Syntheses and X-ray crystal structures of derivatives of 2,2′,4,4′,6,6′-hexaiodobiphenyl

Article abstract of DOI:10.1039/b009666k

Iodination of 1,1′-biphenyl-3,3′,5,5′-tetrol and 1,1′-biphenyl-3,3′-diol with ICl afforded the corresponding 2,2′,4,4′,6,6′-hexaiodo derivatives. Hydrophilic residues aimed at masking the lipophilicity of the iodine atoms were introduced by alkylation of

Full text of DOI:10.1039/b009666k

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Syntheses and X-ray crystal structures of derivatives of
2,2Ј,4,4Ј,6,6Ј-hexaiodobiphenyl
Pier Lucio Anelli,*a Marino Brocchetta,a (the late) Costantino Maffezzoni,a Paola Paoli,b
Patrizia Rossi,b Fulvio Uggeria and Massimo Visigallia
1
a Milano Research Centre, Bracco s.p.a., via E. Folli 50, 20134 Milano, Italy
b Dipartimento di Energetica “Sergio Stecco”, Università di Firenze, via S. Marta 3,
50139 Firenze, Italy
Received (in Cambridge, UK) 1st December 2000, Accepted 23rd March 2001
First published as an Advance Article on the web 20th April 2001
Iodination of 1,1Ј-biphenyl-3,3Ј,5,5Ј-tetrol and 1,1Ј-biphenyl-3,3Ј-diol with ICl afforded the corresponding
2,2Ј,4,4Ј,6,6Ј-hexaiodo derivatives. Hydrophilic residues aimed at masking the lipophilicity of the iodine atoms were
introduced by alkylation of the OH groups. The solid state structures, which were obtained by X-ray crystallography,
of three hexaiodinated derivatives (namely 5, 7 and 13) show that, as expected, the two aromatic rings are forced to
lie in nearly perpendicular planes by the hindrance of the four iodine atoms adjacent to the inter-annular C–C bond.
The hexaiodinated biphenyl skeleton was investigated as the core backbone of a new class of X-ray contrast media.
blood pressure and vasal damages) which are related to hyper-
Introduction
tonicity and high viscosity of the solution. To circumvent these
Our interest in the chemistry of polyiodinated compounds
drawbacks molecules containing two triiodinated benzene
stems from their use as X-ray contrast media. To qualify for
such an application an iodinated derivative must display i) high
rings, the so-called “dimers” (e.g. Iotrolan, 2, Chart 1),3 have
been developed and brought into clinical practice although
iodine content, ii) thorough solubility in water, iii) chemical
without great success. As the result of our studies4 on biphenyl
stability and iv) biological inertia.1 To date, the best performing
derivatives in which the iodine content can be as high as 70–
75%,† we report in this paper i) molecular mechanics and
contrast media (e.g. Iopamidol, 1, Chart 1) share a triiodinated
dynamic calculations on 2,2Ј,6,6Ј-tetrahalogen-substituted
biphenyl systems, ii) the synthesis of a series of 2,2Ј,4,4Ј,6,6Ј-
hexaiodinated biphenyl derivatives and iii) the solid state
structures of some of these derivatives obtained by X-ray
crystallography.
Results and discussion
Preliminary inspections of molecular models suggested that
in a 2,2Ј,6,6Ј-tetraiodinated biphenyl the four iodine atoms
adjacent to the inter-annular bond (later called C6–C7) mask
each other to a certain extent. Therefore, the “exposed” lipo-
philic surface of the molecule decreases and a limited number
of hydrophilic residues could be required to assure water solu-
bility. On this basis we undertook a study to evaluate the
conformational behaviour of biphenyl systems bearing halogen
substituents in positions 2,2Ј,6,6Ј. Despite only being interested
for practical reasons in iodo derivatives, for more speculative
reasons, we also investigated substitutions by fluorine, chlorine
and bromine atoms in these positions.
It is well known that when there are no substituents in the
ortho positions, the biphenyl vapour-phase energy minima are
characterised by a gauche conformation,6 in contrast with the
planar geometry of the crystalline state.7 Two types of inter-
Chart 1
actions mainly affect the torsional potential of the biphenyl
systems: i) the π-conjugation, which stabilises the coplanar
benzene ring as the common structural building block.1
Hydroxy- and polyhydroxy-alkyl substituents, which mask the
lipophilicity of the iodine atoms, are also required to assure
water solubility.2 Since the opacifying power of the contrast
agent is related to the iodine content (e.g. 49% for 1), a product
containing a higher iodine percentage could be administered at
a lower dose level. As a matter of fact, said contrast agents are
formulated as very concentrated (up to 750 mg mlϪ1) water
solutions. After intravenous administration they can cause,
although rarely, undesirable side effects (pain, nausea, low
conformer and ii) the non-bonding interaction, which is
the dominant repulsion term and favours the non-planar
arrangement of the two rings. Despite a great deal of work
having been carried out on the torsional potential of the basic
skeleton of biphenyl,8,9 we could find no results involving
† Whilst we were working on this project, another research group was
developing hexaiodinated biphenyl derivatives bearing different
substituents.5
DOI: 10.1039/b009666k
J. Chem. Soc., Perkin Trans. 1, 2001, 1175–1181
This journal is © The Royal Society of Chemistry 2001
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Fig. 2 Energy profiles for the torsion about the C6–C7 bond in
2,2Ј,6,6Ј-tetrahalogen-substituted biphenyl derivatives as provided by
the conformational search: ꢀ = F; ᭜ = Cl; ᭿ = Br; ᭢ = I.
already emerged from the analysis of the structural data in the
CSD, the angular value of the torsion about C6–C7 progres-
sively increases with the size of the halogen atoms occupying
the ortho positions: from 50Њ (130Њ) for X = F to 90Њ for X = I
[70Њ (110Њ) when X = Cl and Br]. It is noteworthy that at 90Њ the
tetrafluoro-substituted biphenyl shows an energy barrier
(∆E = 3.8 kcal molϪ1); in this case the π-resonance term prevails
over the steric hindrance of the fluorine atoms, the opposite
holds for the hexaiodo-substituted molecule. Concerning the
energy required for a 360Њ rotation about C6–C7, the energy
barriers span from ca. 20 kcal molϪ1 (X = F) to ca. 50 kcal
molϪ1 (X = I). This also indicates that for the lighter derivative
we can reasonably exclude complete rotation at room temper-
ature. Results from molecular dynamics simulations performed
on the model compounds at 300 and 600 K are in keeping with
the latter observation: in all cases no 360Њ rotation about the
inter-annular bond was detected, thus confirming the intrinsic
stiffness of all these molecules.
Fig. 1 Plot in polar coordinates of the number of samples retrieved
from the CSD within each range (10Њ) of θ (torsion angle about the C6–
C7 bond): a) 2,2Ј,6,6Ј-tetrahalogen-substituted biphenyl derivatives (11
molecular fragments); b) 2,2Ј,6,6Ј-tetra(C-bulky)-substituted biphenyl
derivatives (22 molecular fragments).
2,2Ј,6,6Ј-tetrahalogen-substituted biphenyl systems. Therefore,
we focused our attention on the evaluation of the rotational
potential energy profile about the inter-annular bond of such
molecules.
Assuming the four iodine atoms are adjacent to the C6–C7
bond, we selected biphenyl systems containing two further
iodine atoms in the 4,4Ј positions as target molecules. This gives
molecules with an iodine content as high as 70 to 75%. The
relative arrangement of the iodine atoms on each ring was
chosen since o,oЈ,p-triiodination of the aromatic ring with ICl is
smoothly achieved provided that a suitable activating group is
present.11 Accordingly, hydroxy groups, in a position meta to
the inter-annular bond, were chosen. In addition, such groups
could act as either ionizable functions or pivots to attach
hydrophilic substituents. Starting materials for our biphenyl
systems were 1,1Ј-biphenyl-3,3Ј,5,5Ј-tetrol12 3 (Scheme 1) and
1,1Ј-biphenyl-3,3Ј-diol13 4 (Scheme 2), which are compounds
well known in the literature.
The iodination of 3 with ICl at neutral pH did not allow the
isolation of any iodinated tetrol 5. This negative result is likely
to be related to the instability of 5 under the reaction con-
ditions. However, under acidic conditions the iodination
proceeded to completion, albeit slowly. For this reason 3 was
iodinated at 36 ЊC for 4 days in H2O–CH3CN–MeOH (Scheme
1). The reaction medium was selected to circumvent the poor
solubility in water of 3 and of the corresponding iodinated
species. As expected, the iodination of the less activated diol 4
to afford 6 required even higher temperatures and longer
reaction times (Scheme 2).
The solid state structures deposited in the Cambridge Struc-
tural Database (CSD)10 which contain the biphenyl fragment
and feature the presence of either four halogen atoms or four
bulky C groupings at the 2,2Ј,6,6Ј positions have been retrieved.
Attention has been paid to the torsion about the C6–C7 bond
and to the inter-atomic distances between the ortho atoms. The
polar histograms (Fig. 1) concerning the above retrieved frag-
ments are evidence that the chance of a reorientation about
the C6–C7 linkage, i.e. the range of angular values allowed for
the above torsion, is rather small. In addition, as expected, the
larger the ortho-substituents the more perpendicular the
dihedral angle defining the relative orientation of the two
phenyl rings, thus allowing the ortho atoms to lie as far apart as
possible. Nevertheless, the observed inter-atomic distances for
the tetra-halogen derivatives (no iodo derivatives were found in
the CSD) progressively approach the sum of the van der Waals
radii going down the 7A group: the minimum X ؒ ؒ ؒ X distances
are 2.680, 3.746 and 3.973 Å for X = F, Cl and Br, respectively.
We decided to monitor the energy profile for the C6–C7
torsion by means of a systematic search procedure performed
on 2,2Ј,6,6Ј-tetrahalogen biphenyl derivatives (X = F, Cl, Br,
I).‡ Quantitative results are summarised in Fig. 2. As has
‡ The analogous conformational search performed on the biphenyl has
determined the absolute minimum energy to be at a dihedral angle
about the C6–C7 bond of 0 or 180Њ, thus reproducing the planar geom-
etry usually observed in the solid state (the gauche conformation is 1.1
kcal molϪ1 higher). Conversely, a maximum was observed when the two
phenyl rings are at 90Њ to each other (the energy barrier is ca. 14 kcal
molϪ1). Thus the used force field appears to overestimate the π-
resonance term with respect to the non-bonding repulsion interactions.
As a consequence, it seems appropriate to compare our computational
results with solid state structures rather than with vapour phase data.
As mentioned before, tetrol 5 proved unstable toward bases
in the presence of oxygen. Such instability is evidenced by
massive loss of I2 and IϪ. Indeed, degradation of 2,4,6-
triiodoresorcinol under aqueous basic conditions with loss of
iodine is known.14 Furthermore, it has been reported that,
besides the well known oxidation of 1,2- and 1,4-dihydroxy-
benzenes to the corresponding quinones, oxygen can promote
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we converted 5 into 7 in order to study various conditions
for the alkylation of phenol groups. A screening procedure
involving different solvents (aqueous mixtures vs. dipolar
aprotic solvents), bases (NaOH, K2CO3, MeONa and tertiary
amines) and sources of the ethyl residue (EtBr, Et2SO4 and
EtONs) was performed. Several experimental conditions led to
very complicated mixtures of partially alkylated compounds.
However, two sets were identified as the best alkylation con-
ditions: i) H2O–dioxane, NaOH, room temperature and ii)
DMF, N,N-diisopropylethylamine, 50 ЊC. The former con-
ditions were used to react 5 and EtONs to give 7 in 71% yield on
a preparative scale, whereas the latter allowed the conversion of
5 into 8 in 66% yield using tert-butyl bromoacetate as the alkyl-
ating agent (Scheme 1). Tetraester 8 was deprotected with
trimethylsilyl iodide to the corresponding tetraacid 9, which,
after conversion into the tetrachloride, led to the tetraamide 10
by reaction with the appropriate amine.
The alkylation of the biphenyldiol 6 (Scheme 2) proved
much easier than that of 5 since the disalt of the former is not
sensitive to oxygen. Reaction of 6 with the nosyl derivative of
2,2-dimethyl-1,3-dioxolane-4-methanol 11 (MeONa, DMF,
50 ЊC) gave 12, which was deprotected to give 13 with toluene-p-
sulfonic acid in MeOH. Both compounds 12 and 13 were
obtained as diastereomeric mixtures. Analogously, reaction of 6
with methyl bromoacetate gave the diester 14. Saponification
with aq. NaOH to the diacid 15, conversion into the dichloride
and then reaction with the amine yielded the diamide 16.
It is noteworthy that monomeric triiodinated analogues of
diamide 16 afforded, under Smiles’ rearrangement conditions,
products displaying very high solubility in water.16 Accordingly,
diamide 16 was treated with MeONa in DMF–MeOH (i.e.
typical Smiles’ rearrangement conditions for iodinated sub-
strates)17 (Scheme 3). Both products, derived from rearrange-
Scheme 1 Reagents and conditions: i ICl, H2O–CH3CN–MeOH, 36 ЊC,
4 d; ii ethyl nitrobenzene-p-sulfonate (EtONs), NaOH, dioxane–H2O,
rt, 43 h; iii BrCH2CO2tBu, EtiPr2N, DMF, 40 ЊC, 7 h; iv TMSI, CH2Cl2,
0–5 ЊC, 1 h; v a) SOCl2, reflux, 5 h, b) NH2(CH2CH2O)2H, dioxane–
DMF, rt, 4 h.
Scheme 3
ment at two or one amide moieties (i.e. 17 and 18, respectively),
were isolated by chromatography.
Single crystals of some of the hexaiodinated derivatives were
grown (see Experimental section) and submitted to X-ray
diffractometry.
The solid state structures of compounds 5, 7 and 13 (Fig. 3)
confirmed the expected almost perpendicular relative dis-
position of the phenyl rings about the C6–C7 bond. Indeed, the
dihedral angle between the aromatic mean planes is 85.9(4),
85.7(8) and 88.0(9)Њ in 5, 7 and 13, respectively. In addition,
in each compound there is a couple of halogen atoms whose
deviation from the mean plane of the linked aromatic ring is
approximately an order of magnitude greater than that of the
remaining iodine atoms (the largest deviation being Ϫ0.179(3)
Å for I1 in 7). In all cases this shift from the C6 mean plane also
helps to move the four ortho halogen atoms away from each
other. Nevertheless, the inter-atomic distances between these
halogen atoms, which range between 4.238(3) and 4.478(5) Å,
are close to twice the van der Waals radius of the iodine atom
Scheme 2 Reagents and conditions: i ICl, H2O–CH3CN–MeOH, 60 ЊC,
20 d; ii 11, MeONa, DMF, 50 ЊC, 76 h; iii PTSA, MeOH, 25 ЊC (72 h)
then 40 ЊC (15 h); iv BrCH2CO2Me, MeONa, DMF, 45 ЊC, 4.5 h;
v NaOH, dioxane–H2O, 50 ЊC, 9 h; vi a) SOCl2, 70 ЊC, 2.5 h, b)
NH2(CH2CH2O)2H, DMF, rt, 3 h.
an oxidative degradation of 1,3-dihydroxylated aromatic
systems to give 2-hydroxy-1,4-quinonic species.15 Degradation
of tetrol 5 by this mechanism justifies the presence of free
iodine in the degradation mixtures. However, when deproton-
ated in previously degassed solvents and in inert atmosphere, 5
is perfectly stable and can be successfully alkylated (vide infra).
Since handling of the tetrasalt of 5 did not appear to be easy,
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salts of the latter allowed highly concentrated solutions in water
(up to 600 mg mlϪ1 for 9) to be obtained. However, since “non-
ionic” contrast agents are usually safer, 9 and 15 were converted
into the amides 10 and 16, which bear hydrophilic fragments.
Since functionalization of the phenolic groups ineluctably leads
to a decreased iodine content of the molecule, we also planned
the synthesis of compound 13, which contains rather small and
compact hydrophilic fragments. Unfortunately, all the com-
pounds potentially useful as “non-ionic” contrast media, which
we prepared from the hexaiodinated biphenyl backbones (i.e.
10, 13, 16–18), showed exceedingly low solubilities in H2O
(i.e. < 5 mg mlϪ1).
In conclusion, we have shown that the hexaiodinated
biphenyl skeleton can be used as the building block for the
preparation of molecules displaying a very high iodine content.
X-Ray crystal structures of some of these derivatives show that
the four iodine atoms in 2,2Ј,6,6Ј positions mask each other to a
great extent and force the two aromatic rings to lie in nearly
perpendicular planes. These results are in accord with pre-
dictions obtained by means of molecular mechanics studies. We
have obtained compounds of this series which, after conversion
into the corresponding salts at neutral pH give rise to highly
concentrated aqueous solutions. However, to date the right
combination of hydrophilic residues which has to be introduced
in the hexaiodinated biphenyl moiety in order to achieve highly
water soluble compounds without taking advantage of ioniz-
able functions (i.e. “non-ionic” compounds) has still to be
found.
Experimental
Mps (ЊC, uncorrected) were measured with a Büchi 510
instrument. Mass spectra were recorded on a TSQ700 Finnigan
Thermoquest instrument. 13C-NMR spectra were recorded at
50.3 MHz on a Bruker AC-200 spectrometer. 1,1Ј-Biphenyl-
3,3Ј,5,5Ј-tetrol 3 and 1,1Ј-biphenyl-3,3Ј-diol 4 were prepared by
the Ullman reaction from 3,5-dimethoxy(iodo)benzene18 and
3-iodoanisole,19 respectively, followed by deprotection with
BBr3 according to McOmie et al.13
Fig. 3 ORTEP views of the crystal structures of 5, 7 and 13.
(2.15 Å). Therefore, the torsional degree of freedom about the
C6–C7 bond appears very limited making the overall structures
rather stiff (vide supra).
The phenyl-bound oxygen atoms lie in the mean planes of the
phenyl rings, with the exception of O1 in compound 13, which
shows a deviation comparable to those of the iodine atoms
(0.12(2) Å). The geometrical constraints of the sp2 aromatic
carbon atoms result in very short inter-atomic mean I–O dis-
tances (3.2(1), 3.15(2) and 3,16(3) Å in 5, 7 and 13, respectively)
if compared with the sum of the oxygen (1.35 Å) and iodine
(2.15 Å) van der Waals radii.
The ethyl ether side chains of compound 7 all display a trans
conformation, while the two identical side arms of 13 are char-
acterised by a trans–gauche–trans sequence of dihedral angles.
Concerning the crystal packing, with the exception of
compound 5, where all the hydrogens of the OH groupings
interact via H-bonds with the carbonyl oxygen atoms of the
co-crystallised acetone molecules, there are no significant
intermolecular interactions.
2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl-3,3Ј,5,5Ј-tetrol (5)
To a solution of 1,1Ј-biphenyl-3,3Ј,5,5Ј-tetrol 3 (21.8 g; 0.10
mol) in 1 : 1 H2O–CH3CN (1.26 l) stirred at rt, a solution of ICl
(155.9 g; 0.96 mol) in 37% HCl (130 ml) was added over 50 min.
The reaction mixture was stirred at 36 ЊC for 4 days while
MeOH (2.28 l total) was added in portions from time to time in
order to maintain a clear solution. The solution was concen-
trated to 1.5 kg and diluted with H2O (0.5 l). The precipitate
was filtered, washed with H2O, dried, then slurried at first with
MeOH (240 ml) at rt, then three times with acetone (270 ml) at
Ϫ20 ЊC and finally suspended in H2O (220 ml). After filtration
and drying, 5 (77.6 g; 80%) was obtained as white crystals. Mp
210 ЊC (dec.) (Found: C, 15.0; H, 0.5; I, 77.8; O, 6.7. C12H4I6O4
requires C, 14.8; H, 0.4; I, 78.2; O, 6.6%); δC (CD3OD) 158.0
(C-3, s), 155.9 (C-1, s), 78.8 (C-2, s), 75.0 (C-4, s); MS (ESIϪ,
MeOH) m/z 972 (M Ϫ H)Ϫ. Single crystals suitable for X-ray
diffractometry were obtained by slow cooling to rt of a solution
of 5 in acetone prepared at 50 ЊC.
As mentioned above, effective contrast media must give rise
to highly concentrated solutions in H2O. The solubilisation can
be reached by either formation of salts of ionizable functions
(i.e. leading to “ionic” contrast media) or, more preferably, by
introducing suitable hydrophilic residues into the molecular
skeleton (i.e. leading to “non-ionic” contrast media).1
3,3Ј,5,5Ј-Tetraethoxy-2,2Ј,4,4Ј,6,6Ј-hexaiodo-1,1Ј-biphenyl (7)
In this respect, the possibility of obtaining stable solutions of
5 by conversion into the corresponding salt of the phenolic
functions is prevented by the instability of 5 (vide supra). As
expected, the behaviour of 6 towards bases is completely differ-
ent so that it can be easily solubilised in H2O by treatment with
bases, but the pH required (> 10) is not compatible with in vivo
administration. In order to achieve soluble compounds at
physiological pH (i.e. 7.4), 5 and 6 were converted into the
acetic derivatives 9 and 15, respectively. Indeed, the sodium
A 1 M aq. solution of NaOH (120 ml) was quickly added to a
solution of 5 (29.2 g; 0.03 mol) in previously degassed 2.5 : 1
dioxane–H2O (840 ml), stirred at rt while nitrogen was bubbled
into the solution. A solution of 4-nitrobenzenesulfonic acid
ethyl ester (30.5 g; 0.132 mol) in degassed dioxane (300 ml) was
then added dropwise over 20 min. The reaction mixture was
stirred at rt for 43 h while 1 M NaOH (20 + 10 ml) was added as
the pH became neutral. The precipitate was filtered, washed
with H2O and dried. The crude product was dissolved in
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dioxane (455 ml) and the solution was diluted with 1 M NaOH
(5.1 ml) and H2O (360 ml) (since the main impurity is the
trialkylated compound, NaOH was added in order to form a
salt of the residual phenolic function and allow its dissolution
in the mother liquor). The precipitate was filtered, washed with
H2O and the treatment was repeated. After drying, 7 (24.0 g;
71%) was obtained as a white powder. Mp 174–175 ЊC (from
dioxane–H2O) (Found: C, 23.7; H, 2.15; I, 67.5. C20H20I6O4ؒ0.5
C4H8O2 requires C, 23.4; H, 2.1; I, 67.4%); δC (DMSO-d6) 159.9
(C-3, s), 155.5 (C-1, s), 92.1 (C-2, s), 89.3 (C-4, s), 68.9 (CH2, t),
15.3 (CH3, q); MS (ESI+, MeOH) m/z 1109 (M + H + Na)+.
Single crystals suitable for X-ray diffractometry were obtained
by slow evaporation of a solution of 7 in CHCl3.
and the oily residue was added to H2O (700 ml). The precipitate
was filtered and purified by flash-chromatography [silica gel;
CH2Cl2–EtOH gradient (7 : 1 to 1 : 1)] to afford 10 (7.71 g;
50%) as a white solid. Mp 181–183 ЊC (Found: C, 27.7; H, 3.1;
I, 48.9; N, 3.6. C36H48I6N4O16 requires C, 27.8; H, 3.1; I, 49.0; N,
3.6%); δC (DMSO-d6) 166.2 (CO, s), 158.5 (C-3, s), 155.6 (C-1,
s), 92.6 (C-2, s), 89.1 (C-4, s), 72.2 (CH2CH2OH, t), 70.2
(NHCH2CH2, t), 68.7 (CH2CO, t), 60.3 (CH2OH, t), 38.3
(NHCH2); MS (ESI+, MeOH) m/z 1577 (M + Na)+.
2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl-3,3Ј-diol (6)
To a solution of 1,1Ј-biphenyl-3,3Ј-diol 4 (13.4 g, 0.072 mol) in
1 : 1 H2O–CH3CN (900 ml) stirred at rt, a solution of ICl (111
g; 0.684 mol) in 37% HCl (93 ml) was added. The reaction
mixture was stirred at 60 ЊC for 20 days while MeOH (2.7 l
total) was added from time to time in order to maintain a clear
solution. The solution was concentrated causing precipitation
of the crude product. The suspension was diluted with H2O
(500 ml), stored overnight at 5 ЊC and filtered. After drying, the
crude was dissolved in EtOAc (400 ml), the solution was
washed with 5% aq. Na2S2O3 (400 ml) and H2O (400 ml) then
dried. After evaporation, 6 (51.7 g; 76%) was obtained as a
whitish solid. Mp 270 ЊC (dec.) (Found: C, 15.8; H, 0.5; I, 79.4;
O, 4.0. C12H4I6O2 requires C, 15.3; H, 0.4; I, 80.9; O, 3.4%); δC
(acetone–d6) 157.1 (C-3, s), 156.1 (C-1, s), 148.8 (C-5, d), 91.1,
88.4, 85.5 (C-2, C-4, C-6, 3 × s); MS (ESIϪ, MeOH) m/z 941
(M Ϫ H)Ϫ.
2,2Ј,2ЈЈ,2ЈЈЈ-([2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј,5,5Ј-
tetrayltetraoxy)tetraacetic acid tetrakis(1,1-dimethylethyl ester)
(8)
N,N-Diisopropylethylamine (72.4 g; 0.56 mol) and bromoacetic
acid 1,1-dimethylethyl ester (81.9 g; 0.42 mol) were added in
sequence to a solution of 5 (68.15 g; 0.07 mol) in degassed
DMF (1.4 l) stirred at rt under a nitrogen atmosphere. After 7 h
at 40 ЊC the solvent was evaporated. The residue was suspended
in dioxane (1 l) and stirred at rt for 2 h. After filtration, the
brown solution was diluted with H2O (500 ml) and seeded. The
precipitate was filtered, washed with 2.5 : 1 dioxane–H2O, then
with H2O and dried to afford 8 (49.2 g; 49%) as a white solid.
The mother liquor and the washings, combined and diluted
with H2O (700 ml), afforded a crude product that was
analogously purified to give a second crop of 8 (17.2 g; 17%) as
a white solid. Mp 168–170 ЊC (from dioxane–H2O) (Found: C,
30.4; H, 3.0; I, 53.3; O, 13.3. C36H44I6O12 requires C, 30.2; H,
3.1; I, 53.2; O, 13.4%); δC (CDCl3) 166.0 (CO, s), 159.4 (C-3, s),
155.7 (C-1, s), 90.7 (C-2, s), 87.7 (C-4, s), 82.4 (C(CH3)3, s), 69.1
(CH2CO, t), 28.1 (CH3, q); MS (ESI+, MeOH–acetone) m/z
1453 (M + Na)+.
4-Nitrobenzenesulfonic acid (2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl ester (11)
A solution of triethylamine (51.1 g; 0.505 mol) in CH2Cl2 was
added dropwise over 45 min into a solution of 4-nitro-
benzenesulfonyl chloride (104.2 g; 0.470 mol) and 2,2-dimethyl-
1,3-dioxolane-4-methanol (66.7 g; 0.505 mol) stirred at 0–5 ЊC.
After 1 h triethylamine hydrochloride was filtered off and the
solution was washed with H2O (150 ml), 4% aq. NaHCO3 (100
ml) and H2O (3 × 150 ml), dried and evaporated. The crude
product was purified by crystallisation from 8 : 5 n-hexane–
THF (700 ml) to afford 11 (112.66 g; 76%) as a white solid. Mp
85–86 ЊC (Found: C, 45.9; H, 5.0; N, 4.4; S, 9.9. C12H15NO7S
requires C, 45.4; H, 4.8; N, 4.4; S, 10.1%); δC (CDCl3) 150.7
(C-4, s), 141.4 (C-1, s), 129.3 (C-2, d), 124.4 (C-3, d), 110.1 (C, s),
72.7 (CH, d), 70.7 (SO3CH2, t), 65.6 (CH(O)CH2O, t), 26.5,
24.9 (CH3, 2 × q); MS (ESI+, MeOH) m/z 340 (M + Na)+.
2,2Ј,2ЈЈ,2ЈЈЈ-([2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј,5,5Ј-
tetrayltetraoxy)tetraacetic acid (9)
Trimethylsilyl iodide (36.0 g; 0.18 mol) was added dropwise
over 30 min into a solution of 8 (42.9 g; 0.03 mol) in CH2Cl2
(400 ml) stirred at 0–5 ЊC. After 30 min, 4% aq. NaHCO3 (410
ml) was added under vigorous stirring. After separation, the
organic layer was extracted with 4% aq. NaHCO3 (2 × 50 ml).
The aqueous phases were combined, washed with CH2Cl2
(2 × 100 ml), concentrated, decolourised with charcoal and
adjusted to pH 1.8 with 37% aq. HCl to precipitate a whitish
solid. After filtration the crude precipitate was dissolved in H2O
(600 ml) by addition of 1 M NaOH (96 ml) and the solution
was adjusted to pH 1.7 with 1 M aq. HCl (140 ml). The precip-
itate was filtered, washed with H2O and dried to give 9 (33.7 g;
93%) as a white solid. Mp 284 ЊC (dec.) (Found: C, 19.9; H, 1.0;
I, 63.1; O, 15.7. C20H12I6O12 requires C, 19.9; H, 1.0; I, 63.15; O,
15.9%); δC (D2O + KOD) 178.8 (CO, s), 162.2 (C-3, s), 158.4
(C-1, s), 93.3 (C-2, s), 90.8 (C-4, s), 90.8 (CH2, t); MS (ESI+,
MeOH–H2O) m/z 1228 (M Ϫ H + Na)+.
3,3Ј-Bis[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-
2,2Ј,4,4Ј,6,6Ј-hexaiodo-1,1Ј-biphenyl (12)
A 1.05 M solution of MeONa in MeOH (62.9 ml; 66 mmol)
was added to a solution of 6 (31.07 g; 33 mmol) in DMF (300
ml) stirred at rt, then MeOH was evaporated and 11 (24.10 g;
76 mmol) was added. The reaction mixture was stirred at 50 ЊC
for 76 h. As the solution became neutral, K2CO3 (2 × 2.28 g; 32
mmol) and additional 11 (3.10 g; 10 mmol) were added. After
64 h at rt the reaction mixture was concentrated to about half
volume, the inorganic salts were filtered off and the solvent was
evaporated. The oily residue was vigorously stirred with H2O
(350 ml) at rt overnight to afford a solid that was filtered,
washed with H2O and dried. The crude product was purified by
solvation in dioxane (360 ml) followed by dilution with 1 M aq.
NaOH (12 ml) and H2O (230 ml) to give a two-phase system.
The lower layer was separated and stirred with H2O (600 ml) at
rt overnight. After filtration, washing with H2O and drying, 12
(32.12 g; 83%) was obtained as a whitish solid. Mp 77–110 ЊC
(broad softening range) (Found: C, 25.5; H, 2.2; I, 63.55.
C24H24I6O6 requires C, 24.6; H, 2.1; I, 65.1%); δC (DMSO-d6)
163.3 (C-3, s), 160.3 (C-1, s), 152.9 (C-5, d), 114.2 (C(CH3)3, s),
103.6, 100.6, 98.1 (C-2, C-4, C-6, 3 × s), 78.9 (CH, d), 78.1
(ArOCH2, t), 71.4 (CHCH2O, t), 32.2, 30.7 (CH3, 2 × q); MS
(ESI+, MeOH–NaCl) m/z 1192 (M + Na)+, 1208 (M + K)+.
N,NЈ,NЈЈ,NЈЈЈ-Tetrakis[2-(2-hydroxyethoxy)ethyl]-2,2Ј,2ЈЈ,2ЈЈЈ-
([2,2Ј,4,4Ј,6,6Ј-hexaiodo-1,1Ј-biphenyl]-3,3Ј,5,5Ј-tetrayltetra-
oxy)tetraacetamide (10)
Quinoline (13 mg; 0.1 mmol) was added to a suspension of 9
(12.06 g; 10 mmol) in SOCl2 (47.60 g; 400 mmol) then the
mixture was refluxed for 5 h. Cooling to rt led to the precip-
itation of the crude tetrachloride which was filtered, washed
with n-hexane and dried. Without further purification the crude
tetrachloride was dissolved in 5 : 1 dioxane–DMF (60 ml) and
the solution added dropwise over 1 h into a solution of 2-(2-
aminoethoxy)ethanol (12.60 g; 120 mmol) in 5 : 1 dioxane–
DMF (70 ml) stirred at rt. After 4 h the solvent was evaporated
J. Chem. Soc., Perkin Trans. 1, 2001, 1175–1181
1179

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3,3Ј-([2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј-diyldioxy)-
dipropane-1,2-diol (13)
C24H26I6N2O8 requires C, 23.4; H, 2.1; I, 61.8; N, 2.3%); δC
(DMSO-d6) 166.2 (CO, s), 157.3 (C-3, s), 154.9 (C-1, s), 147.7
(C-5, d), 98.1, 95.9, 92.8 (C-2, C-4, C-6, 3 × s), 72.2
(CH2CH2OH, t), 70.3 (NHCH2CH2, t), 68.7 (CH2CO, t), 60.3
(CH2OH, t), 38.4 (NHCH2); MS (ESI+, MeOH–H2O) m/z 1254
(M + Na)+.
PTSAؒH2O (0.42 g; 2.2 mmol) was added to a solution of 12
(25.79 g; 22 mmol) in MeOH (250 ml) stirred at rt. After 72 h,
additional PTSAؒH2O (0.42 g; 2.2 mmol) was added and the
solution heated at 40 ЊC for 15 h. The reaction mixture was
concentrated to about half volume and purified by preparative
HPLC [stationary phase: Lichroprep RP-18 25–40 µm
(250 × 50 mm column); mobile phase: 65 : 35 to 20 : 80 H2O–
CH3CN gradient] to afford 13 (17.77 g; 74%) as a white solid.
Mp 183–186 ЊC (Found: C, 19.95; H, 1.45; I, 69.7. C18H16I6O6
requires C, 19.8; H, 1.5; I, 69.9%); δC (DMSO-d6) 158.6 (C-3, s),
155.0 (C-1, s), 147.5 (C-5, d), 98.4, 94.9, 92.7 (C-2, C-4, C-6,
3 × s), 74.5 (ArOCH2, t), 70.5 (CH, d), 63.5 (CH2OH, t); MS
(ESI+, MeOH) m/z 1112 (M + Na)+. Several attempts to obtain
single crystals suitable for X-ray diffraction were made. Finally,
by slow evaporation of a solution of 13 in H2O–CH3CN single
crystals were obtained, however their diffraction quality was
rather poor (vide infra).
N,NЈ-[2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј-diyl-N,NЈ-
bis[2-(2-hydroxyethoxy)ethyl]diacetamide (17) and N-[2-(2-
hydroxyethoxy)ethyl]-2-[3-(3-{(2-hydroxyacetyl)[2-(2-hydroxy-
ethoxy)ethyl]amino}-2,4,6-triiodophenyl)-2,4,6-triiodophenyl-
oxy]acetamide (18)
A 1.12 M solution of MeONa in MeOH (38 ml; 42.6 mmol)
was added to a solution of 16 (21 g; 17 mmol) in DMF (730
ml)–MeOH (50 ml) stirred at rt. After 10 min the solution was
acidified by addition of 1 M HCl in MeOH (80 ml; 80 mmol)
and evaporated. The oily residue was suspended in H2O (500
ml) and stirred overnight, then the solid was filtered and dried.
The crude product was purified by column chromatography
[silica gel; CHCl3–EtOH gradient (92 : 8 to 85 : 15)] to give 17
(8.78 g; 42%) and 18 (2.30 g; 11%) as white solids. Compound
17: mp 198–205 ЊC (Found: C, 23.4; H, 2.1; I, 61.6; N, 2.3.
C24H26I6N2O8 requires C, 23.4; H, 2.1; I, 61.8; N, 2.3%);
δC (DMSO-d6) 170.9 (CO, s), 155.8, (C-1, s), 148.6, (C-5, d),
145.4 (C-3, s), 108.3, 102.7, 101.0 (C-2, C-4, C-6, 3 × s), 72.3,
(CH2CH2OH, t), 67.5 (COCH2, t), 61.5 (NCH2CH2, t), 60.1
(CH2CH2OH, t), 48.3 (NCH2, t); MS m/z (ESI+, MeOH–
CHCl3) 1254 (M + Na)+. Compound 18: mp 75–120 ЊC (broad
softening range) (Found: C, 23.5; H, 2.0; I, 61.7; N, 2.3.
C24H26I6N2O8 requires C, 23.4; H, 2.1; I, 61.8; N, 2.3%);
δC (DMSO-d6) 170.9 (NCO, s), 166.2 (CONH, s), 157.5 (C-3, d),
155.4, 155.3 (C-1, C-1Ј, 2 × s), 148.5, 147.8 (C-5, C-5Ј, 2 × d),
145.3 (C-3Ј, d), 108.4, 102.6, 101.0 (C-2Ј, C-4Ј, C-6Ј, 3 × s),
98.0, 95.9, 92.9 (C-2, C-4, C-6, 3 × s), 72.3, 72.2 (CH2CH2OH,
2 × t), 70.3 (NHCH2CH2, t), 68.7 (CH2CONH, t), 67.5
(COCH2OH, t), 61.5 (NCH2CH2, t), 60.3, 60.1 (CH2CH2OH,
2 × t), 48.3 (NCH2, t), 39.4 (NHCH2CH2O); MS (ESI+,
MeOH–CHCl3) m/z 1254 (M + Na)+.
2,2Ј-([2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј-diyldioxy)-
diacetic acid dimethyl ester (14)
A 1.1 M solution of MeONa in MeOH (63 ml; 69.3 mmol) was
added to a solution of 6 (28.2 g; 29.9 mmol) in DMF (240 ml)
stirred at rt, then MeOH was evaporated and bromoacetic acid
methyl ester (11.2 g; 73.2 mmol) was added. After 4.5 h at 45 ЊC,
the solvent was evaporated and the oily residue was stirred with
H2O (300 ml). The resulting solid was filtered, washed with H2O
then stirred with MeOH (300 ml) at 50 ЊC for 30 min and at rt
for 15 h. The solid was filtered, washed with MeOH and dried
to afford 14 (30 g; 92%) as a white solid. Mp 174–177 ЊC
(Found: C, 19.95; H, 1.15; I, 70.1. C18H12I6O6 requires C, 19.9;
H, 1.1; I, 70.1%); δC (DMSO-d6) 167.3 (CO, s), 157.5 (C-3, s),
154.9 (C-1, s), 147.7 (C-5, d), 98.0, 95.9, 92.7 (C-2, C-4, C-6,
3 × s), 68.7 (CH2, t), 52.1 (CH3, q); MS (ESI+, acetone–MeOH–
NaCl) m/z 1108 (M + Na)+.
2,2Ј-([2,2Ј,4,4Ј,6,6Ј-Hexaiodo-1,1Ј-biphenyl]-3,3Ј-diyldioxy)-
diacetic acid (15)
Computational details
A 1 M aq. solution of NaOH (46 ml; 46 mmol) was added over
9 h to a solution of 14 (24.9 g; 22.9 mmol) in 4 : 1 dioxane–H2O
(375 ml) stirred at 50 ЊC and maintaining pH at 10.5–11.5. After
adjusting to pH 8.5 with 2 M HCl, the solvent was evaporated
and the residue was dissolved in H2O (300 ml). The solution
was decolourised with charcoal and poured into 0.28 M aq.
HCl (210 ml; 58.8 mmol) under vigorous stirring. The precipi-
tate was filtered, washed with H2O and dried to give 15 (23.1 g;
95%) as a white solid. Mp 162–166 ЊC (Found: C, 18.2; H, 0.8;
I, 72.2. C16H8I6O6 requires C, 18.2; H, 0.8; I, 72.0%); δC
(DMSO-d6) 168.2 (CO, s), 157.6 (C-3, s), 154.9 (C-1, s), 147.6
(C-5, d), 98.0, 95.7, 92.7 (C-2, C-4, C-6, 3 × s), 68.5 (CH2, t);
MS (ESI+, acetone–MeOH) m/z 1056 (M + Na)+.
Conformational searches and molecular dynamics (MD)
simulations were performed on the 2,2Ј,6,6Ј-tetrahalogen
substituted biphenyl derivatives by using the InsightII (98.0)
package supplied by MSI20 and implemented on an IBM 3AT
computer. Model built molecules were used as starting
structures for all the derivatives; before performing the conform-
ational search and the MD protocols the geometry of each
compound was fully optimised by using the CFF91 force field
provided by the Discover® module. The conformational search
was carried out about the inter-annular C6–C7 bond by rotat-
ing it in constant steps of 10Њ (range 0–180Њ) and the energetics
of each conformation was evaluated by means of the CFF91
force field. MD simulations were performed in a vacuum at 300
and 600 K. In each case the equilibration procedure lasted 15 ps
and the trajectories were monitored for 1500 ps, snapshot
conformations were saved every ps.
N,NЈ-Bis[2-(2-hydroxyethoxy)ethyl]-2,2Ј-([2,2Ј,4,4Ј,6,6Ј-
hexaiodo-1,1Ј-biphenyl]-3,3Ј-diyldioxy)diacetamide (16)
Quinoline (13 mg; 0.1 mmol) was added to a suspension of 15
(32.34 g; 30.6 mmol) in SOCl2 (147.5 g; 1.24 mol), then the
mixture was heated at 70 ЊC for 2.5 h. The pale yellow solution
was concentrated to about 90 g and allowed to cool to rt. After
1 h the crystalline precipitate was filtered, washed with n-
hexane and dried. The chloride thus obtained was dissolved in
DMF (100 ml) and the solution was quickly added to a solution
of 2-(2-aminoethoxy)ethanol (12.60 g; 120 mmol) in DMF (1 l)
stirred at rt. After 3 h the solvent was evaporated and the oily
residue was stirred with H2O (400 ml) to afford a crude solid
that was purified by flash-chromatography [CHCl3–96% EtOH
(95 : 5)]. Compound 16 (23.5 g; 62%) was obtained as a white
solid. Mp 197–200 ЊC (Found: C, 23.4; H, 2.1; I, 61.9; N, 2.3.
Crystal structure determination of compounds 5, 7 and 13—
crystal data
Unit cell parameters and intensity data for compounds 5, 7 and
13 were obtained with a Nonius CAD4 diffractometer by using
a graphite monochromated Mo-Kα radiation. Cell parameters
were determined by least-squares fitting of 25 centered reflec-
tions for all the structures. Intensity data were corrected for
Lorentz and polarization effects. Structures were solved using
the SIR97 program21 and subsequently refined by the full-
matrix least squares method of SHELXL97.22 Absorption
corrections were applied once the structures were solved using
1180
J. Chem. Soc., Perkin Trans. 1, 2001, 1175–1181

View Article Online
the Walker and Stuart method.23 The hydrogen atoms of 5, 7
and 13 were introduced at calculated positions and their
coordinates refined in agreement with those of the linked atoms
with overall isotropic temperature factors refined to 0.09(4),
0.08(3) and 0.07(2) Å2, respectively. In all cases the iodine atoms
were refined anisotropically. The same refinement was applied
to the oxygen atoms of 5 and 13 and the carbon atoms of 5. For
the remaining atoms individual isotropic temperature factors
were used. Concerning compound 13, the rather high R indices
could be ascribed to the poor quality of the crystal sample.
Only the racemic mixture of the two enantiomers, having
opposite stereochemical configuration at the two stereogenic
carbon atoms, crystallizes. Geometrical calculations were
performed by PARST97.24 The molecular plots were produced
by ORTEP.25
Compound 5. C12H4I6O4ؒ3C3H6O, M = 1147.8, monoclinic,
a = 13.818(3), b = 16.400(6), c = 14.252(3) Å, β = 106.10(2)Њ,
V = 3103(2) Å3, T = 298 K, space group P21/c, Z = 4, µ = 6.04
mmϪ1, 4259 reflections collected, 4063 unique, final R indices
R1 = 0.0497 (I > 2σI), R1 = 0.0691 and wR2 = 0.1215 (all data),
312 refined parameters.
Compound 7. C18H16I6O6, M = 1089.71, orthorhombic,
a = 21.361(6), b = 29.226(6), c = 8.776(3) Å, V = 5479(3) Å3,
T = 298 K, space group Ccc2, Z = 8, µ = 6.83 mmϪ1, 2161 reflec-
tions collected, 2161 unique, final R indices R1 = 0.0680
(I > 2σI), R1 = 0.0869 and wR2 = 0.2101 (all data), 182 refined
parameters.
References
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3 U. Speck, Eur. Radiol., 1995, 5, S8.
4 (a) Bracco S.p.A., Italy, EP 0 731 786 B1/1995 (Chem. Abstr.,
1995, 123, 169364); (b) Bracco S.p.A.–Dibra S.p.A., Italy, EP
0 714 879 A1/1996 (Chem. Abstr., 1996, 125, 114277).
5 (a) Guerbet S.A., France, EP 0 501 875 A1/1993 (Chem. Abstr.,
1993, 118, 38602); (b) Guerbet S.A., France, WO 94/04488 (Chem.
Abstr., 1994, 120, 322950).
6 A. Almenningen, O. Bastiansen, L. Fernholt, B. N. Cyvin and S. J.
Cyvin, J. Mol. Struct., 1985, 128, 59.
7 C. P. Brock and R. P. Minton, J. Am. Chem. Soc., 1989, 128, 59.
8 A. Karpfen, C. H. Choi and M. Kertesz, J. Phys. Chem. A, 1997,
101, 7426 and references therein.
9 S. Tsuzuki, T. Uchimaru, K. Matsamura, M. Mikami and
K. Tanabe, J. Chem. Phys., 1999, 110, 2858 and references therein.
10 F. H. Allen and O. Kennard, J. Chem. Soc., Perkin Trans. 2, 1989,
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11 Houben-Weyl Methoden der Organischen Chemie Band V/4, ed.
E. Müller, Georg Thieme Verlag, Stuttgart, 1960, pp. 582–588.
12 (a) Beilstein Handbuch der Organischen Chemie, Vol. 6, eds.
B. Prager, P. Jacobsen, P. Schmidt and D. Stern, Springer Verlag,
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Chemie, Vol. 6 (I supplement), ed. F. Richter, Springer Verlag,
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Vol. 6 (II supplement), ed. F. Richter, Springer Verlag, Berlin,
1944, p. 1129.
13 J. F. W. McOmie and D. E. West, Org. Synth., 1969, 49, 50.
14 F. L. Weitl, M. Sovak, T. M. Williams and J. H. Lang, J. Med.
Chem., 1976, 19, 1359.
15 M. Tateishi,, T. Kusumi and H. Kakisawa, Tetrahedron, 1971, 27,
237.
16 E. Felder, A. Gallotti and A. Favilla, Invest. Radiol., 1988, 3, S101.
17 P. L. Anelli, M. Brocchetta, L. Calabi, C. Secchi, F. Uggeri and
S. Verona, Tetrahedron, 1997, 53, 11919.
18 W. Riedl and F. Imhof, Liebigs Ann. Chem., 1955, 597, 153.
19 J. Van Alphen, Recl. Trav. Chim. Pays-Bas, 1931, 50, 1111.
20 MSI, 9685 Scranton Road, San Diego, CA 92121–3752, USA.
21 A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C.
Burla, G. Polidori and M. Camalli, J. Appl. Crystallogr., 1994, 27,
435.
Compound 13. C20H20I6O4, M = 1085.76, monoclinic,
a = 33.10(3), b = 9.30(2), c = 24.23(1) Å, β = 124.92(7)Њ, V =
6116(15) Å3, T = 298 K, space group C2/c, Z = 8, µ = 6.12
mmϪ1, 3382 reflections collected, 3285 unique, final R indices
R1 = 0.0974 (I > 2σI), R1 = 0.1311 and wR2 = 0.2391 (all data),
172 refined parameters.
CCDC reference numbers 155439–155441. See http://
www.rsc.org/suppdata/p1/b0/b009666k/ for crystallographic
data in CIF or other electronic format.
Acknowledgements
22 G. M. Sheldrick, SHELXL-97, University of Göttingen, Germany,
1997.
23 N. Walker and D. D. Stuart, Acta Crystallogr., Sect. A, 1983, 39, 158.
24 M. Nardelli, Comput. Chem., 1983, 7, 95.
25 C. K. Johnson, ORTEP, Rep. ORNL 3794, Oak Ridge National
Laboratory, TN, USA, 1971.
We thank Professor Attilio Citterio for advise and critical
suggestions in the earlier stages of this work. We are also grate-
ful to the group led by Dr Heinrich Bollinger at Eprova AG,
Schaffhausen, Switzerland for performing the iodination of 4
to 6.
J. Chem. Soc., Perkin Trans. 1, 2001, 1175–1181
1181