Cyclam functionalization through isocyanate insertion in Zr-N bonds

Article abstract of DOI:10.1021/ic201750y

The insertion of isocyanates in (Bn₂Cyclam)ZrX₂ is regioselective; (Bn₂Cyclam)Zr(OR)₂ produces urea-like moieties by the insertion of RN=C=O in the Zr-N_amido bonds of the cyclam ring. Depending on the bulkiness of the isocyanate R groups, O- and N-bound ureates are formed. (Bn₂Cyclam)Zr(NH^tBu) ₂ reacts with MesN=C=O at the terminal Zr-N bonds.

Full text of DOI:10.1021/ic201750y

Communication
pubs.acs.org/IC
Cyclam Functionalization through Isocyanate Insertion in Zr−N
Bonds
Luis G. Alves and Ana M. Martins*
Centro de Química Estrutural, Instituto Superior Tec
Portugal
́ ́
nico, Universidade Tecnica de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa,
S
* Supporting Information
ABSTRACT: The insertion of isocyanates in
(Bn2Cyclam)ZrX2 is regioselective; (Bn2Cyclam)Zr(OR)2
produces urea-like moieties by the insertion of RNC
O in the Zr−Namido bonds of the cyclam ring. Depending
on the bulkiness of the isocyanate R groups, O- and N-
bound ureates are formed. (Bn2Cyclam)Zr(NHtBu)2
reacts with MesNCO at the terminal Zr−N bonds.
Figure 1. Molecular structure of 2a. Displacement ellipsoids are shown
at the 40% probability level. Selected bond lengths (Å) and angles
(deg): Zr−O1 2.003(4), Zr−O2 2.008(3), Zr−N1 2.478(4), Zr−N2
2.097(4), Zr−N3 2.474(4), Zr−N4 2.078(4); O1−Zr−O2 91.06(13).
he coordinating ability of cyclam to a large range of metal
T
ions and the significant properties of many of its
compounds are extensively documented.1 Recent applications
of cyclam derivatives in biological and medicinal studies2
mainly focused on the development of (i) selective sensors for
adenosine triphosphate, zinc, and NO regulation/delivering
processes,3 (ii) radiometal chelates for diagnosis and treat-
ment,4 and (iii) anti-HIV agents.5 Modification of the
macrocycle framework by the attachment of substituents at
the nitrogen atoms is a requisite for optimization of these
properties because it allows the design of highly sensitive and
specific molecular probes by increasing the selectivity toward
bonding and providing suitable anchoring functional groups.6 A
major drawback associated with these issues is related to the
lack of efficient synthetic processes for selective functionaliza-
tion of cyclam, which often involve multistep sequences and
low overall yields.7
The reactions of 2a with equimolar amounts of RNCO
i
t
(R = Pr, Bu) result in the insertion of isocyanates into one of
the Zr−Namido bonds of the cyclam ring, leading to the
formation of N-bound urea-like fragments. The formulation of
3a and 3b was suggested by IR and NMR and further
confirmed by X-ray diffraction of 3a, as shown in Figure 2.
The NMR spectra of 3a and 3b reveal a fluxional process
compatible with the equilibrium shown in eq 1. This process,
The work reported here extends our investigation of cyclam-
based diamidodiamine zirconium complexes8 and describes a
new methodology to the syntheses of N-substituted cyclam
derivatives by the insertion of isocyanates in the Zr−Namido
bonds of the cyclam ring.
The insertion of isocyanates into Ti−N or Zr−N bonds was
scarcely reported.9 A mechanistic study carried out with
zirconocene complexes revealed that previous coordination to
the metal is not a requirement. The bonding of the resulting
carbamide groups to the zirconium was postulated through the
oxygen considering the oxophilicity of the metal, but the
authors did not exclude N-coordinated ureate ligands.9b
The treatment of (Bn2Cyclam)ZrCl2 (1) with 2 equiv of
which corresponds to the swinging of the zirconium between
the two amines of the original tetraazaring (in red and blue in
eq 1), fades the difference between the syn and anti macrocyclic
protons that show up as apparent triplets. The pendulum
movement of the metal between the two macrocycle amines
releases interaction of the zirconium with the macrocycle frame
compared to complexes anchored on the four N atoms of the
cyclam ring and accordingly the ring resonances display a high
i
t
LiOR (R = Pr, Bu) proceeds through chloride metathesis to
i
t
give (Bn2Cyclam)Zr(OR)2 (2; R = Pr, 2a; Bu, 2b). The
molecular structure of 2a reveals coordination of the four N
atoms of the macrocycle to the Zr atom in a trigonal-prismatic
geometry (Figure 1) similar to other (Bn2Cyclam)ZrX2
complexes.8a,b
Received: August 11, 2011
Published: December 7, 2011
© 2011 American Chemical Society
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Inorganic Chemistry
Communication
set of resonances due to the cyclam ring suggests a fluxional
process that interconverts the metallacycles. This process likely
involves cleavage of the Zr−Ncyclam bond and isomerization of
the pentacoordinated intermediate, followed by recoordination
of the Ncyclam amine. This type of equilibrium was observed in
titanium and zirconium azametallacycles formed by coordina-
tion of a macrocycle amine and another function (alkoxido or
amido) appended to it.11 The 13C NMR spectrum displays only
one resonance at δ 158.3 ppm for NC(O)N, and the IR
spectrum shows one νCO signal at 1675 cm−1.
The treatment of 2b with 2 equiv of 1-naphthyl isocyanate
led to the insertion of isocyanate in the two macrocycle Zr−
Namido bonds (5 in Figure 3). In contrast to compounds 3 and
4, 5 displays O-bonded ureate moieties that give rise to one
νC−O band at 1388 cm−1 and two νCN bands at 1582 and 1570
cm−1. The 1H NMR spectrum of 5 displays very broad
resonances that spread from δ 1.23 to 3.22 ppm, and the
quaternary carbon of the ureate group shows up at δ 166.7 ppm
in the 13C{1H} NMR spectrum.12 It was not possible to attain a
limit spectrum until −80 °C. The NMR pattern observed for
the cyclam protons of 5 suggests that, analogously to 4, an
exchange between the two four-membered metallacycles,
responsible for the magnetic equivalence of the two C2 and
two C3 chains of cyclam, is taking place in the solution. The
naphthyl groups in 5 are responsible for the fluorescent
behavior observed when the compound is exposed to sunlight.
The UV−vis spectrum of 5 shows an absortion band at 297 nm
and a fluorescence emission band at 375 nm. Hydrolysis of
complexes 3−5 afforded 6, 7, and 8 in almost quantitative yield
(Scheme 1). While NMR data for 7 reveal a C1 symmetry
species, the NMR spectra of 6 and 8 indicate C2 symmetry.
Figure 2. Molecular structure of 3a. Displacement ellipsoids are shown
at the 40% probability level. Selected bond lengths (Å) and angles
(deg): Zr−O1 1.957(2), Zr−O2 1.922(2), Zr−N1 2.507(3), Zr−N2
2.099(2), Zr−N4 2.479(2), Zr−N5 2.253(2), N4−C31 1.523(5),
N5−C31 1.324(5), C31−O3 1.226(4); N4−C31−N5 108.1(3), N1−
Zr−O2 170.55(11), N4−Zr−O1 151.19(10), N2−Zr−N5
154.18(12).
average symmetry,10 even though the OiPr ligands are
inequivalent.
i
The further addition of PrNCO to 3a led to the
insertion of a second isocyanate in the remaining Zr−Namido
1
bond of the macrocycle, 4 (Figure 3). The H NMR spectrum
Scheme 1. Compounds 6−8
The results described show that the Zr−OR bonds of 2 are
inert toward isocyanate insertion, and regardless of the
bulkiness of RNCO, the insertion is regioselective and
takes place at the Zr−N bonds of the cyclam ring; the
formation of N- or O-bonded ligands is likely determined by
the steric bulk of the nitrogen substituent in the isocyanate.
In order to compare the reactivity of a terminal primary
amido ligand with a cyclam-based amido moiety, we performed
the reaction of (Bn2Cyclam)Zr(NHtBu)2 (9) with MesN
CO. (Bn2Cyclam)Zr(NHtBu)2 may be described as a
particular tetraamidozirconium(IV) species displaying two
terminal N(H)tBu ligands and two secondary amido groups
incorporated in the cyclam frame. The Zr−Namine distances are
very elongated, and the geometry around the metal is best
described as tetrahedral with two capped Zr−Namine groups.8c
The 1:1 reaction of 9 with MesNCO led to isocyanate
insertion in the terminal amido ligand with formation of
(Bn2Cyclam)Zr(NHtBu){OC(NHtBu)NMes} (10), display-
ing an O-bonded carbamide fragment (Figure 4). The IR
spectrum of 10 displays a νC−O band at 1330 cm−1 and a νCN
band at 1655 cm−1, which attests to electron delocalization
along the N−C−N fragment. The NMR data of 10 are
Figure 3. Complexes 4 and 5, respectively (Np = 1-naphthyl).
displays broad resonances for the macrocyclic chains, in
agreement with cleavage of the two Zr−Namine bonds of the
cyclam ring, and two nonequivalent OiPr and NiPr fragments.
On the basis of the NMR data, the coordination geometry
around the Zr atom is distorted-octahedral with two cis-OiPr
ligands and two orthogonal four-membered metallacycles
[ZrNcyclamC(O)NiPr] formed upon isocyanate insertion. The
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Inorganic Chemistry
Communication
*E-mail: ana.martins@ist.utl.pt.
ACKNOWLEDGMENTS
■
The authors thank Jose
́
A. Ferreira for the UV−vis spectrum of
5, Jose
́
R. Ascenso for the NOESY NMR correlation of 10, and
Maria C. Oliveira for the electrospray ionization mass
spectrometry spectra of 6 and 7. This work was funded by
FCT, Portugal (SFRH/BD/44295/2008, PTDC/QUI/66187/
2006, and PEst-OE/QUI/UI0100/2011).
REFERENCES
■
Figure 4. Complex 10.
(1) (a) Hajj, F. E.; Sebki, G.; Patinec, V.; Marchivie, M.; Triki, S.;
Handel, H.; Yefsah, S.; Tripier, R.; Gom
Inorg. Chem. 2009, 48, 10416−10423. (b) Shihadeh, Y. A.; Benito, A.;
Lloris, J. M.; Martínez-Manez, R.; Pardo, T.; Soto, J.; Marcos, M. D.
́
ez-García, C. J.; Coronado, E.
1
compatible with a C1 symmetry species. The H chemical shift
of the N(H)tBu moiety is appreciably shifted to low field (δ
6.45 ppm). The resonance assigned to this proton shifts to high
field when the temperature is raised, thus suggesting that it is
involved in a hydrogen bridge. Further information on this
interaction was provided by the NOESY NMR spectrum that
shows cross peaks between the bridging proton (δ 6.45 ppm)
and protons belonging to one C2 and one C3 macrocyclic
chains, as well as the benzylic protons of one AB system. On
the basis of the spectroscopic information, it is possible to
assign a structure to 10 that is represented in Figure 4. It is
noteworthy that, although isocyanate insertion took place at the
terminal NHtBu group, the establishment of a hydrogen bridge
with the macrocyclic amido function points out the availability
of its electron pairs. Thus, it is not surprising that the insertion
reactions in 2 and 3 occur at the cyclam Namido functions
alternatively to the Zr−OR bonds that are less reactive in view
of the high oxophilicity of zirconium.
In conclusion, the reactions described disclose a new
reactivity pattern based on the insertion of isocyanates in the
Zr−N bonds of dianionic cyclam derivatives of 2. The high
oxophilicity of the zirconium is likely responsible for this
behavior, which allows the selective functionalization of cyclam
with one or two urea fragments. The stoichiometric ratio
between RNCO and the complex controls mono- or
diinsertion, and the type of product obtained, O- or N-bonded
ureates, seems to be dictated by the bulkiness of the
isocyanates. To the best of the author’s knowledge, this is the
unique reliable method for the syntheses of these types of
compounds. If (Bn2Cyclam)Zr(NHtBu)2 reacts with MesN
CO, the insertion in the terminal Zr−N bonds is favored.
The reactions of other polar molecules (CS2, CO2, allenes,
isocyanides, and cyclic esters) with (Bn2Cyclam)ZrX2 com-
plexes are currently under study. It is noteworthy that the
insertion of isocyanates does not take place in 1. The results
demonstrate that the bonding of diamido/diamine cyclam
ligands to zirconium is sensitive to the nature of the two
additional ligands that may regulate the reactivity of the
macrocycle toward insertion and, in this way, determine the
significance of this method in cyclam functionalization.
́
̃
Dalton Trans. 2000, 1199−1205. (c) Mahato, P.; Ghosh, A.; Saha, S.;
Mishra, S.; Mishra, S. K.; Das, A. Inorg. Chem. 2010, 49, 11485−11492.
(d) Cho, J.; Sarangi, R.; Kang, H. Y.; Lee, J. Y.; Kubo, M.; Ogura, T.;
Solomon, E. I.; Nam, W. J. Am. Chem. Soc. 2010, 132, 16977−16986.
(2) Liang, X.; Sadler, P. J. Chem. Soc. Rev. 2004, 33, 246−266.
(3) (a) Mahato, P.; Ghosh, A.; Mishra, S. K.; Shrivastav, A.; Mishra,
S.; Das, A. Chem. Commun. 2010, 46, 9134−9136. (b) Majzoub, A. E.;
́
Cadiou, C.; Dechamps-Olivier, I.; Tinant, B.; Chuburu, F. Inorg. Chem.
2011, 50, 4029−4038. (c) Lim, M. H.; Lippard, S. J. Acc. Chem. Res.
2007, 40, 41−51. (d) Ford, P. C. Acc. Chem. Res. 2008, 41, 190−200.
(4) (a) Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J.
Chem. Rev. 2010, 110, 2858−2902. (b) Lebedev, A. Y.; Holland, J. P.;
Lewis, J. S. Chem. Commun. 2010, 46, 1706−1708. (c) Shokeen, M.;
Anderson, C. J. Acc. Chem. Res. 2009, 42, 832−841. (d) Donnelly, P. S.
Dalton Trans. 2011, 40, 999−1010.
(5) Ross, A.; Soares, D. C.; Covelli, D.; Pannecouque, C.; Budd, L.;
Collins, A.; Robertson, N.; Parsons, S.; De Clercq, E.; Kennepohl, P.;
Sadler, P. J. Inorg. Chem. 2010, 49, 1122−1132.
(6) Chong, H.; Garmestani, K.; Ma, D.; Milenic, D. E.; Overstreet,
T.; Brechbiel, M. W. J. Med. Chem. 2002, 45, 3458−3464.
̀
(7) (a) Denat, F.; Brandes, S.; Guilard, R. Synlett 2000, 561−574.
(b) Lebedev, A. Y.; Holland, J. P.; Lewis, S. J. Chem. Commun. 2010,
46, 1706−1708.
́
(8) (a) Munha, R. F.; Namorado, S.; Barroso, S.; Duarte, M. T.;
Ascenso, J. R.; Dias, A. R.; Martins, A. M. J. Organomet. Chem. 2006,
691, 3853−3861. (b) Munha, R. F.; Veiros, L. F.; Duarte, M. T.;
Fryzuk, M. D.; Martins, A. M. Dalton Trans. 2009, 7494−7508.
(c) Alves, L. G.; Antunes, M. A.; Matos, I.; Munha, R. F.; Duarte, M.
T.; Fernandes, A. C.; Marques, M. M.; Martins, A. M. Inorg. Chim. Acta
2010, 363, 1823−1830. (d) Munha, R. F.; Antunes, M. A.; Alves, L.
G.; Veiros, L. F.; Fryzuk, M. D.; Martins, A. M. Organometallics 2010,
29, 3753−3764. (e) Antunes, M. A.; Munha, R. F.; Alves, L. G.;
́
́
́
́
Schafer, L. L.; Martins, A. M. J. Organomet. Chem. 2011, 696, 2−6.
(9) (a) Chandra, G.; Jenkins, A. D.; Lappert, M. F.; Srivastava, R. C. J.
Chem. Soc. A 1970, 2550−2558. (b) Norton, J. R.; Gately, D. A.;
Goodson, P. A. J. Am. Chem. Soc. 1995, 117, 986−996. (c) Wang, H.;
Li, H.-W.; Xie, Z. Organometallics 2003, 22, 4522−4531. (d) Hsieh, K.-
C.; Lee, W.-Y.; Lai, C.-L.; Hu, C.-H.; Lee, H. M.; Huang, J.-H.; Peng,
S.-M.; Lee, G.-H. J. Organomet. Chem. 2004, 689, 3362−3369. (e)
General reference: Braunstein, P.; Nobel, D. Chem. Rev. 1989, 89,
1927−1945.
(10) Ferreira, H.; Dias, A. R.; Duarte, M. T.; Ascenso, J. R.; Martins,
A. M. Inorg. Chem. 2007, 46, 750−755.
ASSOCIATED CONTENT
* Supporting Information
(11) Barroso, S.; Cui, J.; Dias, A. R.; Duarte, M. T.; Ferreira, H.;
Henriques, R. T.; Oliveira, M. C.; Ascenso, J. R.; Martins, A. M. Inorg.
Chem. 2006, 45, 3532−3537.
■
S
Experimental details concerning the syntheses and character-
ization of all new compounds and crystallographic data for 2a
and 3a (CCDC 826142 and 826143). This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Leitch, D. C.; Schafer, L. L. Organometallics 2010, 29, 5162−
5172.
AUTHOR INFORMATION
Corresponding Author
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dx.doi.org/10.1021/ic201750y | Inorg. Chem. 2012, 51, 10−12