Melamine-bridged bis(porphyrin-ZnII) receptors: Molecular recognition properties

Article abstract of DOI:10.1021/jo901749w

(Chemical Equation Presented) Dimeric metalloporphyrin hosts with tweezer-like structures have been synthesized by reacting the cyanuric chloride scaffold, CC, with 5-(4-aminophenyl)-10,15,20-triphenylporphyrin, P, and 5-(4-aminophenyl)-10,15,20-trimesity

Full text of DOI:10.1021/jo901749w

pubs.acs.org/joc
Melamine-Bridged Bis(porphyrin-ZnII) Receptors: Molecular
Recognition Properties
Tommaso Carofiglio,* Elisa Lubian, Ileana Menegazzo, Giacomo Saielli, and
Alessandro Varotto
Department of Chemical Sciences and ITM-CNR, University of Padua, Padua, Italy
tommaso.carofiglio@unipd.it
Received August 14, 2009
Dimeric metalloporphyrin hosts with tweezer-like structures have been synthesized by reacting the
cyanuric chloride scaffold, CC, with 5-(4-aminophenyl)-10,15,20-triphenylporphyrin, P, and 5-(4-
aminophenyl)-10,15,20-trimesitylporphyrin, M, to yield the homoconjugates free bases PP and MM
and the heterodyad PM. Metalation with Zn(II), gives three structurally related ditopic receptors
P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) with differential steric hindrance and conformational
rigidity. The solution structure and supramolecular properties of these porphyrin dimers have been
investigated as isolated molecules and in the presence of aliphatic R,ω-diamines of general formula
H2N-(CH2)n-NH2 (n =4-8) by spectroscopic and theoretical studies including multidimensional NMR,
UV-vis, molecular modeling, and computational NMR methods. Binding constants in the range 4.2 ꢀ
106 to 3.4 ꢀ 107 M-1 are observed in dichloromethane at 298 K, with a 3 orders of magnitude increase as
compared to monodentate nBuNH2, thus indicating the occurrence of a host-guest ditopic interaction.
Linear correlation graphs are obtained by plotting the Soret band shift (Δν, cm-1) of the complex as a
function of the diamine chain length. Combined NMR evidence and OPLS 2005 Force Field conforma-
tional analysis point to a mutual adaption of both the binding partners in the host-guest complex, whose
geometry is mainly dictated by the steric impact of the bulky substituents at the porphyrin periphery.
Introduction
tailored according to the hard-soft acid-base paradigm; (3)
the precise control on the topology and substitution pattern of
the receptor, through well-established synthetic methodolo-
gies that allow the porphyrin macrocycle to be decorated on
demand; and (4) the large aromatic framework of porphyrin
ring serving as spectroscopic probe to monitor host-guest
complexation by a number of techniques (UV-vis,2 circular
Metalloporphyrins are frequently used as key motifs for
elaborating synthetic molecular receptors1 by virtue of some
unique features: (1) axial ligation fostered by the open co-
ordination site at the metal center in the porphyrin core; (2)
specific binding of OH, NH2 functionalities or other ligands
*To whom correspondence should be addressed. Phone: 0039498275670.
Fax: 0039498275239.
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W. Anal. Chem. 2002, 74, 1088–1096. (b) Gulino, A.; Mineo, P.; Bazzano, S.;
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(1) (a) Drain, C. M.; Varotto, A.; Radivojevic, I. Chem. Rev. 2009, 109,
1630–1658. (b) Beletskaya, I.; Tyurin, V. S.; Tsivadze, Y. A.; Guilard, R.;
Stern, C. Chem. Rev. 2009, 109, 1659–1713. (c) Ogoshi, H.; Kuroda, Y.;
Mizutani, T.; Hayashi, T. Pure Appl. Chem. 1996, 68, 411–1415.
Daniele Vitalini, D.; Fragala, I. Chem. Mater. 2005, 17, 4043–4045. (c) Di
Natale, C.; Salimbeni, D.; Paolesse, R.; Macagnano, A.; D’Amico, A. Sens.
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9034 J. Org. Chem. 2009, 74, 9034–9043
Published on Web 11/03/2009
DOI: 10.1021/jo901749w
r
2009 American Chemical Society

Carofiglio et al.
JOCArticle
dichroism,3 fluorescence,4 NMR,5 and resonance Raman
spectroscopy6).
flexible covalent tether. These constructs have been exploited
to assess the absolute stereochemical configuration of chiral
amines,13b,g,h alcohols,13g and carboxylic acids13i through
the sign of the exciton-coupled circular dichroism in the
porphyrin spectral region. Another prosperous field of appli-
cation for bis-porphyrin hosts deals with the self-assembling
of donor-acceptor systems promoted by the π-π stacking
between a fullerene curved surface and a porphyrin macro-
cycle.12a,15 Such fullerene-porphyrin recognition motif has
been successfully employed for selective extraction of higher
fullerenes,15c and to build photovoltaic devices.15b Despite
these desirable features, the synthesis of porphyrin dimers or
oligomers in high yield and purity is often an onerous task
imposing multistep procedures and reiterated chromatogra-
phy purification.
We have recently established a straightforward approach
for the modular synthesis of porphyrin dyads16 that relies on
the unique temperature-dependent reactivity of cyanuric
chloride, CC, toward nucleophiles.17 Typically, the first
chloride reacts rapidly at 0 °C, whereas room temperature
or moderate heating (depending on the nucleophile strength)
promotes the second substitution. The nucleophilic displace-
ment of the third chloride requires harsher conditions (T >
80 °C for multiple hours). Since quantitative yields are often
achieved for these reactions, sequential, one-flask introduc-
tion of various substituents into a triazine ring is also
feasible.
As a result, a number of single-porphyrin receptors have
been developed for the recognition of simple molecules in-
cluding alcohols,7 amines,8 and carbohydrates.9 In these
systems, binding specificity through metal coordination is
aided by secondary sterical interactions operated with bulky
substituents (picket-fence10 porphyrins), as well as by capping
the macrocycle with hydrophobic pockets (basket-handle11
porphyrins). Moreover, decoration of the porphyrin ring
with complementary and multiple hydrogen bonding sites
implements directionality into the recognition process while
improving the selectivity as well. However, these additional
secondary interactions play a fundamental role for shape
discrimination, but they do not necessarily improve the bind-
ing strength of the substrate. In this regard, recognition of
multifunctional molecules can take advantage of more than
one porphyrin site.12 A multisite/substrate-receptor mutual
interaction guarantees an enhanced binding stability thus
allowing the resulting supramolecular assembly to be present
as the main entity in solution. For instance, dimeric metallo-
porphyrin hosts with tweezer-like structures have been
designed to effectively complex bifunctional guests through
a ditopic interaction. A prominent example among these
compounds is the dimeric metalloporphyrin hosts that consist
of two achiral zinc-13 or magnesium-porphyrins14 linked by a
The benefits of this synthetic methodology are readily
envisaged in the design of porphyrin-dyads where the overall
stereoelectronic diversity can be generated by a proper
synthesis/selection of the isolated components in a homo-
dimer arrangement, by the combination of these within an
heterodimeric structure, and/or by differential metalation of
the porphyrin units.16
ꢀ
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Herein, we explore the binding properties of the melamine-
bridged bis-porphyrin scaffold as ditopic receptor for biden-
tate ligands. In particular, the steric constrains of the macro-
cycle components are expected to affect the conformational
stability and binding geometry of the dyad whereby the two
porphyrin units are forced into close proximity as a conse-
quence of the recognition event. To this aim, we used two
amino-porphyrin building blocks P and M, respectively car-
rying phenyl and mesityl meso-subsituents, to yield the homo-
conjugates free bases PP and MM and the heterodyad PM
(Scheme 1). After metalation with Zn(II), a small library of
three structurally related bis-porphyrin receptors is readily
obtained, namely P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M-
(Zn) derivatives. The steric hindrance at the peripheral posi-
tions is supposed to increase steadily from P(Zn)P(Zn) to
M(Zn)M(Zn), the heterodimer P(Zn)M(Zn) being in a mid-
way condition. The binding properties of these receptors have
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been studied vis-a-vis the aliphatic R,ω-diamines of general
formula H2N-(CH2)n-NH2 (n = 4-8). Multidimensional
NMR spectroscopy techniques combined with molecular
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SCHEME 1. Assembly of Melamine-Bridged Bis-Porphyrin
Scaffolds from Selected Building Blocks
SCHEME 2. Synthesis of Melamine-Bridged Porphyrin Di-
mersa
modeling studies have been used to address the solution
structure of the supramolecular host-guest complexes. It
should be pointed out that among the diamines examined,
putrescine (1,4-diaminobutane) and cadaverine (1,5-di-
aminopentane) are commonly used by trained inspectors
and individual consumers for a qualitative evaluation of food
freshness, due to their particularly distinctive smells. Accord-
ingly, there is a need for robust sensor devices which accu-
rately, simply, and rapidly, detect the presence of biogenic
amines in different food matrices thus enhancing food proces-
sing efficiency and giving to the food manufacturers real-time
and online information on their products.
aReagents and conditions: (i) CC, THF, DIPEA, 0 °C; (ii) P or M, THF,
Results and Discussion
DIPEA, 80 °C; (iii) piperidine, THF, DIPEA, 80 °C; (iv) Zn(Ac)2 2H2O,
MeOH/CHCl3, reflux.
3
Synthesis and Characterization of the Bis(porphyrin-ZnII)
Hosts. The preparation of melamine bridged bis(porphyrin)
adducts required the preliminary synthesis of P and M
amino-porphyrin building blocks. In particular, 5-(4-amino-
phenyl)-10,15,20-triphenylporphyrin,18 P, was obtained in
70% yield by direct mononitration of tetraphenylporphyrin
followed by reduction to the corresponding amino-porphyr-
in with SnCl2 in concentrated HCl. On the other hand, 5-(4-
aminophenyl)-10,15,20-trimesitylporphyrin,19 M, was syn-
thesized in 4.6% yield by using a modification of the
Alder-Longo method by reacting pyrrole with a binary
mixture of mesitylbenzaldehyde and 4-acetamidobenzalde-
second equivalent of amino-porphyrin derivative (P or M
depending on whether the target molecule was a homodimer,
PP and MM, or a heterodimer, PM) was added to the
solution and the reaction mixture was stirred at 80 °C for
24 h to afford the corresponding bis(porphyrin) adduct.
Finally, the third chloride atom was reacted with piperidine
producing a soluble compound (Scheme 2). Noticeably, the
third substitution might also afford a convenient route for
supporting such porphyrin dimers onto solid materials car-
rying amino-functionalities, such as Tentagel-amino resin
beads, amino-silanized porous glass particles, as well as
amino-cellulose. This strategy offers a very convenient route
to supported catalysts or chemical sensors.20
After standard workup, purification of the crude PP, PM,
and MM derivatives was accomplished by preparative col-
umn chromatography. Identity and purity of the products
were assessed by 1H NMR spectroscopy, ESI-MS, and
HPLC analysis. The isolated yields for PP, PM, and MM
dimers were 71%, 88%, and 90% respectively.
hyde in the presence of BF3 Et2O catalyst. The desired
3
monoamidoporphyrin was recovered by preparative column
chromatography and hydrolyzed in acidic conditions to
produce the corresponding amino-derivative M.
Bis(porphyrin) receptors were prepared according to the
“one-flask” synthetic protocol outlined in Scheme 2.16
Briefly, the amino-porphyrin P or M was reacted with
1 equiv of cyanuric chloride in THF at 0 °C in the presence
of diisopropylethylamine (DIPEA). The reaction was stirred
at room temperature until TLC analysis indicated the com-
plete disappearance of the starting materials and the forma-
tion of the corresponding monoadduct. At this point, a
Metalation of the porphyrin units was accomplished in
quantitative yield by reacting PP, PM, and MM dimers with
an excess of Zn(Ac)2 2H2O in a CHCl3/MeOH solvent
3
mixture. The reaction occurs smoothly under reflux condi-
tions as witnessed by (i) the red-shift of the Soret band,
(18) Kruper, W. J.; Chamberlin, T. A.; Kochanny, M.; Lang, K. J. Org.
Chem. 1989, 54, 2753.
(19) Aratani, N.; Osuka, A. Macromol. Rapid Commun. 2001, 22, 725–
(20) Carofiglio, T.; Schiorlin, M.; Tonellato, U. J. Porph. Phthal. 2007,
11, 749–754.
740.
9036 J. Org. Chem. Vol. 74, No. 23, 2009

Carofiglio et al.
JOCArticle
obtain the value of the binding constant by using the fitting
procedure provided by the program HYPERQUAD.22 This
software allows a simultaneous fit of the absorbance values
at all the wavelengths as a function of the analytical con-
centration of the diamine, thus yielding a binding constant
calculation with higher precision compared to conventional
methods based on a single wavelength monitoring (generally
the one corresponding to the most intense absorption peak).
The binding constant values for all the hosts with the
diamines are collected in Table 1. For comparison purposes,
Table 1 also reports the corresponding binding constants for
the monodentate nBuNH2.
Scrutiny of data in Table 1 shows that bis(porphyrin-ZnII)
receptors display a high affinity toward the aliphatic dia-
mines under examination, with binding constants in the
range 4.2 ꢀ 106 to 3.4 ꢀ 107 M-1. In contrast, the mono-
dentate benchmark, nBuNH2, binds to the ditopic hosts,
with a 3 orders of magnitude smaller constant (entry 6,
Table 1). This behavior is likely ascribed to the simultaneous
binding of both amino groups of the aliphatic diamine to the
two Zn(II) recognition sites of the porphyrin dyad, acting as
a molecular tweezer. Noteworthy, the association constants
found here are 1 or 2 orders of magnitude smaller than those
previously reported (for the same series of diamines) with use
of a porphyrin tweezer with a flexible pentandiol linker.23
This is likely due to the interplay of both the rigidity of the
melamine bridge and the bulky meso-substituents at the
porphyrin periphery, which turns out to impart some con-
formational constrains to the receptors.
A point of interest is the differential binding affinity shown
by the three porphyrin dyads with respect to the diamine
homologues, which is ascribable both to steric effects on the
porphyrinic macrocycles and to the conformational flexibi-
lity of the bound diamine. In particular, peak affinities are
registered for the short-chain diamines (n = 5, 6) binding to
the low hindered receptor P(Zn)P(Zn). This latter displays
the highest binding constants for the diamine with n = 5
(K = 3.4 ꢀ 107 M-1). On the other hand, the increase of the
steric constrains in the P(Zn)M(Zn) dimer is responsible for
its preferential binding to the diamine with n = 6 (K = 2.8 ꢀ
107 M-1), featuring an elongated alkyl chain and a conse-
quent enhanced conformational flexibility with respect to
lower homologues. The MM host forms remarkably stable
host:guest adducts as well, but without any special prefer-
ence for any of them. Interestingly, the receptor rigidity
seems to affect also the kinetics of the binding process. This
is especially apparent in the titration of the P(Zn)M(Zn) and
M(Zn)M(Zn) receptors with the shortest chain diamine
(n = 4, entry 1 in Table 1). Indeed, an immediate and
pronounced red-shifting of the Soret band was observed
upon addition of the first aliquots of the diamine, followed
by a slow blue-shift evolution of the spectrum that required
5-10 min to reach equilibrium. This behavior might result
from a fast formation of a 1:1 host:guest complex involving
only one of the two amino-groups of the diamine, followed
by a slow intramolecular complexation likely hampered by
the mesityl substituents at the periphery of the porphyrin
macrocycle. For such a reason, these data were considered
FIGURE 1. UV-vis spectra evolution in DCM at 298 K upon
titration of P(Zn)P(Zn) (1.1 μM) with H2N(CH2)5NH2 (0-1.7 μM).
TABLE 1. Binding Constants (M-1) Determined by Spectrophoto-
metric Titration of P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) with
Diamines H2N(CH2)nNH2 (n = 4-8) and with Monodentate nBuNH2, in
DCM at 298 K
amine
bis(ZnIIporphyrin), K (M-1
)
entry H2N(CH2)nNH2 P(Zn)P(Zn) P(Zn)M(Zn) M(Zn)M(Zn)
1
2
3
4
5
6
n = 4
n = 5
n = 6
n = 7
n = 8
nBuNH2
4.8 ꢀ 106
3.4 ꢀ 107
1.3 ꢀ 107
4.5 ꢀ 106
4.2 ꢀ 106
3.2 ꢀ 104
n.d.a
n.d.a
8.1 ꢀ 106
2.8 ꢀ 107
7.2 ꢀ 106
5.3 ꢀ 106
2.7 ꢀ 104
8.5 ꢀ 106
9.0 ꢀ 106
6.9 ꢀ 106
5.2 ꢀ 106
1.9 ꢀ 104
aThe binding constant was not determined due to slow binding
phenomena (see the discussion in the main text).
(ii) the decrease of the Q-band number from four to two, and
(iii) the disappearance of the pyrrolic proton signal in the
upfield region of 1H NMR spectra.
Binding Properties of the Bis(porphyrin-ZnII) Hosts. Zinc-
porphyrins are known to coordinate nitrogenous bases to
form five-coordinated complexes.21 Hence, the melamine-
bridged bis(porphyrin-ZnII) derivatives are expected to be-
have as ditopic receptors suitable for binding of diamine
ligands. Indeed, a marked color variation from purple to
blue was consistently observed upon adding aliphatic R,ω-
diamines of general formula H2N(CH2)nNH2 (n = 4-8) to a
dichloromethane (DCM) solution of any of the three bis-
(porphyrin) receptors. Formation of a receptor-diamine
host-guest complex could be studied in DCM, at 298 K,
by UV-vis monitoring the characteristic red-shift of the
porphyrin Soret band upon diamine complexation. To this
purpose, a solution of the bis(ZnII-porphyrin) maintained at
a constant micromolar concentration was titrated by adding
incremental amounts of diamine in DCM. Figure 1 shows a
typical spectral change observed for P(Zn)P(Zn) upon addi-
tion of H2N(CH2)5NH2.
Depletion of the Soret band at 420 nm was accompanied
by the formation of a new absorption peak at 426 nm,
ascribable to the host-guest complex. The appearance of a
sharp isosbestic point at 423 nm is suggestive of a 1:1 binding
stoichiometry. The spectral data were analyzed in order to
(22) Gans, P.; Sabatini, A.; Vacca, A. Talanta 1996, 43, 1739–1753.
(23) Huang, X.; Borhan, B.; Berova, N.; Nakanishi, K. J. Indian Chem.
Soc. 1998, 75, 725–728.
(21) Weiss, J. J. Inclusion Phenom. Macro. Chem. 2001, 40, 1–22.
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Carofiglio et al.
JOCArticle
halved slope of the linear curve fit. This behavior depends on
the mesityl substituent clash, limiting the conformational
freedom of the M(Zn)M(Zn) tweezer. Since this is a key issue
for understanding the molecular recognition properties of
this class of receptors, we decided to investigate in more
detail their structure by computational modeling.
Molecular Modeling of the Bis-Porphyrin Dimers and Their
Complexes with Diamines. Inspection of a CPK model of the
P(Zn)P(Zn) dimer confirmed that the melamine bridge plays
a major role in determining the interplanar distance between
the two porphyrin units. Indeed, by rotating the porphyrin
rings along the C-N bond link of the melamine bridge, it is
possible to bring them into a cofacial arrangement at a
˚
distance of about 5-6 A (syn-syn conformer in Figure 3).
On the other hand, it is also possible to move the two
˚
porphyrins far away, at about 19 A, for the syn-anti con-
˚
former, or about 21 A for the anti-anti conformer (see
Figure 3). In this latter circumstance, however, the piperidine
ring would occupy a position between the two porphyrins,
thus hampering the distal coordination of an incoming
bidentate guest.
FIGURE 2. Variation of the Soret band red-shift (Δν, cm-1) of
P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) upon complexation
with H2N(CH2)nNH2 (n = 4-8), as a function of the diamine chain
length, in DCM at 298 K. Correlation parameters (slope and
correlation coefficient, R) are as follows: (a) slope = 22 ( 2,
R= 0.990; (b) slope= 22 ( 1, R = 0.994; and (c) slope= 14 ( 2,
R = 0.978.
A molecular modeling study provided more quantitative
information to infer the structure adopted by the bis-
(porphyrin) receptors. To this purpose, a conformational
search for the PP dimer was performed by using a
MMFF94 force field as implemented in the SPAR-
TAN’0225 package and by allowing rotations only about
the two triazine-amino and the two amino-phenylporphyr-
in bonds. It should be pointed out that the conformational
analysis was carried out for the free PP dimer, rather than
for the metalated one, to avoid complications arising from a
poor parametrization of Zn(II) in the MMFF94 force field.
The energy profile for the PP conformers is reported in
Figure 4, together with the model structures of three
representative conformations. This analysis showed a pre-
ferential arrangement with a syn-syn structure in which the
two porphyrin units are almost parallel to each other. This
conformer is almost 5 kcal/mol more stable than a similar
syn-syn arrangement with a V-shaped disposition of the two
porphyrins, and 9 kcal/mol more stable than the syn-anti
conformer (Figure 4).
inappropriate for an accurate determination of the corre-
sponding binding constants.
As reported in the literature for analogous receptors,23
the red-shift of the Soret band changes almost linearly with
the chain length of the diamine. This fact is the result of
two counteracting effects: (i) the amine binding to the
metalloporphyrin, which leads to a red shift of the absorp-
tion bands, and (ii) the proximity of the two chromophores
by effect of the bridging diamine, causing an exciton
coupling blue-shift. Figure 2 reports the Soret band shift
(Δν, cm-1) for the different porphyrin dimers upon di-
amine addition. The values have been calculated from the
titration data, by evaluating the difference between the
wavelength of the Soret band for the free receptor (νfree
)
and that at the end of the titration (νcomplex). A table that
collects the numerical Δν values has been included in the
Supporting Information. It is evident from the graphs in
Figure 2 that for all three receptors, the Δν values change
linearly with the number of carbon atoms of the aliphatic
diamine.
Finally, the analysis did not produce any anti-anti con-
former. The calculated interporphyrin distance in the lower
˚
energy syn-syn structure was about 6 A. On the other hand,
the CPK models of the aliphatic diamines in extended “zig-
zag” all-trans conformation showed that the N-N distance
This approach represents a very simple but useful tool to
gather information about the tweezer flexibility. It is clear
from these data that the extent of the exciton coupling
between the two chromophores decreases as a function of
the diamine chain elongation. On the other hand, it is known
that the exciton coupling depends both on the distance and
the angle between the two interacting chromophores.24 In
this case, due to the rigid nature of the melamine bridge, we
expect that the molecular receptor would accommodate the
diamine mostly by changing the interplanar angle between
the two porphyrin units, as a modification of their distance
could be done only to a minor extent. Indeed, according to
the correlation graphs in Figure 2, the most hindered recep-
tor M(Zn)M(Zn) exhibits a modest response to the diamine
structural change (Figure 2c), as it appears from the roughly
˚
is in the range 6.22-11.22 A, for n = 4 to 8. Moreover, the
Zn-N coordination bond for Zn-porphyrin complexes with
amines is typically 2 A.26 Therefore, we expect a significant
˚
deformation of both the receptor cavity and the diamine
ligand in the supramolecular assembly.
A systematic examination of the host-guest structures was
undertaken by using molecular modeling methods. The large
molecular sizes of the complexes would make these calcula-
tions exceedingly computationally demanding if carried out
at semiempirical or higher level. However, it has been demon-
strated that molecular mechanics calculations with the
recently developed OPLS-2005 force field27 implemented in
(25) Spartan 02; Wavefunction, Inc., www.wavefun.com.
(26) Collins, D. M.; Hoard, J. L. J. Am. Chem. Soc. 1970, 92, 3761–3771.
(27) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. J. Am. Chem. Soc.
1996, 118, 11225–11236.
(24) Hunter, C. A.; Meah, M. N.; Sanders, J. K. M. J. Am. Chem. Soc.
1990, 112, 5773–5780.
9038 J. Org. Chem. Vol. 74, No. 23, 2009

Carofiglio et al.
JOCArticle
FIGURE 3. CPK models of three limit structures obtained by rotation of triazine-aminoporphyrin bonds (a and a0).
FIGURE 5. Simplified models of the lower energy structures
(top = side view, bottom = front view) calculated for the host-
guest complexes resulting from the binding of H2N(CH2)nNH2
(n = 4) to P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) receptors.
FIGURE 4. Conformational analysis of the PP dimer and model
structures of three representative conformers.
the MacroModel package28 can be fairly accurate in describ-
ing systems very closely related to our bis(porphyrin-ZnII)
derivatives. This is especially true since the OPLS-2005 force
field incorporates the appropriate parametrization for de-
scribing Zn-porphyrin-amine complexes.13g Therefore, we
subjected to Monte Carlo conformational analysis all the
complexes formed between the three host derivatives and
the five H2N(CH2)nNH2 (n = 4-8) guests. Figure 5 depicts
the models of the lower energy conformers for the P(Zn)P-
(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) receptors complexed to
diamine with n = 4. This latter case is the most representative
to discuss the steric impact of the receptors under examination
on the recognition event. For clarity of representation, the
model structures do not show the hydrogen atoms, the
unnecessary phenyl or mesityl substituents, and the triazine
bridge. In the three host-guest complexes, the two porphyrin
rings open up in a “V”-shaped conformation where the
˚
Zn-Zn distance is about 9 A. As a consequence of such an
arrangement, two of the peripheral phenyl groups come in
close contact with each other, and the minimal distance
between the two porphyrin planes (arbitrarily measured
between the meso-carbon atoms carrying these phenyl
˚
substituents) turns out to be 6.15, 6.19, and 7.43A respectively
for P(Zn)P(Zn), P(Zn)M(Zn), and M(Zn)M(Zn) (Figure 5).
The longest interplanar distance observed in the case of
M(Zn)M(Zn) is justified to reduce the steric hindrance
between the methyl groups of the mesityl substituents and
it is achieved through a twisted distortion of the “V-shaped”
(28) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440–467.
J. Org. Chem. Vol. 74, No. 23, 2009 9039

Carofiglio et al.
JOCArticle
TABLE 2. Results of Monte Carlo Conformational Searches with the OPLS 2005 Force Field
˚
˚
˚
entry
host
guest H2N(CH2)nNH2
d(Zn-Zn)complex (A)
d(N-N)complex (A)
d(N-N)free (A)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
P(Zn)P(Zn)
4
5
6
7
8
4
5
6
7
8
4
5
6
7
8
9.01
9.51
9.55
9.98
10.7
8.75
9.51
9.96
9.72
10.12
8.92
9.10
9.66
10.08
11.43
6.22
6.59
7.14
7.12
9.10
5.31
6.42
7.37
7.16
7.59
5.85
5.45
6.91
7.07
9.17
6.21
7.43
8.75
9.98
11.29
P(Zn)M(Zn)
M(Zn)M(Zn)
porphyrin-porphyrin arrangement (more evident in the
front view of Figure 5).
region, and (iii) the piperidine methylenic protons, at 3.94
1
and 1.75 ppm. The H NMR spectrum of free diamine in
The results of the Monte Carlo conformational searches
for all the possible host-guest combinations are reported in
Table 2. In particular, the relevant geometrical parameters of
the most stable structures include the Zn-Zn distance,
d(Zn-Zn), and the N-N distance of the diamine substrate
in the host-guest complex, d(N-N)complex. For comparison
purposes, also the N-N distance of the free diamine,
d(N-N)free, has been calculated for the extended all-trans
conformers. Data in Table 2 show that, for all receptors, the
d(Zn-Zn) increases upon binding of diamines with incre-
mental chain length. This behavior is consistent with the
experimental trend registered for the Soret band red-shift
(Δν) described in the previous paragraph, thus validating the
computational studies. As far as the diamines are concerned,
we note that in general d(N-N)complex < d(N-N)free. The
only exception is observed in the case of the P(Zn)P(Zn)-
CHCl3 at 298 K is also reported in Figure 3b. The resonance
1
assignments have been carried out by H-1H COSY and
DQF-COSY.
Noteworthy, at millimolar concentration, the P(Zn)P(Zn)
dimer undergoes aggregation phenomena, which result in the
progressive broadening of the NMR signal and ultimately
yield a massive precipitation of a porphyrin-based material.
On the other hand, addition of the diamine guest induces the
reversible dissolution of this precipitate, by effect of supra-
molecular complexation. This behavior is also reflected in
the NMR titration experiments outlined in Figure 7.
The evolution of the NMR spectrum during the titration
experiments can be conveniently discussed by analyzing the
two separate regions pertaining to the aromatic resonances of
the receptor from 9.5 to 7.0 ppm, and to the bound diamine
signals found between -1.0 and -6.0 ppm (Figure 7).
Upon incremental addition of the diamine, up to 1 equiv,
the aromatic host region shows two distinct sets of chemical
shifts, corresponding to the protons of free host and to those
of the host-guest assembly (Figure 7a-d). For the latter
complex, the new resonances build up at significant upfield
chemical shift. Precisely, the amount of shifting was about
0.25 ppm for the pyrrolic protons, whereas the aromatic
protons shifted upfield to a smaller extent (0.12-0.16 ppm)
(Figure 7). This effect is associated with the proximity of the
two porphyrin π-systems, upon diamine binding, causing the
signals to experience a large ring-current induced shift.29 A
further remark is that broadening of all the aromatic signals
is observed as well. In this respect, speciation of the receptor
may be complicated by aggregation phenomena, occurring
in the time course of the titration experiments. A key
observation is that upon reaching the 1:1 host-guest ratio,
the resulting NMR spectrum contains just the aromatic
signals ascribable to the supramolecular complex, where
the ortho and meta protons of the meso-phenyl substituents
become nonequivalent, and give rise to sharp multiplets
(Figure 7e). Similar splitting is often observed in porphyrin
systems with nonequivalent faces.30
H2N(CH2)4NH2 complex (entry 1) where d(N-N)complex
≈
d(N-N)free. Hence, the formation of the host-guest adduct
is not only related to the differences between the steric
features of the receptors, but it is also affected by the
conformational flexibility of the bound diamines. As a
matter of fact, the formation of the host-guest adduct
requires an adaption of both the binding partners. In parti-
cular, the host increases the d(Zn-Zn) by assuming a
V-shaped configuration and/or by twisting the two porphyr-
in rings in order to minimize the steric interactions between
the bulky substituents. Conversely, the diamine modifies its
more stable extended conformation by assuming a more
compact shape with some s-cis carbon-carbon bonds.
Solution Studies by NMR Spectroscopy. The solution
structure of the supramolecular complex has been further
addressed by NMR spectroscopy. We focused on the solution
behavior of the free P(Zn)P(Zn) receptor and on the forma-
tion of the host-guest complex with H2N(CH2)5NH2. This
latter is characterized by the highest binding constant among
all the supramolecular complexes under examination.
The 1H NMR spectrum of free P(Zn)P(Zn) dimer freshly
prepared in CHCl3 at 298 K is shown in Figure 6a, together
with the resonance assignments obtained by two-dimen-
sional homonuclear correlation spectroscopy techniques
(DQF-COSY). The spectrum shows three main sets of
signals: (i) the porphyrin β-pyrrolic-protons, around
9 ppm, (ii) the porphyrin phenyl protons, in the 8.5-7 ppm
ꢀ
(29) Ballester, P.; Costa, A.; Deya, P. M.; Frontera, A.; Gomila, R. M.;
Oliva, A. I.; Sanders, J. K. M.; Hunter, C. A. J. Org. Chem. 2005, 70, 6616–
6622.
ꢀ
(30) Ballester, P.; Costa, A.; Castilla, A. M.; Deya, P. M.; Frontera, A.;
Gomila, R. M.; Hunter, C. A. Chem.;Eur. J. 2005, 11, 2196–2206.
9040 J. Org. Chem. Vol. 74, No. 23, 2009

Carofiglio et al.
JOCArticle
FIGURE 6. 1H NMR (400 MHz, CDCl3) of (a) P(Zn)P(Zn) and (b) H2N(CH2)5NH2 together with the resonance assignments according to
H-H COSY and DQF-COSY (X denotes an impurity).
FIGURE 7. Signal changes in the host and guest region during the 1H NMR (400 MHz, CDCl3) titration of P(Zn)P(Zn) (0.1 mM) with
H2N(CH2)5NH2. Spectraa,b,c,d,and e respectivelyrepresentthe1HNMRspectraacquired afteradding0.0, 0.3, 0.6, 0.9, and1.2equivofdiamine.
The signals of the diamine protons, in turn, exhibit signifi-
cant upfield shifts by effect of complexation, due to ring-current
anisotropy from porphyrin π-planes.31 Indeed, with substoi-
chiometric diamine, the guest signals are found between -2and
-5 ppm chemical shift (Figure 7a-d). This evidence is con-
sistent with the bidentate amine being bound within the P(Zn)-
P(Zn) concave, via ditopic interaction, and exposed to the ring-
current effects of porphyrin macrocycles. The resonances of the
diamine, while complexed within the host, could be assigned by
DQF-COSY and TOCSY experiment as reported in Figure 7.
On the basis of this assignments, we could quantify the upfield
shift of the methylene groups (Figure 8). The order of shift
found experimentally is H1 > H2 > H3. Interestingly, above
1 equiv of diamine, the guest signals coalesce due to a fast
exchange equilibrium and cannot be observed separately
(Figure 7e).
We decided to investigate further, by computational meth-
ods, the strong high-field shift induced by the extended πsystem
of the porphyrin rings to the resonances of the diamines.32
Shielding calculations require high level DFT methods33 and,
(32) Gomila, R. M.; Garau, C.; Frontera, A.; Quinonero, D.; Ballester,
ꢀ
(31) Packer, M. J.; Zonta, C.; Hunter, C. A. J. Magn. Reson. 2003, 162,
102–112.
P.; Costa, A.; Deya, P. M. Tetrahedron Lett. 2004, 45, 9387–9390.
(33) Bagno, A.; Saielli, G. Theor. Chem. Acc. 2007, 117, 603–619.
J. Org. Chem. Vol. 74, No. 23, 2009 9041

Carofiglio et al.
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absolute stereochemical determination of chiral guests as well as
their potential for the construction of multicomponent sensing
arrays for biogenic amine detection are currently under study.
Experimental Section
Bis(phenyl-porphyrin) Homodymer, PP. The synthesis and
characterization of this compound were already reported.16
We add here the ESI-MS analysis (CH3CN þ 1% HCOOH as
eluent): 1420.7 (calcd for C96H71N14þ - [MH]þ 1420.68), 710.8
(calcd for [MH2]2þ 710.84), 474.1 (calcd for [MH3]3þ 474.32).
Bis(phenylporphyrin-ZnII) Homodymer, P(Zn)P(Zn). The
synthesis and characterization of this compound were already
reported.16 We add here the ESI-MS analysis (CH3CN þ 1%
FIGURE 8. Energy-minimized conformation obtained for the
P(Zn)P(Zn)-H2N(CH2)5NH2 host-guest complex, and experi-
mental versus calculated Δδ values evaluated for the free and
bonded diamine ligand.
þ
HCOOH as eluent): 1547.4 (calcd for C96H71N14Zn2
- [MH]þ1547.47), 774.4 (calcd for [MH2]2þ 774.2), 516.1
(calcd for [MH3]3þ 516.5).
in turn, considering the size of the complexes, a high computa-
tional effort, especially if relativistic effects are considered.
Thus, we have first tested the effect of relativity on the proton
chemical shifts by running zeroth-order regular approximation
(ZORA)34 calculations at the Scalar and Spin-Orbit level
(BLYP/TZ2P).35 To this end, we have first considered a
simplified model system made by a single Zn-porphyrin having
an ethylamine bound to the Zn ion. Comparison of nonrelati-
vistic results with those obtained at the Scalar and Spin-Orbit
level reveals that relativistic effects can be safely ignored.
Indeed, relativistic proton chemical shifts, even for the NH2
protons, the closest to the heavy atoms, differ only by less than
0.1 ppm from the nonrelativistic results. We run shielding
calculations for the most stable conformer resulting from the
conformational analysis carried out with Macromodel
(Figure 8). Relative chemical shifts, Δδ, observed for the free
and complexed diamine are then evaluated. Comparisons of
calculated and experimental Δδvalues stand in good agreement
(Figure 8). Moreover the strong deshielding of the signals and
the general trend as a function of the distance is correctly
reproduced, although a somewhat larger error is found for the
NH2 protons.
(Phenyl-porphyrin)(mesityl-porphyrin) Heterodimer, PM. To
a solution of porphyrin P (10 mg, 13 μmol) in THF (1.0 mL)
cooled at 0 °C were added a THF solution of cyanuric chloride
(2.4 mg, 13 μmol) and DIPEA (2 mg, 16 μmol). After being
stirred for 10 min at 0 °C, the solution was left to reach room
temperature. TLC analysis (silica gel, petroleum ether/ethyl
acetate 3:1 v/v) showed the disappearance of porphyrin P
(Rf 0.33) and the formation of a new TLC spot at Rf 0.7
corresponding to the monoadduct derivative between P and
cyanuric chloride. One equivalent of porphyrin M (8.3 mg,
13 μmol) was then added together with 1.2 equiv of DIPEA
and the reaction was stirred at 80 °C for 24 h, then an excess of
piperidine (3.3 mg, 39 μmol) was added together with 1.2 equiv of
DIPEA (6.2 mg, 48 μmol) and the mixture was stirred at 80 °C for
a further 3 h. The solvent was evaporated and the purple solid was
purified by flash silica gel chromatography (silica gel, petroleum
ether/ethyl acetate3:1v/v) to afford18 mg ofPMderivative (88%
yield). 1H NMR (CDCl3, 250 MHz, δ) 8.84 (m, 4H, β-pyrrole),
8.68-8.61 (m, 12H, β-pyrrole), 8.22-8.06 (m, 21H, phenyl
aromatic protons), 7.77-7.67 (m, 8H, phenyl amino), 4.00 (br
s, 4H, piperidine), 2.62 (s, 9H, mesityl), 1.84 (br s, 18H, mesityl),
1.74 (s, 6H, piperidine), -2.54 (s, 2H, pyrrole mesitylporphyrin),
-2.75 (s, 2H, pyrrole phenylporphyrin). ESI-MS (CH3CN þ 1%
þ
HCOOH as eluent): 1546.8 (calcd for C105H89N14 - [MH]þ
1546.92), 773.9 (calcd for [MH2]2þ 773.96), 516.1 (calcd for
[MH3]3þ 516.32), 387.4 (calcd. for [MH4]4þ 387.49). UV-vis
(CH2Cl2, nm) 420, 516, 552, 593, 647. Anal. Calcd for
C105H88N14: C, 81.58; H, 5.74; N, 12.68. Found: C, 81.33; H,
5.90; N 12.70.
Conclusions
A general approach to the construction of a new class of
molecular tweezers has been demonstrated by nucleophilic
substitution of the triazine scaffold with tailored aminoporphy-
rin subunits. Stereoelectronic diversity of the ditopic receptor is
readily accessed by the systematic variation of the porphyrin
substituents, and homo- or heterocombination of the two
appended porphyrin moieties. The Zn(II) derivatives under
examination provide an enhanced binding interaction with
R,ω-aliphatic diamines, resulting in supramolecular complexes
with more than 3-order of magnitude higher stability constants
as compared to the monodentate reference amine. The influence
of the porphyrin substituents on the conformational mobility of
the resulting dimeric receptor and on their recognition capabi-
lities has been demonstrated by structure-reactivity correla-
tion, NMR solution speciation, and computational studies.
Utility of the title tweezers for the molecular recognition of
diamines with rigid spacers and for the determination of the
(Phenyl-porphyrin-ZnII)(mesityl-porphyrin-ZnII) Heterodimer,
P(Zn)M(Zn). To a solution of PM (10 mg, 7 μmol) in CHCl3
(5 mL) was added a saturated solution of zinc acetate dihydrate
(in CH3OH 0.5 mL) then the mixture was refluxed for 1 h. After
removing the solvent, the residue was dissolved with CH2Cl2 and
washed with water in order to remove the excess of zinc salt. The
organic phase was dried over Na2SO4 then filtered and the solvent
was evaporated under reduced pressure to give a purple solid that
was purified by short column chromatography on silica gel
1
(eluent: CHCl3). Yield: 97%. H NMR (CDCl3, 250 MHz): δ
8.84 (m, 4H, β-pyrrole), 8.68-8.61 (m, 12H, β-pyrrole), 8.22-
8.06 (m, 21H, phenyl aromatic protons), 7.77-7.67 (m, 8H,
phenyl amino), 4.00 (br s, 4H, ortho piperidine), 2.62 (s, 9H,
p-methylphenyl), 1.84 (br s, 18H, o-methylphenyl), 1.74 (s, 6H,
m-/p-piperidine). UV-vis (CH2Cl2, nm): 423 (ε 1 168 000 M-1
cm-1), 551, 592. ESI-MS (CH3CN þ 1% HCOOH as eluent): in
the acidic conditions needed for the analysis demetalation of the
compound. Anal. Calcd for C105H84N14Zn2: C, 75.39; H, 5.06; N,
11.72. Found: C, 75.00; H, 4.90; N 11.95.
(34) de Velde, G.; Bikelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.;
van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. J. Comput. Chem. 2001, 22,
931–967.
(35) (a) Becke, A. D. Phys. Rev. A 1998, 38, 3098–3100. (b) Lee, C.; Yang,
W.; Parr, G. Phys. Rev. B 1988, 37, 785–789. (c) Miehlich, B.; Savin, A.; Stoll,
H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200–206.
Bis(mesityl-porphyrin) homodymer, MM. To a solution of
porphyrin M (10 mg, 13 μmol) in THF (1.0 mL) cooled at
0 °C were added a THF solution of cyanuric chloride (2.4 mg,
9042 J. Org. Chem. Vol. 74, No. 23, 2009

Carofiglio et al.
JOCArticle
þ
13 μmol) and DIPEA (2 mg, 16 μmol). After being stirred for
10 min at 0 °C, the solution was left to reach room temperature.
The reaction was complete, as resulting from TLC analysis
(silica gel, petroleum ether/ethyl acetate 5:1 v/v) showing the
disappearance of porphyrin M (Rf 0.38). A second equivalent
of porphyrin M (10 mg, 13 μmol) was then added together with
1.2 equiv of DIPEA and the reaction was stirred at 80 °C for 24 h
then an excess of piperidine (3.4 mg, 39 μmol) was added
together with 1.2 equiv of DIPEA and the mixture was stirred at
80 °C for 3 h. After removal of the solvent, the residue was purified
by flash silica gel chromatography (eluent: petroleum ether/ethyl
acetate 5:1 v/v) affording 20 mg of MM derivative. Yield: 90%. 1H
NMR (CDCl3, 250 MHz): δ 8.88 (m, 4H, β-pyrrole), 8.69-8.62
(m,12H,β-pyrrole), 8.21-8.04 (m, 20H, phenyl aromatic protons),
7.05 (br s, 2H, NH), 3.99 (br s, 4H, piperidine), 2.61 (s, 18H,
mesityl), 1.84 (br s, 36H, mesityl), 1.74 (s, 6H, piperidine), -2.56
(s, 4H, pyrroleNH). ESI-MS(CH3CNþ 1% HCOOH as eluent):
1672.9 (calcd for C114H107N14þ - [MH]þ 1673.16), 837.0 (calcd
for [MH]2þ 837.08), 558.3 (calcd for [MH]3þ 558.39), 419.0 (calcd
for [MH]4þ 419.05). UV-vis (CH2Cl2, nm): 420, 516, 550, 593,
648. Anal. Calcd for C114H106N14: C, 81.88; H, 6.39; N, 11.73.
Found: C, 82.10; H, 6.52; N 12.03.
C
114H103N14Zn2 - [MH]þ 1799.95). UV-vis (CH2Cl2, nm)
423 (ε 1 121 000 M-1 cm-1), 550, 593. Anal. Calcd for
114H102N14Zn2: C, 76.11; H, 5.72; N, 10.90. Found: C, 76.60;
C
H, 5.46; N, 10.75.
Acknowledgment. Financial support for this project came
from the University of Padua (Progetti di Ricerca di Ateneo-
CPDA088228/08 and Progetti Strategici 2008-HELIOS). We
thank Dr. Arianna Bassan and Dr. Elena Fioravanzo for helpful
discussions about the use of Macromodel software. NMR
shielding calculations were run on the Linux cluster of the
Laboratorio Interdipartimentale di Chimica Computazionale
of the Department of Chemical Sciences, University of Padova.
Supporting Information Available: Description of the Gen-
eral Experimental Methods, 1H NMR spectra, ESI-MS and
HPLC analyses for free and Zn(II) receptors (Figures S1-S14),
1H-1H COSY free H2N(CH2)5NH2 in CDCl3 (Figure S15),
DQF-COSY and TOCSY of H2N(CH2)5NH2 complexed to
bis(ZnII-porphyrin) host (0.3 equiv of guest present in solution)
(Figure S16), DQF-COSY free receptor P(Zn)P(Zn), and in the
presence of 1.2 equiv of H2N(CH2)5NH2 (Figure S17), HY-
PERQUAD outputs for all UV-vis titrations (Figures
S18-S33), Table S1 giving the heat of formation and XYZ
coordinates for all the host-guest complexes resulting from
theoretical calculations, and Table S2 giving the numerical
values of the Soret band shift (Δν) upon complexation with
diamines. This material is available free of charge via the
Internet at http://pubs.acs.org.
Bis(mesityl-porphyrin-ZnII) Homodymer, M(Zn)M(Zn). This
derivative was prepared from MM following the same procedure
described for compound P(Zn)P(Zn). Yield: 97%. 1H NMR
(CDCl3, 250 MHz): δ 8.98 (m, 4H, β-pyrrole), 8.78-8.71 (m,
12H, β-pyrrole), 8.23-8.06 (m, 20H, phenyl aromatic protons),
7.07 (br s, 2H, NH), 4.00 (br s, 4H, piperidine), 2.63 (s, 18H,
mesityl), 1.85 (br s, 36H, mesityl), 1.74 (s, 6H, piperidine). ESI-
MS (CH3CN þ 1% HCOOH as eluent): 1799.9 (calcd for
J. Org. Chem. Vol. 74, No. 23, 2009 9043