Models for thyroxine: Aromatic iodine-assisted self-assemblies

Article abstract of DOI:10.1016/j.poly.2006.11.024

Trying to understand the different recognition factors between thyroxine and its binding proteins, the chemistry of the ternary complexes between copper and o-iodobenzoylglycine (I-hip) [or o-iodobenzoylglycilglycine (B^IGG)] as simple thyroxine models were studied with 2,2′-bipyridyl as secondary ligand. Two new compounds have been synthesized and structurally characterized: [Cu(I-hip)(bpy)₂]⁺(I^-) · 1.5H₂O and [Cu(B^IGG)(bpy)₂]⁺(I^-) · 4H₂O. These compounds and other previously reported by us offer interesting recognition patterns that could have biological relevance: iodine-iodine short interactions, iodine-hydrogen(aliphatic or aromatic) interactions, iodine-metal bonds, iodine-π interactions (like C-H?π), and aromatic self-assemblies assisted by iodine atoms. These patterns can be coupled in a synergistic manner, producing, for instance, a new C-I?π?π?I-C cluster pattern.

Full text of DOI:10.1016/j.poly.2006.11.024

Polyhedron 26 (2007) 1417–1426
www.elsevier.com/locate/poly
Models for thyroxine: Aromatic iodine-assisted self-assemblies
a
a,
a
b
*
´
´
´
Miquel Barcelo-Oliver , Angel Terron , Angel Garcıa-Raso , Elies Molins
a
Departament de Quı´mica, Universitat de les Illes Balears, Campus UIB, Cta. Valldemossa km 7.5, Edifici Mateu Orfila, E-07122 Palma de Mallorca, Spain
b
` `
Institut de Ciencia dels Materials de Barcelona (CSIC), Campus de la Universitat Autonoma, E-08193 Cerdanyola, Spain
Received 18 October 2006; accepted 11 November 2006
Available online 23 November 2006
Dedicated to Professors O. Yamauchi for lend us a hand in locate and give importance to these interactions
and L.G. Marzilli who suggest us to work with o-iodohippurate ligand.
Abstract
Trying to understand the different recognition factors between thyroxine and its binding proteins, the chemistry of the ternary com-
plexes between copper and o-iodobenzoylglycine (I-hip) [or o-iodobenzoylglycilglycine (BIGG)] as simple thyroxine models were studied
with 2,20-bipyridyl as secondary ligand.
Two new compounds have been synthesized and structurally characterized: [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O and [Cu(BIGG)-
(bpy)2]+(Iꢀ) Æ 4H2O. These compounds and other previously reported by us offer interesting recognition patterns that could have
biological relevance: iodine–iodine short interactions, iodine–hydrogen(aliphatic or aromatic) interactions, iodine–metal bonds,
iodine–p interactions (like C–Hꢁ ꢁ ꢁp), and aromatic self-assemblies assisted by iodine atoms. These patterns can be coupled in a syner-
gistic manner, producing, for instance, a new C–Iꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁI–C cluster pattern.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Iodine interactions; Coordination chemistry; Iodohippuric acid; Stacking; Thyroxine models
1. Introduction
role of iodine in these molecules and the binding patterns
involved in their function [13–16], we present a structural
study about the recognition patterns came into play by a
model compound we have selected: ortho-iodohippuric acid
(I-hipH) (Scheme 1), which presents some different kinds of
interaction involving its iodine substituent.
Synthesis of the [Zn(II), Cu(II) and Ag(I) – ortho-
iodohippuric acid] binary complexes and several ternary
complexes has been previously reported: [Zn(I-hip)2-
(OH2)2]2 Æ 3H2O (1) [17], [Ag(I-hip)] Æ 1.25H2O (2) [18],
[Cu(I-hip)2(OH2)3] Æ 2H2O (3) [19], [(Co, Ni or Zn)(I-hip)2-
(acv)(OH2)3] (4) [17] and [Cu(I-hip)(phen)2]+(I-hipꢀ) Æ 7H2O
(5) [19].
Thyroxine, a tetraiodinated derivative of the aminoacid
tyrosine (3:5,30:50-tetraiodothyronine, T4) (see Scheme 1),
is the major thyroid hormone and the natural precursor
for the most active form of this hormone, which has less
iodinated (3:5,30-triiodothyronine, T3). Normally the
99.95% of these two hormones are bounded to carrier pro-
teins principally to thyroxine-binding globulin (TBG), to a
lesser extent thyroxine-binding pre-albumin (TBPA or
transthyretin (TTR)) and to albumin. The free hormone
fractions are metabolically active at the tissue and cellular
level.
The influence of the presence of metal ions in the inter-
action between thyroxine and proteins is a topic of increas-
ing interest [1–12]. In order to understand the important
On the other hand, two new ternary copper (II) com-
plexes with 2,20-bipyridyl (bpy) have been synthesized
and structurally characterized: [Cu(I-hip)(bpy)2]+(Iꢀ) Æ
1.5H2O (6) and [Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O (7). We
have been achieved a revision work about the influence
of iodine atoms on the crystal stabilization according to
*
Corresponding author. Tel.: +34 971 173 249; fax: +34 971 173 426.
´
E-mail address: angel.terron@uib.es (A. Terron).
0277-5387/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2006.11.024

1418
M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
I
9
13
I
O
I
12
11
8
7
10
11
14
9
O
HO
I
O
6
8
10
3
3
5
7
I
O
O
I
HN
O
4
N
H
4
6
5
O
H2N
N
H
2
2
OH
1
OH
OH
1
T4, Thyroxine
o-iodohippuric acid, I-hipH
o-iodobenzoilglycilglycine,BIGG
Scheme 1. Formulae of thyroxine and two model compounds of it: o-iodohippuric acid and o-iodobenzoylglycilglycine.
the new results obtained and the previously reported by us,
in three binary and four ternary complexes involving ortho-
iodohippuric acid derivatives and acyclovir (acv) or 1,10-
phenanthroline (phen).
and the resulting precipitate was filtered off and washed
with cold water. The neutralization-washing process was
repeated three times and finally the crude o-iodobenzoyl-
glycilglycinate sodium salt were washed with diethyl ether,
filtered off and dry at room temperature (yield: 65%).
The isolated product, white powder, was the monohy-
drated sodium salt: sodium o-iodobenzoylglycilglycinate
(BIGG) monohydrate. Anal. Calc. for C11H12IN2NaO5:
C, 32.86; H, 3.01; N, 6.97. Found: C, 32.73; H, 3.12; N,
6.95%. IR (cmꢀ1): 414vw, 433vw, 546m, 586m, 611m,
637m, 680m, 728w, 749m, 775w, 872w, 914vw, 943vw,
985m, 999s, 1015m, 1041w, 1093m (br), 1239s, 1263m,
1293m, 1347m, 1432s, 1443s, 1463m, 1535s, 1587m,
1620vs, 1664s, 1711s, 2043m, 3343vs. 1H NMR ([D6]
DMSO): d 12.03 [bs, 1H, C(2)OO(1)-H], 8.61 [t, 1H,
N(7)-H, J = 5.7 Hz], 8.08 [t, 1H, N(4)-H, J = 5.4 Hz],
7.85 [d, 1H, H(14), J = 7.8 Hz], 7.42 [s(br), 2H, H(11 and
12)], 7.15 [m, 1H, H(13)], 3.85 [d, 2H, C(6)-H2, J =
5.7 Hz], 3.76 [d, 2H, C(3)-H2, J = 5.4 Hz].
2. Experimental
Elemental microanalyses were carried out using a
Thermo Finnigan model Flash 1112 microanalyzer. IR
spectra in the solid state (KBr pellets) were measured in
the 4000–400 cmꢀ1 range on a Bruker IFS 66 spectrometer.
1H NMR spectra were recorded at room temperature on a
Bruker AMX 300 (300 MHz). Proton chemical shifts in
deuterated dimethylsulfoxide ([D6] DMSO) were refer-
enced to [D6] DMSO (d[D6] DMSO: 2.47 ppm).
Reagents were used as received from Sigma, Merck or
Aldrich. o-Iodohippuric acid (o-iodobenzoylglicine) was
prepared according to the literature procedure [20,21] or
supplied by Aldrich. o-Iodobenzoylglycilglycine (BIGG)
was also synthesized according to the general procedure
for hippuric acid [20,21] (see below).
2.2. [Cu(I-hip)(bpy)2]+(I ꢀ) Æ 1.5H2O (6)
Synthesis of binary complexes, [Zn(I-hip)2(OH2)2]2 Æ
3H2O (1) [17], [Ag(I-hip)] Æ 1.25H2O (2) [18] and [Cu-
(I-hip)2(OH2)3] Æ 2H2O (3) [19] are reported previously.
Moreover, we have tried to form some ternary complexes
between these compounds and others ligands: [(Co, Ni or
Zn)(I-hip)2(acv)(OH2)3] (4) [17], [Cu(I-hip)(phen)2]+-
(I-hipꢀ) Æ 7H2O (5) [19], [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O
(6) and [Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O (7).
Basic copper carbonate [CuCO3 Æ Cu(OH)2] (1 mmol)
and I-hipH (3 mmol) in water (100 ml) were refluxed for
2 h, then the excess of insoluble reactants were filtered
off, followed by the addition of solid bpy (3 mmol) and
subsequently the mixture was refluxed for two more hours.
Finally, sodium iodide (1.5 mmol) was added to the solu-
tion to assist the crystallization. This synthesis is similar
to that previously reported to prepare acyclovir ternary
compounds [17]. Green crystals of [Cu(I-hip)(bpy)2]+(Iꢀ) Æ
1.5H2O (6) suitable for X-ray diffraction studies were
obtained after 4–5 days from the parental solution and
has been separated one-to-one of others brown crystals
corresponding to the non-desired reaction by-product
[Cu(I)(bpy)2]+ Æ Iꢀ [22]. The ternary complex obtained
decomposes on air by lose of water molecules (yield: ca.
30%). Repetitions of this synthesis without sodium iodide
addition yield a mixture of two types of crystals corre-
sponding to [Cu(I-hip)(bpy)2]+(I-hipꢀ) Æ 4H2O and a cer-
tain quantity of the previously described ternary complex
2.1. Synthesis of o-iodobenzoilglycilglycinate sodium salt
(BIGG)
Sodium bicarbonate (42 mmol) was added to a solution
of glycilglycine (20 mmol) in water (35 ml). The mixture
was stirred for 1 h until complete solution and o-iodobenzoyl
chloride (20 mmol) was added together with acetone (5 ml)
(in order to increase the solubility and reactivity of the o-
iodobenzoil chloride). The reaction was slightly heated at
50 ꢁC and stirred for 4 h. Subsequently, the reaction mix-
ture was neutralized with HCl of 1 N, stirred for 15 min,

M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
1419
[Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O where the origin of the
iodide counter ion is not clear (an impurity or a decompo-
sition of I-hip).
excess of insoluble reactants were filtered off, followed by
the addition of solid bpy (3 mmol) and subsequently the
mixture was refluxed for two more hours. An oily complex
material was obtained in all attempts. Only one crystal suit-
able for X-ray diffraction studies could be obtained.
[Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O (6): Green crystals.
Anal. Calc. for C29H23CuI2N5O3 (completely dehydrated
sample): C, 43.17; H, 2.87; N, 8.68; I, 31.46. Found: C,
43.19; H, 2.89; N, 7.86; I, 32.14%. IR (cmꢀ1): 417vw,
482vw, 568w, 636w, 661w, 689w, 730m, 745m, 770vs,
831vw, 870vw, 914vw, 949vw, 985vw, 999w, 1014m,
1059vw, 1101w, 1121vw, 1164m, 1254m, 1297m, 1318m,
1382s, 1430m, 1445s, 1459m, 1473s, 1497s, 1513s, 1582vs,
1601s, 1648vs, 1669s, 3059m, 3379m.
2.4. X-ray crystallographic study
Suitable crystals of 6 and 7 were selected for X-ray single
crystal diffraction experiments and mounted at the tip of
glass fibres on an Enraf-Nonius CAD4 diffractometer pro-
ducing graphite-monochromated Mo Ka radiation (k =
[Cu(I-hip)(bpy)2]+(I-hipꢀ) Æ 4H2O: Blue crystals. Anal.
Calc. for C38H38CuI2N6O10: C, 43.22; H, 3.63; N, 7.96.
Found: C, 42.50; H, 3.54; N, 7.96%. IR (cmꢀ1): 416vw,
440vw, 456vw, 532w, 579w, 624w, 636w, 652w, 663w,
672w, 715w, 732m, 762m, 772m, 867vw, 955vw, 1013m,
1031vw, 1062vw, 1086vw, 1106vw, 1158vw, 1175w, 1232w,
1253m, 1261m, 1311m, 1398vs, 1448m, 1457m, 1470m,
1506s, 1582s, 1600s, 1634s, 1652vs, 3061w, 3313m, 3394m,
3486m.
0.71073 A). In each case, after the random search of 25
˚
reflections, the indexation procedure gave rise to the cell
parameters (see Table 1 for a summary of the crystal data).
Data were collected in the x-2h scan mode. Absorption
correction for 6 was performed following the empirical
DIFABS method. The structural resolution procedure
was made using the WinGX package [23]. Solving for
structure factor phases was performed by SHELXS-97 [24]
for 6 and SIR-2004 [25] for 7, and the full matrix refinement
by SHELXL-97 [26]. Non-H atoms were refined anisotropi-
cally and H-atoms were introduced in calculated positions
and refined riding on their parents atoms. A summary of
refinements parameters can also be seen in Table 1.
H-atoms of water molecules could not be located in any
2.3. [Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O (7)
Basic copper carbonate (1 mmol) and BIGG sodium salt
(3 mmol) in water (100 ml) were refluxed for 2 h, then the
Table 1
Selected crystallographic data for compounds 6 and 7
Identification code
6
7
Empirical formula
Formula weight
Temperature (K)
C58H52Cu2I4N10O9
1667.78
294(2)
C31H34CuI2N6O8
935.98
293(2)
˚
Wavelength (A)
0.71073
0.71073
Crystal system
Space group
Unit cell dimensions
monoclinic
P21/n
triclinic
ꢀ
P1
˚
a (A)
15.912(3)
17.705(4)
22.472(4)
90
101.474(14)
90
6204(2)
4
1.785
12.515(3)
12.993(3)
13.662(4)
66.144(16)
65.31(2)
71.84(2)
1818.6(8)
2
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
Volume (A )
Z
Dcalc (Mg/m3)
Absorption coefficient (mmꢀ1
F(000)
1.709
2.353
922
)
2.738
3248
Crystal size (mm)
h Range for data collection (ꢁ)
Index ranges
0.46 · 0.38 · 0.21
1.44–24.98
0.46 · 0.42 · 0.29
1.73–24.98
ꢀ18 6 h 6 18, ꢀ21 6 k 6 0, 0 6 l 6 26
ꢀ14 6 h 6 13, ꢀ15 6 k 6 14, ꢀ16 6 l 6 0
Reflections collected
11182
6606
Independent reflections (Rint
Completeness to final h (%)
)
10888 (0.0397)
99.9
6309 (0.0295)
98.7
Maximum and minimum transmission
Refinement method
0.5971 and 0.3657
full-matrix least-squares on F2
10888/748
full-matrix least-squares on F2
6309/457
Data/parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
1.024
1.299
R1 = 0.0666, wR2 = 0.1746
R1 = 0.1257, wR2 = 0.2099
1.767 and ꢀ1.686
R1 = 0.0765, wR2 = 0.2488
R1 = 0.1263, wR2 = 0.3253
2.072 and ꢀ2.050
ꢀ3
˚
Largest difference in peak and hole (e A
)

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M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
case. Largest diffraction peaks and holes were located close
to heavy atoms in Fourier difference map. The ORTEP [27]
representations of the two complexes were made at 50%
probability.
The software used to generate the figures and to calcu-
late the distances and angles values are MERCURY 1.4.1
[28], which can be obtained free of charge from CCDC,
and Accelrys DS Viewer Pro 5.0 [29], which a 30-days trial
version can also be obtained free of charge.
complex units are present in the asymmetrical unit where
the two copper(II) ions present distorted octahedral coor-
dinations. These ions are linked to two oxygen atoms of
the carboxylate anion of I-hip by means of a strong and
an ancillary bonds [Cu–O distances: O(9), 2.100(8) and
˚
O(10), 2.71 A for Cu(1); O(43), 2.217(9) and O(44),
˚
2.47 A for Cu(2)] and to the four nitrogen atoms from
two bpy molecules [Cu–N distances: N(11), 1.972(8);
˚
N(22), 2.064(7); N(23), 2.164(8) and N(34), 1.975(7) A
Dpln, DAtn and Dlim distances as well as h, u and x
angles in C–Iꢁ ꢁ ꢁp interactions are calculated as defined by
Prasanna and Guru-Row [30].
for Cu(1); N(45), 2.131(8); N(56), 1.990(7); N(57),
1.982(7) and N(68), 2.089(8) A for Cu(2)]. The positive
˚
charges of complex units are compensated by the presence
of iodide atoms (one per formula unit). The structure is
completed by three water molecules per asymmetrical
unit.
In this compound, the Addison parameter (s) presents a
value of s = 0.41. It means that, considering a coordination
number CN = 5, the real coordination polyhedron is about
halfway between a square pyramidal and a trigonal bipyra-
midal coordinations.
The 3D structure of this compound is formed by bi-
dimensional layers coincident with the a–c-plane.
There is not present any intramolecular interaction, but
the crystal unit is built by means of a lot of intermolecular
interactions among complex units and also with the water
molecules. The more relevant interactions should be:
In order to measure the distortions of the coordination
polyhedron from the square pyramid to the trigonal bipyr-
amid (CN = 5), the Addison parameter (s) has been calcu-
lated according to the literature procedures [31], as an
indication of the degree of trigonality. s is defined as
(b ꢀ a)/60, where b and a are the two trans-basal angles.
For a perfectly square pyramidal geometry s is equal to
zero, while it becomes unity for a perfectly trigonal-bipyra-
midal geometry.
3. Results and discussion
3.1. Crystal structure of [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O
(6)
In X-ray crystal structure of [Cu(I-hip)(bpy)2]+(Iꢀ) Æ
1.5H2O (6) (Fig. 1), we detect, in a first approach, that
the coordination environment is coincident with that for
compound [Cu(I-hip)(phen)2]+(I-hipꢀ) Æ 7H2O (5). Two
(a) Stacking [32] between bipyridyl rings in the couple of
complexes in the asymmetrical unit [distance
˚
C(27)ꢁ ꢁ ꢁC(50) or C(29)ꢁ ꢁ ꢁC(52), ca. 3.34 A; torsion,
179ꢁ] strengthened by Caromatic–Hꢁ ꢁ ꢁp interactions
I1
O1
C2
C3
C5
N7
I3
C4
C13
I4
C7
O7
C8
O9
C9
O10
C14
C12
N11
Cu1
C52
C53
C66
C65
C64
C15
C18
C67
N68
C54
N22
C63
C61
O2
Cu2
C19
C25
C20
C30 C31
O43
C26
C59
C42
O41
C39
C38
C37
N41
C41
I2
O3
C36
Fig. 1. ORTEP representation (50% probability) of the asymmetrical unit in [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O (6). Numeration of several atoms has been
omitted for clarity.

M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
1421
Fig. 2. ORTEP representation (50% probability) of the complex [Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O (7).
˚
˚
for
each
bipyridyl
[distance
H(2)ꢁ ꢁ ꢁC(28),
3.41 A and 144ꢁ; C(47)–H(47)ꢁ ꢁ ꢁO(7), 3.22 A and
˚
H(36)ꢁ ꢁ ꢁC(50) and H(36)ꢁ ꢁ ꢁC(51); 2.79, 2.70 and
127ꢁ;C(32)–H(32)ꢁ ꢁ ꢁO(41), 3.39 A and 146ꢁ; C(18)–
˚
2.87 A], which yields a more extended and complex
H(18)ꢁ ꢁ ꢁO(44), 3.33 and 143ꢁ; and C(64)–
˚
C–Hꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁH–C interaction.
H(64)ꢁ ꢁ ꢁO(10), 3.46 A and 158ꢁ].
(b) An extended stacking, normal to the described
C–Hꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁH–C units, between four aromatic
rings, two o-iodobenzoyl rings, which are part of
the C–Hꢁ ꢁ ꢁp contact, at the inside [distance
(d) And finally, iodine atoms interact with their environ-
ment: thus, iodine from o-iodobenzoyl rings, shows
an intramolecular contact between this halogen and
the oxygen atom from amide bond [distances
˚
˚
C(2)ꢁ ꢁ ꢁC(38) or C(4)ꢁ ꢁ ꢁC(36), ca. 3.36 A; torsion,
I(1)ꢁ ꢁ ꢁO(7) and I(2)ꢁ ꢁ ꢁO(41), 3.42 and 3.26 A].
175ꢁ], and two bipyridyl ligands which do not partic-
Although the contact angle is not very adequate
[angle C@Oꢁ ꢁ ꢁI, 80ꢁ], we observe a decrease in the
torsion between the aryl ring and the peptidic bond
of the I-hip ligand, with regard to the binary I-hip
complexes, which could be explained by the presence
of this interaction. And finally, the iodide anions
ipate in that interaction at the outside of the group
˚
˚
[distance C(2)ꢁ ꢁ ꢁC(21) or C(3)ꢁ ꢁ ꢁC(21), ca. 3.25 A
and torsion, 158ꢁ; distance C(67)ꢁ ꢁ ꢁC(36), ca. 3.31 A
and torsion, 157ꢁ]. This p-cluster unit, is extended
along the a direction, like a wire, assisted by the for-
mation of another stacking between the winger bipyr-
˚
interact with I–Caromatic [distance I(4)ꢁ ꢁ ꢁI(1), 3.89 A]
˚
idyl rings [distance C(16)ꢁ ꢁ ꢁC(64), ca. 3.49 A and
and H–Caromatic moieties [distance I(4)ꢁ ꢁ ꢁH(41),
2.83; I(4)ꢁ ꢁ ꢁH(58), 3.08; I(3)ꢁ ꢁ ꢁH(14), 3.07; and
torsion 173ꢁ] and strengthened by contacts between
O(44)ꢁ ꢁ ꢁH(18) and O(10)ꢁ ꢁ ꢁH(64) (see below). These
infinite stacking chains are intertwined by orthogonal
C–Hꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁH–C clusters which grow from the
two central o-iodobenzoyl rings to right and left sides.
These crisscrossed strings form 2D networks which
are piled in the b direction related, for instance, by
the iodine anions and water molecules (for more
information see Section 3.3.1.5).
˚
I(3)ꢁ ꢁ ꢁH(48), 3.10 A]. All these contacts are shorter
than the corresponding van der Waals values [Iꢁ ꢁ ꢁI,
˚
3.96; Iꢁ ꢁ ꢁO, 3.50; and Iꢁ ꢁ ꢁH, 3.18 A] calculated by
Bondi [33].
3.2. Crystal structure of [Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O
(7)
(c) An interesting Caromatic–Hꢁ ꢁ ꢁO hydrogen bonds1
between carboxylate or carboxamide from I-hip ligand
and bipyridyl [distance and angle: C(27)–
In this X-ray structure, the copper(II) ion present a
distorted octahedral coordination (see Fig. 2), being
linked to the two O atoms of the carboxylate in I-hip
[Cu(1)–O distances: O(1), 2.012(7) and O(2), 2.74 A]
and to the four N atoms from two bpy molecules
[Cu(1)–N distances: N(1A), 2.041(8); N(12A), 1.993(9);
˚
˚
H(27)ꢁ ꢁ ꢁO(43), 3.34 A and 153ꢁ; C(52)–H(52)ꢁ ꢁ ꢁO(9),
˚
1
N(1B), 2.175(10) and N(12B), 2.016(9) A]. The coor-
All hydrogen bond distances are given between the donor and the
acceptor atoms; angles of interaction correspond to D–Hꢁ ꢁ ꢁA.
dination environment is again coincident with the

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M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
corresponding to compounds 5 and 6 and the complex
unit is positively charged and compensated by the pres-
ence of one iodide atom. The presence of seven water
molecules completes the structure (water molecules
O1W and O2W have complete occupancy (100%); but
O3W, O4W and O5W have only 40%; O6W, 30%; and
O7W, 50% occupancy). The 3D structure of this com-
pound is also formed by bi-dimensional layers in the
a–b-plane.
The Addison parameter (s) relating to this compound
presents a value of s = 0.33. In this compound, the geom-
etry is a little nearer to a square pyramid than those for
compound 6, but anyway it is also faraway from any of
the two perfect geometries.
Every cationic complex recognizes another one (head to
tail) by means of a tandem of hydrogen bonds between
peptide moieties [distance and angle O(5)ꢁ ꢁ ꢁH(7)–N(7),
˚
2.94 A and 167ꢁ] and each of these couples interacts with
another one via water molecules and iodide atoms. In order
to form the molecular planes within the crystal structure,
each bipiridyl ring of one couple interacts with the corre-
sponding one of other couple by means of stacking interac-
tions [distance C(10A)ꢁ ꢁ ꢁC(4A) and C(4A)ꢁ ꢁ ꢁC(10A),
˚
˚
3.35 A; distance C(6A)ꢁ ꢁ ꢁC(8A) and C(8A)ꢁ ꢁ ꢁC(6A),
3.43 A; torsion 170ꢁ] [distance C(6B)ꢁ ꢁ ꢁC(9B) and C(9B)
˚
ꢁ ꢁ ꢁC(6B), 3.33 A; distance C(7B)ꢁ ꢁ ꢁC(8B) and C(8B)ꢁ ꢁ ꢁ
˚
C(7B), 3.36 A; torsion 171ꢁ].
With regard to iodine interactions, one short contact
between iodine moiety and iodide anion are present
˚
[distance I(10)ꢁ ꢁ ꢁI(15), 3.81 A], shorter than the corre-
sponding van der Waals distance must be mentioned
and the iodide anion also interacts with H–Caromatic, as
˚
in compound 6 [distance I(15)ꢁ ꢁ ꢁH(9B), 3.09 A].
Finally, two Caromatic–Hꢁ ꢁ ꢁO hydrogen bonds are also
present between O atoms from carboxylato/peptide and
bipyridyl (type A) moieties [distance and angle: C(4A)–
˚
H(4A)ꢁ ꢁ ꢁO(5), 2.98 A and 119.9ꢁ; C(5A)–H(5A)ꢁ ꢁ ꢁO(2),
˚
˚
3.52 A and 166.1ꢁ; and C(8A)–H(8A)ꢁ ꢁ ꢁO(2), 3.46 A and
163.5ꢁ].
Fig. 3. Iodine–iodine interaction in compound [Cu(I-hip)2(OH2)3] Æ 2H2O
˚
(3). In order to centre this short contact with a value of 3.78 A, only the
nearness of iodine atoms has been represented (more structural informa-
tion in Ref. [19]).
Fig. 4. Iodine–hydrogen interaction (depicted with black lines) and
iodine–metal bond (depicted as a standard bond) in compound 2 [18].
(For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
Fig. 5. C–Iꢁ ꢁ ꢁp interaction in compound [Zn(I-hip)2(OH2)2]2 Æ 3H2O (1)
˚
[17]. The Iꢁ ꢁ ꢁCaromatic distance values are 3.56 and 3.74 A alternatively.

M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
1423
3.3. Iodine interactions present in these compounds
3.3.1.2. Iodine–hydrogen interaction (Iꢁ ꢁ ꢁH–C). Another
type of interaction is present between iodine and hydro-
gen(-C) atoms as, for instance, in complex [Ag(I-hip)] Æ
1.25H2O (2), where iodine moiety is closed to two hydro-
gen atoms from glycine moieties (Fig. 4). These distances
Different levels of interactions and self-assemblies
involving iodine atoms have been detected in the seven
compounds previously described.
˚
are approximately 3.10 A whereas the calculated van der
˚
3.3.1. A simple type of recognition patterns
Waals distance is 3.18 A.
3.3.1.1. Iodine–iodine interaction (Iꢁ ꢁ ꢁI). [Cu(I-hip)2-
(OH2)3] Æ 2H2O (3) presents a short contact between two
iodine atoms in I-hip rings (Fig. 3). The bond distance is
In the other compounds, as in [(Co, Ni or Zn)(I-hip)2-
(acv)(OH2)3] (4), [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O (6) and
[Cu(BIGG)(bpy)2]+(Iꢀ) Æ 4H2O (7), is also detected this
kind of interaction, where the hydrogen atoms belong to
aromatic rings instead of aliphatic chains.
˚
about 0.2 A shorter than de van der Waals value and the final
3D structure is generated by means those reported iodine
contacts which yields different planes in the c direction.
Similar type of interaction is also present in compound
[(Co, Ni or Zn)(I-hip)2(acv)(OH2)3] (4). Likewise, an equiv-
alent contact Ph-Iꢁ ꢁ ꢁIꢀ appears in compounds [Cu(I-hip)-
(bpy)2]+(Iꢀ) Æ 1.5H2O (6) and [Cu(BIGG)(bpy)2]+(Iꢀ) Æ
4H2O (7). In all cases, these iodide interactions are very
important to maintain the 3D crystal structure.
3.3.1.3. Iodine–metal bond (I–Ag). Complex [Ag(I-hip)] Æ
1.25H2O (2) also presents direct bonds between iodine
˚
(I-hip) and two silver atoms at 3.15 and 3.36 A (Fig. 4). These
contacts are in the levels described in the literature for Ag–I
short contact or large bond. Iodine bonded to metals is
only present in silver complexes.
Fig. 6. Two types of connected interactions which direct the formation of a planar structure in compound [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O (6). The
stacking piled along the a direction extended to all the crystal is depicted with green lines (vertical in the center of the figure) and the C–Hꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁH–C
patterns which are observed in horizontal and indicated with black lines (one on the left side and another one on the right side). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)

1424
M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
3.3.1.4. Iodine–p system interaction (C–Iꢁ ꢁ ꢁp). Binary
derivative [Zn(I-hip)2(OH2)2]2 Æ 3H2O (1) holds, in its crys-
tal structure, a close contact between iodine atoms and aro-
matic rings which remember us a C–Hꢁ ꢁ ꢁp interaction. In
these complex an extended C–Iꢁ ꢁ ꢁp interaction (Fig. 5)
where one iodine moiety of I-hip contacts closely with
the aromatic ring of another I-hip molecule is present.
The interaction occurs in the neighbourhood of the iodine
moieties (see Fig. 5). This fact tells us than the iodine atom
is important in the interaction not only to bond another
ring, but also to active the aromatic ring in order to be
bonded.
aromatic rings. Thus, in [Cu(I-hip)(bpy)2]+(Iꢀ) Æ 1.5H2O
(6) is not possible to detect any important iodine interac-
tion, but there are very important stacking self-assemblies.
In Fig. 6 are depicted the 2D plane formed by these inter-
actions. In green colour represent the stacking along the a
direction, which crosses all the crystal, whereas in black
colour two C–Hꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁH–C cluster patterns are shown.
Detailed distances of these interactions have been reported
in Section 3.1.
There are other examples in which the presence of a
iodine substitution in the aromatic rings helps to stabilize
the formation or reinforcement of stacking interactions.
For instance, in compound [(Co, Ni or Zn)(I-hip)2-
(acv)(OH2)3] (4), it is possible to detect a stacking
interaction between acyclovir and I-hip which enforce the
formation of two enantiomeric structures.
A recent publication [30] has been defined various param-
eters (three distances and three angles) in order to explore
and compare this interaction type. In compound 1, the six
parameter values are (for shorter/longer interactions): Dpln
,
˚
˚
˚
3.577/3.778 A; DAtn, 3.559/3.739 A; Dlim, 3.493/3.709 A; h,
78.13–78.02ꢁ/80.70–77.93ꢁ; u, 79.70–79.40ꢁ/78.33–81.16ꢁ
and x, 84.10ꢁ/84.22ꢁ. In the cited paper, is also defined de
maximum distance at which a iodine–aromatic ring contact
can be considered as interaction: Dmax, identified as sum of
the van der Waals radii of iodine and half-thickness of aro-
matic ring with an added tolerance of 5% of this sum in
order to address electrostatic contributions to the interac-
3.3.2. A complex pattern of recognition factors
3.3.2.1. Iodine–iodine (Iꢁ ꢁ ꢁI) plus iodine–hydrogen (Iꢁ ꢁ ꢁH–C)
interactions. [(Co, Ni or Zn)(I-hip)2(acv)(OH2)3] (4) show
two types of described single recognition patterns involving
iodine atoms (Fig. 7). Thus, the resulting iodine network is
˚
formed by iodine–hydrogen(aromatic) contacts at 3.15 A
˚
[van der Waals value, 3.18 A] and iodine–iodine bonds at
˚
˚
˚
tion, has a value of 3.86 A. Our results, confirm the direc-
3.80 A [van der Waals value, 3.96 A]. In the picture, the first
ones are indicated in green thin lines, and the second ones
are indicated in black thin lines.
tional preference of the C–Iꢁ ꢁ ꢁp interactions.
3.3.1.5. Interactions promoted by iodine atoms which do not
directly participate in them. Iodine substitution in aromatic
rings improves the capability of interaction between these
3.3.2.2. C–Iꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁI–C. Another interesting way of
interaction between iodine atoms is by means a long
Fig. 7. Network of interactions in complex [(Co, Ni or Zn)(I-hip)2(acv)(OH2)3] (4) [17]. There are hydrogen–iodine interactions depicted with green lines
and iodine–iodine contacts indicated with black lines. These two types of recognitions form to chains of iodine atoms which are related to each other by
means of tandems of C–Hꢁ ꢁ ꢁI interactions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of
this article.)

M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
1425
(like C–Hꢁ ꢁ ꢁp) and aromatic self-assemblies assisted by
iodine atoms. These interactions could be similar to their
formed between thyroxine and its binding molecules
because of the similarity between thyroxine and the differ-
ent iodohippurate compounds studied in the present work.
Acknowledgments
´
One of us, Miquel Barcelo-Oliver, is grateful to ‘‘Con-
´
i Innovacio’’ of the
selleria d’Economia, Hisenda
Government of Balearic Islands for a Ph.D. fellowship
[FPI05-34068589T]. The authors also thank the ‘‘Vicerecto-
´
´
´
rat de Investigacio i Polıtica Cientıfica’’ of the University of
Balearic Islands (project number UIB2005/5), the ‘‘Con-
´
selleria d’Economia, Hisenda i Innovacio’’ (competitive
groups grant) of the Government of Balearic Islands and
´
´
´
´
the ‘‘Direccion General de Investigacion Cientıfica y Tec-
nica’’ of the Spanish authorities (project number
CTQ2006-09339/BQU) for their generous financial support.
Appendix A. Supplementary material
CCDC 237826, 269073, 285764, 237828, 237827,
285763, 624402 and 624403 contain the supplementary
crystallographic data for 1, 2, 3, 4 (Co complex), 4 (Zn
complex), 6 and 7. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.
html, or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.poly.
2006.11.024.
Fig. 8. New C–Iꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁI–C cluster pattern presents in complex [Cu-
(I-hip)(phen)2]+(I-hipꢀ) Æ 7H2O (5) [19]. As it is the most complex iodine
interactions observed in the family of compounds presented in this work,
we have represented the implied atoms as boundary surfaces in order to
well understand the composition of recognition patterns.
distance C–Iꢁ ꢁ ꢁpꢁ ꢁ ꢁpꢁ ꢁ ꢁI–C as can be observed in [Cu(I-hip)-
(phen)2]+(I-hipꢀ) Æ 7H2O (5). Fig. 8 illustrates these ideas
and show this new pattern of molecular recognition: an
stacking interaction between two aryl rings from I-hip
References
[1] F. Zhang, W. Nianqing, X. Wang, L. Zhu, Z. Chai, Biol. Trace Elem.
Res. 97 (2004) 125.
[2] J. Hemberger, M. Orlando, PCT Int. Appl. (2003) 38 [Application:
WO 2003-EP2083 20030228].
[3] M.G. Wade, S. Parent, K.W. Finnson, W. Foster, E. Younglai, A.
McMahon, D. Cyr, G. Daniel, C. Hughes, Toxicol. Sci. 67 (2002) 207.
[4] S. Farr, PCT Int. Appl. (2001) 222 [Application: WO 2000-US30474
20001103].
[5] B. Kochel, R. Andrzejak, M. Jurga, T. Tomkalsli, J. Lesczyszyn, B.
Radomska, Proc. Int. Symp. Met. Ions Biol. Med. (1998) 539.
[6] F. Gao, C. Niu, J. Ni, T. Jin, R.WangX. Wang, Wuji Huaxue Xuebao
13 (1997) 119 [CAN 127:161601 AN 1997:441156 CAPLUS].
[7] M.D. Chen, P.Y. Lin, W.H. Lin, Gaoxiong Yixue Kexue Zazhi 7
(1991) 628 [CAN 116:212346 AN 199:212346 CAPLUS].
[8] W. Cash, D. William, H.E. Harold, S.W. Cox, E.A. Ekong, J.S.
Epstein, S.G. Gabbe, R.M. Sigel, Endocrinology 81 (1967) 291.
[9] W. Cash, D. William, M. Gardy, H.E. Carlson, E.A. Ekong, J. Biol.
Chem. 241 (1966) 1745.
˚
[distance, 3.39 A; torsion, 180ꢁ] reinforced by two interest-
˚
ing C–Iꢁ ꢁ ꢁC(ring) interactions [distance, 3.60 and 3.55 A],
similar to a C–Hꢁ ꢁ ꢁp one, on each stacked ring. We can
also understand this cluster as two C–Iꢁ ꢁ ꢁp interactions
locked by a stacking between two other o-iodobenzoyl
rings (four iodophenyl moieties are implied in these kind
of interaction).
The six distance parameters for compound 5 are: Dpln
,
˚
˚
˚
4.158 A; DAtn, 3.551–3.602 A; Dlim, 3.509 A; h, 54.90–
57.26ꢁ; u, 106.64–103.88ꢁ and x, 115.04ꢁ. These results
are also in agreement with the discussion about this type
of interaction, made for compound 1.
4. Conclusion
[10] A. Wahlborg, E. Frieden, Arch. Biochem. Biophys. 111 (1965) 672.
[11] G. Litwack, J. Biol. Chem. 228 (1957) 823.
[12] E.C. Wolff, E.G. Ball, J. Biol. Chem. 224 (1957) 1083.
[13] F. Zhang, Y.-Z. Li, X. Gao, H.-L. Chen, Q.-T. Liu, A. Odani, O.
Yamauchi, Chem. Lett. 33 (2004) 556.
[14] F. Zhang, A. Odani, H. Masuda, O. Yamauchi, Inorg. Chem. 35
(1996) 7148.
Different and interesting patterns of molecular recogni-
tion involving iodine atoms are shown in this paper.
Among these interactions it is possible to include: Iꢁ ꢁ ꢁI,
Iꢁ ꢁ ꢁH–C(aromatic or aliphatic), Iꢁ ꢁ ꢁM(metal ion), Iꢁ ꢁ ꢁp

1426
M. Barcelo´-Oliver et al. / Polyhedron 26 (2007) 1417–1426
[15] F. Zhang, T. Yajima, H. Masuda, A. Odani, O. Yamauchi, Inorg.
Chem. 36 (1997) 5777.
[16] F. Zhang, T. Yajima, A. Odani, O. Yamauchi, Inorg. Chim. Acta 278
(1998) 136.
[24] G.M. Sheldrick, SHELXS-97: Program for the Solution of Crystal
Structures, University of Go¨ttingen, Go¨ttingen, Germany, 1997.
[25] M.C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G.L. Cascar-
ano, L. De Caro, C. Giacovazzo, G. Polidori, R. Spagna SIR-2004: an
improved tool for crystal structure determination and refinement, J.
Appl. Crystallogr. 38 (2005) 381.
´
´
´
[17] M. Barcelo-Oliver, A. Terron, A. Garcıa-Raso, J.J. Fiol, E. Molins,
C. Miravitlles, J. Inorg. Biochem. 98 (2004) 1703.
´
´
´
[18] M. Barcelo-Oliver, A. Tasada, J.J. Fiol, A. Garcıa-Raso, A. Terron,
[26] G.M. Sheldrick, SHELXL-97: Program for Crystal Structure Analysis
(Release 97-2), University of Go¨ttingen, Go¨ttingen, Germany, 1997.
[27] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.
[28] C.F. Macrae, P.R. Etgington, P. McCabe, E. Pidcock, G.P. Shields,
R. Taylor, M. Towler, J. van de Streek, J. Appl. Crystallogr. 39 (2006)
453.
E. Molins, Polyhedron 25 (2006) 71.
´
´
´
[19] M. Barcelo-Oliver, A. Garcıa-Raso, A. Terron, E. Molins, M.J.
´
´
´
´
Prieto, V. Moreno, J. Martınez, V. Llado, I. Lopez, A. Gutierrez,
P.V. Escriba, J. Inorg. Biochem. (accepted for publication).
´
[20] A.H. Blatt, Organic Synthesis Collective, vol. 2, Wiley, New York,
1943.
[21] F. Wild, Identificacion de Compuestos Organicos (Spanish transla-
tion of Characterization of Organic Compounds, Cambridge Uni-
versity Press, Cambridge), S.A. Gustavo Gili (Ed.), Spain, 1951, pp.
186–200.
[29] Accelrys DS Viewer Pro 5.0. Available from: <http://
www.accelrys.com>.
´
´
[30] M.D. Prasanna, T.N. Guru-Row, Cryst. Eng. 3 (2000) 135.
[31] A.W. Addison, T. Nageswara-Rao, J. Reedijk, J. van Rijn, G.C.
Verschoor, J. Chem. Soc., Dalton Trans. (1984) 1349.
[32] O. Yamauchi, A. Odani, M. Takani, J. Chem. Soc., Dalton Trans.
(2002) 3411, and references therein.
[22] G.A. Barclay, B.F. Hoskins, C.H.L. Kennard, J. Chem. Soc. (1963)
5691 [CCDC code: IBIPCI].
[23] L.J. Farrugia, J. Appl. Crystallogr. 32 (1999) 837.
[33] A. Bondi, J. Phys. Chem. 68 (1964) 441.