l) an d extracted with 4 × 40 m l of ch loroform .
Th e organ ic ph ases were dried (an h ydrous Na2SO4), evaporated an d th e residue was dis-
solved in dry ben zen e (70 m l). Dieth yl ph osph ite (0.99 g, 7 m m ol) was added, th e flask was
equipped with a m agn etic stirrer an d Dean –Stark apparatus. Dry paraform aldeh yde (0.31 g,
11 m m ol) was slowly added (30 m in ) to th e refluxin g m ixture. Th en th e m ixture was left
un der reflux for 1.5 h . Th e reaction was followed usin g TLC (B): th e am oun t of th e startin g
am in e (RF 0.35) decreased an d N-m on oph osph on ated cyclam (RF 0.6) togeth er with
N,N′′-diph osph on ated cyclam (RF 0.9) was detected. Th e m ixture was left to cool down ,
evaporated on a rotary evaporator an d th e residue was dissolved in aqueous HCl (1 : 1, 50 m l);
un like am in e 3a, th e residue was soluble in h ydroch loric acid. Ph osph orous acid (1.00 g, 12
m m ol) was added an d th e m ixture was refluxed for 1 h . Aqueous form aldeh yde (4.0 m l of
35%, 0.5 m l portion s) was th en added un der reflux over 4 h an d th e m ixture was left un der
reflux for an oth er 4 h . Th e m ixture was cooled an d wh ite precipitate (crude h ydroch loride
of th e product) was filtered off, wash ed with eth an ol an d aceton e, an d dried on filter. Th e
solid was suspen ded in water (15 m l) an d dissolved in a m in im um am oun t of th e con cen -
trated aqueous am m on ia added dropwise. Th e sligh tly yellow solution was in troduced on to
a Dowex 50 colum n (H+-form ; 25 × 4 cm ). Acids were eluted with water an d th e product
was obtain ed on elution with 10% aqueous am m on ia. Fraction s con tain in g th e product were
evaporated an d excess of am m on ia was rem oved by co-distillation with water (th ree tim es).
Th e pure product was obtain ed after recrystallisation from boilin g water (60 m l). Th e yield
of 4a ·9H2O (H4L1·9H2O) was 1.75
g (70%). TLC (A): RF 0.5; m .p. 168–169 °C. For
C
26H60N4O15P2 (730.7) calculated: 42.74% C, 8.28% H, 7.67% N; foun d: 42.70% C,
8.13% H, 7.62% N. 1H NMR (1
M KOD): 1.71 br m , 4 H (CH2CH2CH2); 2.57 m , 4 H
(Bn NCH2CH2CH2); 2.57 d, 4 H, 2J(P-H) = 11.6 (NCH2P); 2.73 t, 4 H, 3J(H-H) = 7.6
(CH2CH2CH2N~P); 2.77 m , 4 H (Bn NCH2CH2); 2.91 m , 4 H (CH2CH2N~P); 3.71 s, 4 H
(NCH2Ph ); 7.36–7.43 m , 10 H (C6H5). 31P{ H} NMR (1 M KOD): 15.87. TG an alysis: Th e com -
1
poun d deh ydrates in th e ran ge 50–100 °C; weigh t loss 22.36% (th eory for 9 H2O 22.20%);
th e an h ydrous com poun d is decom posed above 270 °C.
1,4,8,11-Tetraazacyclotetradecan e-4,11-di(m eth ylph osph on ic Acid) (4e, H4L5)
Th e n on ah ydrate of ph osph on ic acid 4a (H4L1; 2.00 g, 2.7 m m ol) was suspen ded in dry THF
(50 m l) an d h exam eth yldisilazan e (HMDSA, 20 m l) was added. Th e m ixture was refluxed for
1 h (th e suspen sion dissolved durin g 10 m in ). After coolin g, volatile m atters were rem oved
in vacuum with bath tem perature 50 °C to give a yellow-brown oil. Th e residue was dis-
solved in dry THF (50 m l) an d ben zyl ch loroform ate (6.0 m l, 43 m m ol) was added. Th e m ix-
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1296
Kotek et al.:
ture was stirred at room tem perature for 36 h (optim um tim e) an d EtOH (5 m l) an d
con cen trated aqueous NH3 (5 m l) was added dropwise to h ydrolyse silyl ester groups an d ex-
cess of ch loroform ate. After 30 m in volatile m atters were rem oved on a rotary evaporator
an d th e residue was dissolved in 30% HBr/AcOH (35 m l), stirred at room tem perature for
1 h an d evaporated. Th e dark residue was m ixed with water (30 m l) an d th e solution was
extracted with ch loroform (20 m l) to rem ove n on -polar im purities. Th e water solution was
in troduced on to a Dowex 50 W × 8 colum n (H+-form ; 30 × 3 cm ) an d elution with water
an d 10% aqueous NH3 afforded th e product. Th e fraction s con tain in g desired ligan d were
evaporated to give th e crude product wh ich con tain ed som e partly deph osph on ylated
m acrocycle (31P NMR an alysis) an d several m in or n in h ydrin positive com poun ds. It was pu-
rified by ch rom atograph y on carboxylic cation exch an ge resin (Am berlite in H+-form ; 30 × 5
cm ; elution with water). Th e pure product was eluted after approxim ately 600 m l of water.
Th e fraction s con tain in g product were evaporated, th e resultin g solid was dissolved in warm
water (30 m l) an d th e product crystallised on slow addition of aceton e (150 m l) an d stan d-
in g in a refrigerator overn igh t. Colorless n eedles were filtered off, wash ed with aceton e an d
dried in air. Th e yield of 4e·4H2O (H4L5·4H2O) was 1.01 g (81%). TLC (A): RF 0.4; m .p.
289–290 °C (dec.). For C12H38N4O10P2 (460.4) calculated: 31.29% C, 8.32% H, 12.17 % N;
foun d: 31.73% C, 8.47% H, 12.06% N. 1H NMR (1 M KOD): 1.78 m , 4 H (CH2CH2CH2); 2.67 t,
4 H, 3J(H-H) = 5.2 (CH2CH2NH); 2.73 t, 4 H, 3J(H-H) = 5.6 (CH2CH2CH2NH); 2.76 d, 4 H,
2J(P-H) = 10.0 (NCH2P); 2.81 t, 4 H, 3J(H-H) = 5.8 (P~NCH2CH2CH2); 2.90 t, 4 H, 3J(H-H) =
1
5.2 (P~NCH2CH2). 31P{ H} NMR (D2O): 21.80; 31P NMR (H2O, borate buffer pH 9.18): 19.72 d,
2J(P-H) = 10.5. TG an alysis: Th e com poun d deh ydrate in th e ran ge 80–100 °C; weigh t loss
15.98% (th eory for 4 H2O 15.65%); th e an h ydrous com poun d is decom posed above 290 °C.
4-Ben zyl-11-m eth yl-1,4,8,11-tetraazacyclotetradecan e-1,8-di(m eth ylph osph on ic Acid)
(4b, H4L2) an d 4,11-Dim eth yl-1,4,8,11-tetraazacyclotetradecan e-1,8-di(m eth ylph osph on ic
Acid) (4c, H4L3)
Appropriate am in e (3b or 3c, respectively; 4.4 m m ol) an d dieth yl ph osph ite (1.80 g,
13.3 m m ol) were dissolved in dry ben zen e (50 m l) in a flask equipped with th e Dean –Stark
apparatus. Paraform aldeh yde (0.53 g, 17.7 m m ol) was added in to th e refluxin g solution in
sm all portion s over 2 h . Th e reaction m ixture was evaporated to give a yellow oil wh ich was
dissolved in aqueous HCl (1 : 1) an d th e solution was refluxed for 2 h . Ph osph orous acid
(1.00 g, 12.2 m m ol) was added an d 37% aqueous form adeh yde solution (4.0 m l, 50 m m ol)
was added in portion s (0.5 m l) in to th e refluxin g m ixture over 4 h . Th e resultin g cloudy so-
lution was refluxed for 8 h . Th e cooled m ixture was evaporated to dryn ess an d acids were
rem oved on Dowex 50 W × 8 (150 m l) by elution with water followed by elution with 10%
aqueous am m on ia. Th e fraction s con tain in g product were collected, evaporated an d dis-
solved in a m in im um am oun t of water an d tran sferred on to an Am berlite 50/AR colum n
(carboxylic ion exch an ger; 300 m l). Th e product was eluted with ≈600 m l of water. Th e
fractions containing product were evaporated to dryness, the residue was dissolved in water (30 ml)
by h eatin g an d decolorised with ch arcoal. Th e pure product was precipitated on slow addi-
tion of aceton e an d stan din g overn igh t in a refrigerator. It was filtered off, wash ed with ace-
ton e an d dried on filter. Th e yield of 4b·8H2O (H4L2·8H2O) 1.35 g (85%). TLC (A): RF 0.5;
m .p. 171–172 °C. For C20H54N4O14P2 (636.6) calculated: 37.73% C, 8.54% H, 8.80% N;
foun d: 37.91% C, 8.41% H, 8.83% N. 1H NMR (1 M KOD): 1.70 br, 4 H (CH2CH2CH2); 2.26 s,
3 H (NCH3); 2.50–2.57 m , 4 H (MeNCH2CH2CH2 + Bn NCH2CH2CH2); 2.58–2.61 m , 2 H
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Derivatives of Cyclam
1297
(MeNCH2CH2); 2.59 an d 2.60 d + d, 2 H + 2 H, 2J(P-H) = 12 + 12 (NCH2P); 2.68–2.77 m , 4 H
(Bn NCH2CH2 + Bn NCH2CH2CH2); 2.79 t, 2 H, 3J(H-H) = 8.0 (MeNCH2CH2CH2); 2.84–2.91 m ,
1
4 H (P~NCH2CH2); 3.70 s, 2 H (Ph CH2N); 2.37–2.45 m , 5 H (C6H5). 31P{ H} NMR: 21.58 an d
21.26 (D2O); 15.94 (1 M KOD). TG an alysis: Th e com poun d deh ydrates in th e ran ge 40–100 °C;
weigh t loss 21.17% (th eory for 8 H2O 22.64%); th e an h ydrous com poun d decom posed
above 280 °C.
Th e yield of 4c·6H2O (H4L3·6H2O) 1.42 g (80%). TLC (A): RF 0.4; m .p. 256–259 °C (dec.).
For C14H46N4O12P2 (524.5) calculated: 32.05% C, 8.84% H, 10.68% N; foun d: 32.44% C,
8.54% H, 10.49% N. 1H NMR (1 M KOD): 1.71 m , 4 H (CH2CH2CH2); 2.23 s, 6 H (NCH3);
2.50 t, 4 H, 3J(H-H) = 6.8 (CH2CH2CH2NMe); 2.55 t, 4 H, 3J(H-H) = 7.7 (CH2CH2NMe);
2.62 d, 4 H, 2J(P-H) = 12.0 (NCH2P); 2.76 t, 4 H, 3J(H-H) = 8.2 (P~NCH2CH2CH2); 2.87 t, 4 H,
1
3J(H-H) = 7.7 (P~NCH2CH2). 31P{ H} NMR (D2O): 21.59; 31P NMR (H2O, borate buffer pH
9.18): 18.77 t, 2J(P-H) = 10.4. TG an alysis: Th e com poun d deh ydrates in th e ran ge 80–120 °C
in two distin ct steps; weigh t loss 20.01% (th eory for 6 H2O 20.60%); th e an h ydrous com -
poun d decom posed above 260 °C.
4-Meth yl-1,4,8,10-tetraazacyclotetradecan e-1,8-di(m eth ylph osph on ic Acid) (4d , H4L4)
Com poun d 4b·8H2O (H4L2·8H2O; 0.25 g, 0.4 m m ol) was dissolved in water (8 m l) an d acidi-
fied with con cen trated form ic acid (1 m l). Pd/C (10%, 0.05 g) was added an d th e m ixture
was stirred an d kept un der pressure of h ydrogen in a rubber balloon for 48 h . Th e suspen -
sion was filtered an d th e filtrate evaporated to dryn ess. Th e residue was dissolved in water
(5 m l) an d precipitated by slow addition of aceton e. Th is procedure was repeated on ce again
to obtain pure product. It was filtered, wash ed with aceton e an d dried in air. Th e yield of
4d ·5.5H2O (H4L4·5.5H2O) 0.19 g (95%). TLC (A): RF 0.4; m .p. 256–260 °C (dec.). For
C
13H43N4O11.5P2 (501.5) calculated: 31.11% C, 8.66% H, 11.17% N; foun d: 31.17% C,
8.75% H, 11.32% N. 1H NMR (1 M KOD): 1.72 br, 4 H (CH2CH2CH2); 2.21 s, 3 H (NCH3);
2.50 t, 2 H, 3J(H-H) = 6.4 (CH2CH2CH2NMe); 2.53 t, 2 H, 3J(H-H) = 7.6 (CH2CH2NMe);
2.61 d, 2 H, 2J(P-H) = 11.6 (Me~NCH2P); 2.63 d, 2 H, 2J(P-H) = 11.2 (H~NCH2P); 2.69–
2.72 m , 6 H (NHCH2CH2 + MeNCH2CH2CH2 + NHCH2CH2CH2); 2.76 t, 2 H, 3J(H-H) = 8.2
(NCH2CH2CH2); 2.84–2.88 m ,
4 H M KOD): 16.24
(P~NCH2CH2). 31P{1H} NMR (1
(Me~NCH2P); 16.36 (H~NCH2P). TG an alysis: Th e com poun d deh ydrates in th e ran ge
30–110 °C in two distin ct steps; weigh t loss 20.00% (th eory for 5.5 H2O 19.76%); th e an -
h ydrous com poun d decom posed above 260 °C.
Dieth yl 4,11-Diben zyl-1,4,8,10-tetraazacyclotetradecan e-1-(m eth ylph osph on ate) (5) an d
Tetraeth yl 4,11-Diben zyl-1,4,8,10-tetraazacyclotetradecan e-1,8-di(m eth ylph osph on ate) (6)
Dieth yl ph osph ite (1.15 g, 7.8 m m ol) an d am in e 3a (2.00 g, 5.2 m m ol) were dissolved in dry
ben zen e (60 m l) in a flask equipped with th e Dean –Stark apparatus. Un der reflux an d vigor-
ous stirrin g, paraform aldeh yde (0.31 g, 10.4 m m ol) was added in sm all portion s to th e solu-
tion over 3 h an d th e m ixture was refluxed for 4 h . Th e reaction was followed by TLC (B). It
sh owed h igh con version of th e startin g am in e 3a to dieth yl ester 5 an d tetraeth yl ester 6 as
m ajor com pon en ts an d to a m in or com pon en t with RF about 0.2. Th e m ixture was evapo-
rated an d separated by ch rom atograph y on silica (B) to give tetraeth yl ester 6 (RF 0.9), di-
eth yl ester 5 (RF 0.6) an d startin g am in e 3a (RF 0.35).
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1298
Kotek et al.:
Pure diester 5 was obtain ed as a clear oil. Yield 1.16 g (42% based on startin g am in e 3a).
For C29H47N4O3P (530.7) calculated: 65.57% C, 8.94% H, 10.54% N; foun d: 65.30% C,
8.76% H, 10.20% N. 1H NMR (CDCl3): 1.26 t, 6 H, 3J(H-H) = 7.2 (OCH2CH3); 1.70 m , 2 H
(CH2CH2CH2); 1.81 br, 2 H, (CH2CH2CH2); 2.44–2.48 m , 2 H; 2.51–2.56 m , 4 H; 2.61 br,
2 H; 2.71 br, 2 H; 2.77 br, 4 H; 2.82 d, 2 H, 2J(P-H) = 9.2 (NCH2P); 2.85 br m , 2 H; 3.62 br d,
1
2 H (NCH2Ph ); 4.01 m , 4 H (POCH2CH3); 7.2–7.4 m , 5 H (C6H5). 31P{ H} NMR (CDCl3):
24.6.
Pure oily tetraester 6 afforded after ch rom atograph ic purification (see above) was dis-
solved in aceton e (10 m l) an d water (5 m l). Aceton e was slowly evaporated on a rotary evap-
orator to give 6 as tin y wh ite leaves in soluble in rem ain in g water. It was cen trifuged,
wash ed with water an d dried in a vacuum desiccator over P2O5. Th e yield of 6 was 0.94 g
(27% based on 3a). M.p. 83–84 °C. For C34H58N4O6P2 (680.8) calculated: 59.98% C, 8.59% H,
8.23% N; foun d: 60.29% C, 8.51% H, 8.56% N. 1H NMR (CDCl3): 1.26 t, 12 H, 3J(H-H) = 7.2
(OCH2CH3); 1.66 m , 4 H (CH2CH2CH2); 2.47 t, 4 H, 3J(H-H) = 6.6; 2.59 t, 4 H, 3J(H-H) = 6.4;
2.70 t, 4 H, 3J(H-H) = 7.0; 2.77 d, 4 H, 2J(P-H) = 8.2 (NCH2P); 2.81 t, 4 H, 3J(H-H) = 6.4; 3.55 s,
1
4 H (CH2Ph ); 4.03 m , 8 H (POCH2CH3); 7.20–7.35 m , 10 H (C6H5). 31P{ H} NMR (CDCl3):
24.1.
1,4,8,11-Tetraazacyclotetradecan e-1-(m eth ylph osph on ic Acid) (7, H2L6)
Diester 5 (500 m g, 0.94 m m ol) was dissolved in EtOH (10 m l), acidified with con cen trated
form ic acid (1 m l) an d 10% Pd/C (0.1 g) was added. Th e suspen sion was stirred an d kept un -
der pressure of h ydrogen in a rubber balloon for 48 h . Palladium was filtered off an d eth a-
n ol was evaporated in vacuo. Th e residual oil was dissolved in 30% HBr/AcOH (5 m l) an d
stirred overn igh t. Th e solven t was evaporated an d th e residue was dissolved in water (2 m l),
decolorised with ch arcoal an d evaporated to dryn ess. Th e solid residue was dissolved in con -
cen trated HBr (2 m l) an d th e product was precipitated with EtOH to give 570 m g of
H2L6·3.5HBr·2.5H2O·0.5C2H5OH (95%). TLC (A): RF 0.2; m .p. 195–198 °C (dec.). For
C
12H38.5Br3.5N4O6P (645.6) calculated: 22.31% C, 6.02% H, 43.31% Br, 8.67% N; foun d:
22.48% C, 5.42% H, 42.25% Br, 8.91% N. 1H NMR (D2O): 2.01 an d 2.24 2 × m , 4 H
(CH2CH3CH2); 2.79 t, 2 H, 3J(H-H) = 6.4; 2.81 d, 2 H, 2J(P-H) = 11.2 (NCH21P); 3.04–3.06 m ,
2 H; 3.30 t, 2 H, 3J(H-H) = 5.6; 3.34–3.39 m , 4 H; 3.52–3.63 m , 8 H. 31P{ H} NMR (D2O):
19.70.
RESULTS AND DISCUSSION
Syntheses
Arm s bearin g ph osph on ate group were attach ed usin g th e Man n ich reac-
tion between appropriate m acrocyclic am in e, form aldeh yde an d a ph os-
ph orus precursor with P–H bon d (Sch em e 1). Th e optim um way to reduce
th e exten t of th e m ain side reaction , reductive N-m eth ylation of th e sec-
on dary am in e24, seem s to use aqueous HCl (1 : 1) as a solven t at a m oderate
tem perature25. Un fortun ately, 1,8-diben zylcyclam 3a was alm ost in soluble
in aqueous HCl (1 : 1). Th erefore, Man n ich reaction of 3a un der an h ydrous
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1299
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1300
Kotek et al.:
con dition s h ad to be used. It sh ould be n oted th at th e quality of para-
form aldeh yde used is a crucial poin t for success of such reaction s. Th e m ost
reactive form foun d was obtain ed from old aqueous form aldeh yde solution ;
com m ercial sam ples were less suitable. Th e reaction in ben zen e proceeded
in two steps. With excess of paraform aldeh yde an d dieth ylph osph ite in th e
reaction , reductive m eth ylation took place in th e exten t of 10–15%. Un for-
tun ately, tetraeth yl ester 6 could n ot be separated from N′′-m eth yl
N-m on oph osph on ylated ester (N-CH3 3.1 ppm in CDCl3), as well as free
acid 4a (H4L1) con tam in ated with N′′-m eth yl derivative (obtain ed after h y-
drolysis in reflux in aqueous HCl (1 : 1) for 12 h or treatm en t with 30%
HBr/AcOH for 12 h ). However, th e pure tetraester 6 togeth er with diester 5
were obtain ed if th e reaction was stopped before con sum in g of th e startin g
am in e. Fin ally, acid 4a (H4L1) was obtain ed by th e reaction in ben zen e an d
followed by ph osph on ylation in water. Th e reaction in ben zen e was
stopped after partial ph osph on ylation an d esters in th e m ixture were in situ
h ydrolysed; th us, in term ediates becam e soluble in 1 : 1 h ydroch loric acid,
an d th e preparation was fin ish ed in th is solven t with excess of H3PO3 an d
form aldeh yde. Surprisin gly, it was observed th at pure dieth yl ester of 5 was
exten sively decom posed to th e startin g am in e 3a an d (h ydroxy-
m eth yl)ph osph on ic acid in h ydrolysis in refluxin g with HCl (1 : 1) or usin g
Me3SiBr in aceton itrile at room tem perature. In spite of decom position of
in term ediate 5, syn th esis of 4a (H4L1) in aqueous HCl was successful as 4a
was again con sum ed in th e Man n ich reaction . Com poun ds 4b (H4L2) an d
(4c, H4L3) were prepared un der sim ilar con dition s (Sch em e 1).
Th e protectin g ben zyl group is usually rem oved usin g h ydrogen ation ,
wh ich was com m on ly used in syn th esis of sim ple (am in oalkyl)ph osph on ic
or ph osph in ic acids. Un fortun ately, 4a (H4L1) is soluble on ly in h ot water,
in cold water above pH 5 or in warm form ic acid. Attem pts to rem ove
ben zyl groups in 4a (H4L1) by tran sfer h ydrogen ation with HCOOH on 10%
Pd/C at 40 °C as well as h ydrogen ation in n eutral water solution led to
cleavage of th e C–P bon d an d quan titative recovery of 1,8-dim eth ylcyclam .
An oth er m eth od for rem oval of ben zyl group from am in es is th e reaction
with ch loroform ates26. Prelim in ary results on deprotection of tetraeth yl es-
ter 6 usin g ch loroform ates in dicated th at a n um ber of by-products were re-
duced. Th e desired product was fin ely obtain ed usin g trim eth ylsilyl ester
prepared in situ from th e free acid an d h exam eth yldisilazan e. Th e use of
silyl ester group seem s to be critical for th e deprotection as n o con dition s
were foun d for clean deprotection of esters 5 an d 6 with ClCOOEt or
ClCOOBn . Bon ds in th e N–C–P m oiety in esters 5 or 6 are weaken ed by in -
fluen ce of th e electron egative am in e n itrogen atom s wh ereas th e silyl
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1301
group is an electropositive electron -don atin g group, th us, stren gth en in g
th e N–C–P bon ds. Bis(ph osph on ic acid) 4e (H4L5) could be easily separated
from sm all am oun ts of by-products by ch rom atograph y on a carboxylate
cation exch an ge resin as th ey are n ot eluted from th e resin with water. Be-
cause of h igh solubility of 4b (H4L2) in acidified water, its ben zyl group was
easily rem oved by h ydrogen ation on 10% Pd/C to give 4d (H4L4).
In search for optim um syn th esis of pure ester 6, we also obtain ed pure es-
ter 5. Both esters 5 an d 6 were h ydrogen ated in EtOH to rem ove ben zyl
groups; subsequen tly, th e esters were h ydrolysed with out ch aracterisation
with 30% HBr/AcOH to give h ydrobrom ides of 4e (H4L5) an d 7 (H2L6), re-
spectively. Th is procedure is a route for syn th esis of a n ew ligan d 7 (H2L6)
but is n ot con ven ien t for syn th esis of 4e (H4L5) due to a low overall yield.
Crystal and Molecular Structures
Solvin g structures, we wan ted to con firm proton ation of th e n itrogen at-
om s an d con form ation of th e rin gs. Of th e com poun ds studied, 4a (H4L1),
4b (H4L2), 4c (H4L3) an d 4e (H4L5) were foun d to form sin gle crystals suit-
able for X-ray an alysis. Molecular structures of 4a (H4L1), 4b (H4L2), 4c
(H4L3) an d 4e (H4L5) are sh own with th e n um berin g sch em e in Fig. 1 an d
th e crystal packin g of 4a·9H2O (H4L1·9H2O) an d 4e·4H2O (H4L5·4H2O) are
depicted in Figs 2 an d 3. Tables II an d III list selected bon d distan ces an d
an gles for all th e com poun ds.
In th e crystallin e state, all th e com poun ds exist as zwitterion s with two
proton ated rin g n itrogen atom s n ot bearin g th e m eth ylph osph on ic acid
m oiety. Th e structures of sym m etrically substituted m olecules con tain th e
cen tres of sym m etry. A com parison of bon d distan ces an d an gles in th e
rin gs sh ows th at th e rin g con form ation for all th e structures is virtually th e
sam e as th e com m on (3,4,3,4)-B con form ation of th e cyclam rin g2 wh ich
was also observed for 1c·4H2O (H4tetpPh ·4H2O) an d (AdNH3)21c·6H2O
((AdNH3)2(H2tetpPh )·6H2O)30. As observed in structures of th e m en tion ed
ph osph in ic acid derivatives, th e rin g con form ation s are stabilised by h ydro-
gen bon ds N–H···O2 in th e ran ge of 2.64–2.87 Å. In addition , th e N1···N4
distan ces ran ge from 2.82 to 2.93 Å, wh ich would poin t to addition al h y-
drogen bon ds. However, th e an gles N1–H···N4 are less th an 110° (100–110°)
an d, h en ce, we assum e on ly its weak con tribution to stabilisation of th e
con form ation . Th e sh ortest in tram olecular h ydrogen bon ds were foun d in
dim eth yl derivative 4c (H4L3, Table III).
Th e coordin ation aroun d th e ph osph orus atom s sign ifican tly deviates
from th e regular tetrah edron . In th e structures, th e P–O distan ces are
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1302
Kotek et al.:
a
C7
C2
O2
C5
C3
N1
C6
C8
N4
P1
O1
O3
C9
C21
C22
C26
C25
C23
C24
C15 O11
b
O13
C14
P1
N1
C3
C13
C2
O12
C24
C23
C12
N11
C18
N4
C22
C25
C26
C9
C21
C10
C5
C17
O22
C6
P2
N8
C16
C7
O21
O23
FIG. 1
Molecular structure of 4a (H4L1) (a), 4b (H4L2) (b), 4c (H4L3) (c) an d 4e (H4L5) (d) with th e
n um berin g sch em e
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1303
O3
c
O2
P1
C9
N4
O1
C8
C3
C2
N1
C6
C5
C7
d
C7
C2
C5
C3
C6
N1
C8
N4
O1
P1
O2
O3
FIG. 1
(Continued)
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1304
Kotek et al.:
TABLE II
Th e geom etry on ph osph orus atom s (selected bon d len gth s, Å an d an gles, °)
Param eter
4a (H4L1)
4b (H4L2; P1) 4b (H4L2; P2)
4c (H4L3)
4e (H4L5)
P–O(H)
P–O (N)
P–O
1.535(7)
1.534(7)
1.486(7)
1.798(8)
1.546(2)
1.502(2)
1.532(2)
1.809(2)
1.537(2)
1.496(2)
1.532(2)
1.800(3)
1.577(1)
1.508(1)
1.501(1)
1.818(1)
1.563(2)
1.514(2)
1.505(2)
1.808(2)
P–C
Z
0
Y
FIG. 2
Crystal packin g of 4a·9H2O (H4L1·9H2O)
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1305
stron gly in fluen ced by h ydrogen bon ds an d also by proton ation . Th e m ole-
cules in 4b·8H2O (H4L2·8H2O) an d 4e·4H2O (H4L5·4H2O) are lin ked in to
ch ain s th rough in term olecular h ydrogen bon d of about 2.55 Å between th e
P–O–H group an d th e P=O m oiety of an oth er m olecule. In structures of
4a·9H2O (H4L1·9H2O) an d 4c·6H2O (H4L3·6H2O), ligan d m olecules are
lin ked th rough water m olecules with H-bon d distan ces 2.61–2.84 Å. Th ese
differen ces in th e lin kin g are sh own in Figs 2 an d 3 wh ere crystal packin g
of 4a·9H2O (H4L1·9H2O) an d 4e·4H2O (H4L5·4H2O) are depicted.
Protonation Constants
Proton ation con stan ts determ in ed in th is work are presen ted in Table IV
an d dissociation con stan ts of our ligan ds are com pared with th ose of re-
lated com poun ds in Table V. It is kn own th at fully substituted acetate2,27
an d ph osph on ic acid16,28 derivatives of cyclen , an d partly also cyclam , form
quite stable com plexes with alkali m etal ion s (especially with Na+) an d,
th erefore, th ey would be titrated in th e presen ce of n on -com plexin g back-
Z
0
X
Y
FIG. 3
Crystal packin g of 4e·4H2O (H4L5·4H2O)
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1306
Kotek et al.:
TABLE III
Selected h ydrogen bon ds an d an gles
Param eter
4a (H4L1)
4b (H4L2; 1,4)
4b (H4L2; 8,11) 4c (H4L3)
4e (H4L5)
In tram olecular bon d
d(N O), Å
2.72(1)
–
2.732(4)
171(1)
2.701(4)
166(1)
2.645(2)
174.7(8)
2.875(4)
160(1)
(N–H O), Å
In term olecular bon ds
(P)O–H O#–(P)
d(O O#), Å
(O–H O#), °
–
–
2.536(4)
2.546(4)
168(1)
–
–
2.554(4)
165(1)
176(1)
(P)O–H Ow
d(O Ow), Å
(O–H Ow), °
2.65(1)
–
–
–
–
–
2.620(3)
174.7(2)
–
–
#
Atom of a n eigh bourin g m olecule.
TABLE IV
Proton ation con stan ts of bis(m eth ylph osph on ic acid) cyclam derivatives (0.1 M KNO3, 25 °C)
Con stan ts
4a (H4L1)
4b (H4L2)
4c (H4L3)
4d (H4L4)
4e (H4L5)
log β1
log β2
log β3
log β4
log β5
log β6
10.53(2)
21.212(7)
28.31(1)
34.75(1)
10.87(2)
22.289(4)
29.53(1)
35.918(8)
37.51(2)
38.5(1)
11.47(1)
23.642(3)
30.840(6)
37.166(5)
38.69(1)
39.54(8)
–
–
24.82(2)
32.57(4)
38.16(4)
39.79(4)
26.41(1)a
33.19(1)
38.55(2)
39.70(3)
a
Determ in ed usin g NMR titration (see Experim en tal).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1307
groun d cation s like tetraalkylam m on ium ion s. Th e com plexation is m ain ly
caused by arran gem en t of pen dan t arm s suitable for such com plexation
an d, for ph osph on ic acid derivatives, also by h igh n egative ch arge of an -
ion s. In th is case, because of structure of th e ligan ds (cyclam skeleton ) an d
stron g in tram olecular h ydrogen bon ds, we can suppose th at K+ used in th e
backgroun d electrolyte does n ot form so stable com plexes to in fluen ce val-
ues of proton ation con stan ts determ in ed h ere. In addition , th e h igh values
of pK1 an d pK2 th em selves poin t to n o in teraction s of K+ with th e ligan ds.
Th e last two con stan ts 4e (H4L5) with values of pKA > 12.5 were determ in ed
by m ean s of NMR titration experim en ts. Th e acid con stan ts of 4a (H4L1)
could n ot be determ in ated due to in solubility of th e com poun d below
pH ≈ 5.
On th e basis of a com parison with literature data for sim ilar lig-
an ds15,16,30,31, of th e values of th e con stan ts, of m olecular structures of 4a
TABLE V
Com parison of dissociation con stan ts of bis(m eth ylph osph on ic acid) derivatives of cyclam
an d sim ilar ligan ds
Ligan d
pK1
pK2
pK3
pK4
pK5
pK6
4a(H4L1)
10.53
10.87
11.47
10.68
11.42
12.17
7.10
7.24
7.20
7.75
6.78
8.82
4.09
1.85
9.28
8.47
4.68
3.95
2.75
6.44
6.38
6.33
5.59
5.36
7.75
3.35
4b(H4L2)
1.60
1.52
1.63
1.15
6.25
1.0
4c(H4L3)
0.85
4d (H4L4)
24.82
26.41
26.1
4e(H4L5)
1b(H8tetp)a
1a(H4teta)b
1c(H4tetpPh
5.42
5.22
10.52
9.85
10.17
9.94
12.2
10.72
9.76
9.62
7.27
c
)
2b(H8dotp)a
2e(H4do2p)d
2a(H4dota)e
2d (H2do2a)f
2c(H4dotpPh
13.7
8.09
6.39
4.11
2.62
1.45
6.12
2.37
12.80
11.74
11.38
11.44
c
)
a
b
c
Refs11b,16 (0.1 M (Me4N)NO3, 25 °C). Ref.29a (0.1 M (Me4N)NO3, 25 °C). Ref.30 (0.1
M
M
KNO3, 25 °C). Ref.31 (0.1 M KCl, 25 °C). Ref.29c (0.1 M (Me4N)NO3, 25 °C). Ref.32 (0.1
d
e
f
Me4NCl, 25 °C).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1308
Kotek et al.:
(H4L1), 4b (H4L2), 4c (H4L3), 4e (H4L5) an d of NMR titration s of 4c (H4L3)
an d 4e (H4L5) (see below), we suggest a proton ation sch em e for th e
bis(m eth ylph osph on ic acid) ligan ds. Th e first two proton s are boun d to th e
opposite n itrogen atom s sim ilarly to 2b (H8dotp)16,28, 1b (H8tetp)16 an d th e
tetraazatetraacetic m acrocyclic ligan ds33. However, th ere are two n on -
equivalen t n itrogen atom s an d we assign ed proton ation sites to th e n itro-
gen s with out ph osph on ic acid arm s. Proton ation of both n itrogen atom s is
a h igh ly con certed process as th e abun dan ce of m on oproton ated form HL3–
is low for all th e ligan ds (Fig. 4).
With th e dissociation s con stan ts n ow discussed, we n oticed th e reversed
order of pK1 an d pK2 of 4a (H4L1), 4b (H4L2) an d 4c (H4L3) (Table V). Th e ef-
fect, h owever un sual, is a sim ple m ath em atical con sequen ce of low abun -
dan ce of HL3– species in th e equilibria an d it can be explain ed by th e
distribution diagram s in Fig. 4. It could be seen th at species (HL3)3– is pres-
en t at m axim um abun dan ce about 13%. With such abun dan ce, th e curve
for th e species crosses curves represen tin g fully deproton ated (L3)4– an d
diproton ated (H2L3)2– form s at –log [H+] values (equal to values of pK1 an d
pK2) in poin ts correspon din g to th e reverse order of con stan ts. Th e m ath e-
m atics h as an oth er two im plication s: (i) dissociation con stan ts pK1 an d pK2
would h ave an equal value on ly if abun dan ce of th e m on oproton ated spe-
cies were just 33% an d (ii) dissociation con stan t pK2 can n ot be foun d if th e
m axim um abun dan ce of th e HL3– form is less th an about 10% as, in such
case, –log [H+] (an d th e pH-m etric titration curve) is in fluen ced by th e pres-
100
5
(H5L )+
3
5
(H2L )2–
(L )4–
3
(H4L )
ligand, %
80
3
3
(H6L )2+
(H2L )2–
5
(H4L )
5
(H3L )–
5
(L )4–
60
40
20
0
3
(H3L )–
3
(H5L )+
3
(HL )–
0
2
4
6
8
10
12
14
+
–log [H ]
FIG. 4
Distribution diagram s of 4c (H4L3, dotted lin e) an d 4e (H4L5, full lin e)
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1309
en ce of th e m on oproton ated species on ly m argin ally an d its in fluen ce on
th e [H+] ch an ge is below th e sen sitivity lim it of poten tiom etry. Th e last ex-
am ple applies to 4d (H4L4) an d 4e (H4L5) as on ly on e con stan t over two
deproton ation s (proton ation s) could be determ in ed. Th e reverse order of
dissociation con stan ts h as been foun d for acid con stan ts of cyclam itself34
30
an d its ph en ylph osph in ic acid derivative 1c (H4tetpPh
)
an d on ly on e con -
stan t was also determ in ed for last two deproton ation s of 1b (H8tetp)16. Th e
effect seem s to be a ch aracteristic feature of cyclam derivatives probably
due to altern ative arran gem en t of th e eth ylen e an d trim eth ylen e ch ain s be-
tween th e n itrogen atom s in th e rin g. Th e proton ated species of tetraaza-
m acrocycles with acid pen dan t arm s are stabilised by in tram olecular
h ydrogen bon ds (see crystal structures an d ref.30).
Th e n ext two proton s are sh ared by both th e ph osph on ic m oieties to give
th e oth er relatively stable zwitterion with overall ch arge equal to zero
(Fig. 4). Th e n ext proton (s) sh ould be boun d to th e rem ain in g n itrogen at-
om s of th e (am in om eth yl)ph osph on ate m oiety. Th e suggestion of n itrogen
proton ation by th e fifth (an d sixth ) proton (s) is supported by a decrease in
31P NMR sh ift of 4c (H4L3) an d 4e (H4L5) at pH below 2 (see NMR part). Th e
fifth proton could also be attach ed to th e double-bon ded ph osph oryl oxy-
gen , wh ich is, h owever, in con ven ien t if we assum e th e presen ce of th e
in tram olecular h ydrogen bon d. Th e suggestion is supported by determ in a-
tion of m olecular structure of (H6L3)2+ in crystal of 4c·2HCl·4H2O
(H4L3·2HCl·4H2O)35. In th e cation , all th e rin g n itrogen atom s are
proton ated an d on e proton is boun d to each ph osph on ic acid m oiety. A
con form ation of rin g is ch an ged an d th e in tram olecular h ydrogen bon ds
discussed above are n ot presen t.
Com parison of pKA values of th e ligan ds with acetate29, ph osph o-
n ic16,28,31 an d ph osph in ic30,36a acid derivatives of tetraazam acrocycles con -
firm s th e expected h igh overall basicity of ph osph on ic acid com poun ds.
Th e h igh er basicity sh ould im ply h igh th erm odyn am ic stability of com -
plexes with appropriate m etal ion s. Con stan ts of 4e (H4L5) are very close to
th e correspon din g con stan ts of 1b (H8tetp; pK1, pK2, pK5 an d pK6) wh ich
suggests a sim ilar proton ation sch em e of both ligan ds. Th e values of th e
secon d proton ation con stan ts (log β21, proton ation of both n itrogen atom s)
of th e ligan ds ch an ge with electron ic effects of th e substituen ts on th e n i-
trogen s with out th e m eth ylph osph on ic acid m oiety ((NH)2 > (NH)(NMe) >
(NMe)2 > (NBn )(NMe) > (NBn )2), wh ich is an in direct proof of th e above
proton ation sch em e. We could n ot assign sites of proton ation in th e asym -
m etric ligan ds due to a low abun dan ce of HL3– species but we can assum e
th at th e N–H group in (L4)4– an d N–Me group in (L2)4– are proton ated first.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1310
NMR Titrations
Kotek et al.:
Depen den ce of NMR spectra on pH sh ould con firm proton ation sites ex-
pected for th is kin d of ligan ds. Ch an ges in ch em ical sh ifts for differen t n u-
clei can be used for assign m en t of sites of proton ation s37. It is well
docum en ted th at δP of sim ple (α-, β- an d γ-am in oalkyl)ph osph on ic acids38,
ph osph on ic acid com plexon es39 an d m acrocycles28,31,40 or ph osph in ic
acids14,36a,41 decreases with deproton ation of th e ph osph orus m oiety with
a steep in crease in th e ph osph orus ch em ical sh ift wh ile rem ovin g th e
last proton from th e proton ated α-am in o group. Th e steep in crease in δP is
explain ed by breakin g th e in tram olecular h ydrogen bon d(s) between
proton ated am in o group an d ph osph on ic (ph osph in ic) acid m oiety38. Th e
sm allest value of δP in th e titration curve pH–δP is assign ed to th e
NH+(CH2)nP(O)(R)O– (R = O–, alkyl, or aryl; n = 1–3) zwitterion ic m oiety in
wh ich th e h ydrogen bon d is stabilised to th e largest exten t. In 1H NMR
spectra, successive rem oval of proton s from an y acid or basic groups in
am in o acids usually causes a m on oton ic decrease in δH of an adjacen t CHn
groups37–40
.
Measurem en ts of NMR spectra in depen den ce on pH for th e th ree m ost
in terestin g com poun ds 4c (H4L3), 4d (H4L4) an d 4e (H4L5) sh ow th e pres-
en ce of dyn am ic equilibria on NMR tim escale at room tem perature after at-
tach m en t of two proton s to th e ligan ds (see Fig. 5 for 4e). Because of th e
dyn am ic effects, 13C NMR spectra could n ot be obtain ed an d on ly partial
1
assin gm en t of H NMR spectra could be m ade in n eutral or acid solution s.
Th e spectra are well resolved an d could be fully assign ed on ly in stron gly
alkalin e solution s. Th e ph osph orus NMR sign als are sh arp down to acid pH
becom in g progressively broader below pH about two (th e effect is m ore pro-
n oun ced for th e dim eth yl derivative).
Th e ph osph orus ch em ical sh ift of both th e sym m etrical com poun ds
(Fig. 6) in creases in pH region 10–13 with attach m en t of th e first two pro-
ton s as well as in pH region 5–8 wh ere two oth er proton s are boun d. Th e
direction of th e δP ch an ges poin ts to th e proton ation of ph osph orus atom s;
h owever, th e ph osph on ate m oiety is proton ated on ly in n eutral pH region .
Th e m ost basic sites are n itrogen atom s. Proton ation of th e n itrogen atom s
n ot bearin g th e m eth ylph osph on ic acid group was con firm ed by th e pH–δH
depen den ce of th e N-Me proton s of 4c (H4L3, Fig. 6) as well as by th e ligan d
structure in th e solid state. Th e ch em ical sh ift of th e m eth yl group m oves
down field with decreasin g pH (pH 10–13) an d is alm ost con stan t down to
acid pH with on ly a sm all down field sh ift due to proton ation of distan t
ph osph on ic acid groups at n eutral pH. Th e δH of m eth ylen e in th e NCH2P
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1311
m oiety of th e 4d (H4L4, Fig. 6) an d 4e (H4L5, n ot sh own ) in alkalin e solu-
tion s surprisin gly decreases with lowerin g pH. Th e ch an ge is opposite to
th e com m on tren d for δH of m eth ylen e in th e NCH2P m oiety on proton -
ation of th e am in e or ph osph on ate groups an d could be caused by som e
con form ation al ch an ges if we assum e form ation of in tram olecular h ydro-
gen bon ds sim ilar to th ose foun d in th e solid state. Th e presen ce of th e h y-
drogen bon d can also explain th e ch an ge of δP in th e alkalin e region as
“proton ation ” of th e ph osph on ic acid m oiety th rough th e h ydrogen bon d.
Th e doublet of m eth ylen e proton s in th e NCH2P m oiety could n ot be re-
solved at n eutral pH for th e acids. A sim ilar preferable proton ation of th e
secon dary am in e groups was observed in aqueous solution for 2d (H2do2a)
with th e con com itan t rigidifyin g of th e structure of th e diproton ated spe-
pH
14.20
13.52
10.97
6.06
3.33
1.12
0.00
3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6
ppm
FIG. 5
1H NMR spectra of 4e (H4L5) at differen t pH an d at 25 °C
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1312
Kotek et al.:
cies32. However, 2e (H4do2p) is proton ated in solution first on th e tertiary
n itrogen atom s of (am in om eth yl)ph osph on ic acid groups form in g again a
structure stabilised by h ydrogen bon ds31. In both th e com poun ds, th e n ext
two proton s are attach ed to th e ph osph on ic acid arm s.
In acid solution s, δP steeply drops an d th e 31P NMR sign al becom es pro-
gressively broader. At th e sam e tim e, th e sign al of NCH2P proton s of 4e
(H4L5) is sh ifted down field m uch m ore th an th at of m eth yl proton s 4c
22
δP, ppm
20
5
H L
4
18
16
4
H L (N-H)
4
4
H L (N-Me)
4
3
H L
4
14
12
0
2
4
6
8
10
12
14
pH
3.50
δH, ppm
3.25
3.00
3
H L (N-Me)
4
4
H L (N-Me)
4
2.75
2.50
5
H L (NCH P)
4
2
4
H L (NCH P)
4
2
2.25
2.20
3
H L (NCH P)
4
2
0
2
4
6
8
10
12
14
pH
FIG. 6
Depen den ce of 31P (a) an d 1H (b) ch em ical sh ifts on pH for 4c (H4L3: ꢀ (N–Me) an d ꢀ
(NCH2P)), 4d (H4L4: ꢀ (N–H), ꢀ (N–Me) an d ∆,
(NCH2P)) an d 4e (H4L5: ꢀ (NCH2P)); for
abun dan ces of species, see Fig. 4
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Derivatives of Cyclam
1313
(H4L3) (for H4L3, th e sign al of NCH2P proton s could n ot be assign ed). Th e
ch an ges could be explain ed by proton ation of th e n itrogen atom of th e
NCH2P m oiety (down field sh ift of δP) with possible form ation of a n ew or
oth er h ydrogen bon d between th e proton ated α-am in o an d ph osph on ic
acid groups (broaden in g of th e sign als) sim ilar to th at suggested for sim ple
(α-am in oalkyl)ph osph on ic acids38 or m acrocyclic m eth ylph osph on ic acid
derivatives28,31,40. Proton ation of all rin g n itrogen s was observed in (H6L3)2+
in th e solid state (see above)35.
For th e un sym m etrical derivative 4d (H4L4), th e depen den ce of 1H an d
31P NMR spectra on pH exh ibits th e sam e features as th e spectra disscused
above. Th e ch an ges in th e m ost alkalin e region correspon din g to NCH2P
m oieties are sim ilar. Th e th ird proton (pH 7–9) is probably attach ed to th e
ph osph on ate group adjacen t to th e secon dary am in o group as on ly its
31P NMR sign al is ch an ged an d th e sign al of th e m eth yl group is n ot in flu-
en ced (Fig. 6). In pH region 4–6.5, th e sign als of th e m eth yl group as well as
th at of th e adjacen t ph osph orus atom m ove to h igh er δ, wh ich in dicates
proton ation of th e ph osph on ic group. Th is can be explain ed by differen t
stren gth s of th e stabilisin g h ydrogen bon ds. Th e h ydrogen bon ds are
sh orter in 4c (H4L3) th an in 4e (H4L5) (Table III) an d, th erefore, th ey with -
draw m ore th e electron den sity from th e adjacen t ph osph on ic groups. Con -
sequen tly, th e ph osph on ic group close to N-Me becam e less basic.
1
Broaden in g of H NMR sign als after proton ation of two n itrogen atom s
suggests som e kin d of dyn am ic equilibria. Th erefore, in a prelim in ary
study, we m easured NMR spectra of 4e (H4L5) at pH 10.97 in water (100%
fom ation of (H2L5)2–) at differen t tem peratures (0–90 °C, 10 °C steps). Co-
alescen ce of gem in al proton s of th e cen tral m eth ylen e group (δH aroun d
2.0 an d 1.8 ppm ) in th e trim eth ylen e ch ain was observed between 50 an d
60 °C. We were able to determ in e activation param eters of th e process
(∆H# = 82(3) kJ m ol–1 an d ∆S# = 44(10) kJ m ol–1 K–1 with Ea = 85(3) kJ m ol–1)
by treatm en t of th e variable–tem perature data. If we assum e th at th e pro-
cess correspon ds to rupture of th e h ydrogen bon ds discussed above, th en ,
∆H# an d ∆S# suggest a stron g h ydrogen bon d an d a tran sition from a h igh ly
ordered state, respectively. Th e h igh value of th e activation en ergy is also in
agreem en t with th e h igh stren gth of h ydrogen bon ds presen t in th e
(H2L5)2– species.
Th e results presen ted h ere support our previous in terpretation of solution
30
beh aviour for 2c (H4dotpPh ) an d 1c (H4tetpPh
)
wh ere th e presen ce of som e
stable con form ation s of th e ligan ds was suggested an d explain ed ten ta-
tively by th e presen ce of an in tram olecular h ydrogen bon d of th e sam e
kin d like h ere an d by h ydroph obic in teraction s between ph en yl substitu-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1314
Kotek et al.:
en ts. But, at th at tim e we did n ot h ave in h an d direct con firm ation of th e
presen ce of such h ydrogen bon ds in aqueous solution s.
CONCLUSIONS
We foun d a suitable route for syn th esis of m on o- an d bis(m eth ylph osph o-
n ic acid) derivatives of cyclam em ployin g ben zyl protection for secon dary
am in o groups. Lability of (N–)C–P an d N–C(–P) bon ds durin g deprotection
procedures was observed. Structures of th e ph osph on ic acid ligan ds in th e
solid state reveal th e presen ce of stron g in tram olecular h ydrogen bon ds be-
tween th e ph osph on ic m oiety an d am in o group over th e adjacen t eth ylen e
ch ain . Th e h ydrogen bon d is presen t even in aqueous solution . It was con -
firm ed by values of proton ation con stan ts as well as titration an d variable–
tem perature NMR experim en ts. High basicity of our ph osph on ate ligan ds is
a con sequen ce of th e h ydrogen bon d an d n ot of spreadin g of electron den -
sity of th e h igh ly ch arged ph osph on ate group, wh ich was used as an expla-
n ation of h igh er basicity of th e am in o group in sim ple (α-am in oalkyl)-
ph osph on ic acids42. In tram olecular h ydrogen bon d was presen ted as an
explan ation of h igh proton ation con stan ts of ph osph on ic acid an alogues of
H3n ta an d H4edta39c. High basicity of th e ligan ds suggests a h igh th erm ody-
n am ic stability of th eir m etal com plexes; kin etic stability of th e com plexes
sh ould be also en h an ced due to con ven ien t steric arran gem en t an d
h exaden ticity of th e ligan ds. In vestigation s of com plexin g properties of th e
ligan ds are un der way.
We thank Dr M. Tkadlecová (Prague Institute of Chemical Technology) for help with variable–
temperature NMR data treatment and to Dr J. Ederová (Prague Institute of Chemical Technology) for
TG measurements. This work was supported by the Ministry of Education of the Czech Republic (grant
No.VS96140 and project J13/98:113100001), programmes EU COST (COST D8 and COST D18), by
the Grant Agency of the Charles University (grant No. 243/1999/BCH, to P. V.) and by the Grant
Agency of the Czech Republic (grant No. 203/97/0242, to I. C.).
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