On the structure and spectroscopic properties of the cis- and trans-isomers of cyclen- and cyclam-glyoxal

Journal of Molecular Structure (Theochem) 582 (2002) 187±193

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On the structure and spectroscopic properties of the cis- and trans-isomers of cyclen- and cyclam-glyoxal V. Galasso a,*, F. Chuburu b, H. Handel b, M. Le Baccon b, D. Jones c a Dipartimento di Scienze Chimiche, UniversitaÁ di Trieste, I-34127 Trieste, Italy Universite de Bretagne Occidentale, 6 av. Le Gorgeu, BP 809, 29285 Brest, France c Istituto dei Composti del Carbonio Contenenti Eteroatomi e loro Applicazioni, C.N.R., via Gobetti 101, I-40129 Bologna, Italy b

Received 24 September 2001; accepted 12 November 2001

Abstract The equilibrium structures of the cis- and trans-isomeric derivatives of the cyclen and cyclam condensation products with glyoxal were investigated with the density functional theory (DFT) model B3LYP/6-31G(d,p). According to calculations, the trans-fused condensation product is more stable than the cis product by 2 kcal mol 21 in the case of cyclam. For cyclen, the stability order is instead inverted, the cis-fusion being much more preferred by 9.8 kcal mol 21. The 13C NMR chemical shifts were recorded and analyzed by means of continuous set of gauge transformations (CSGT) calculations performed with the HFB3LYP/6-3111G(2d,p) hybrid functional model. The He(I) photoelectron spectra were measured and interpreted by means of ab initio outer valence Green function (OVGF) calculations, which give a consistent, overall description of the uppermost bands, associated with the four nitrogen lone pair orbitals. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Ab initio and DFT calculations; Structures; NMR chemical shifts; Photoelectron spectra

1. Introduction A homologous series of tetracyclic tetraamines may be prepared by glyoxal-macrocyclic tetraamine condensation [1]. Of these systems, the cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives are of current interest due to the biomedical importance of their complexing properties. The synthetic routes, thus far reported, have succeeded in obtaining the cyclam condensation products with both the cis- and trans-con®guration of the central two-carbon bridge. These two compounds, in the following referred to as cis- and trans-DTAP (decahydro* Corresponding author. Fax: 139-040-676-3903. E-mail address: [email protected] (V. Galasso).

1H,6H-3a,5a,8a,10a-tetraazapyrene), have been fully characterized [1±5]. In contrast, only the cisfused condensation product of cyclen with glyoxal has been prepared and characterized [5±7], and it has been argued that its hitherto unreported transfused isomer is thermodynamically less stable because of a severe steric strain. These isomers will be referred to as cis- and trans-DTAC (decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene). Given the differences in the size of the fused rings and in the con®guration of the central bridge, but having four tetrahedrally arranged N lone pair orbitals (LPOs) in common, a combined investigation of the structural and spectroscopic properties of all four compounds therefore seemed useful. Here, we report calculations of the equilibrium molecular structures of all four of these systems using density functional

0166-1280/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S 0166-128 0(01)00781-3

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Table 1 Ê , sum of bond angles at central carbons and Theoretical structural data of DTAC and DTAP: relative energies in kcal mol 21, bond lengths in A nitrogens and torsion angles in degrees, and hybridization of nitrogen lone pair orbitals

DE r(C1C2) r(C3C4) P a (C1) P a (N1) P a (N2) N1(LPO) N2(LPO) t (H1C1C2H2) t (N1C4C3N4) t (C1N1C4C3) t (N1C1C2N2) t (N1C1C2N3) t (N2C1C2N4)

cis-DTAC

trans-DTAC

0 1.514 1.570 333.30 326.63 335.36 sp 5.11 sp 6.20 43.68 8.82 19.08 45.88 164.84 73.07

9.80 1.477 1.583 324.68 335.08 sp 6.16 180 0 27.69 65.20 180

theory (DFT) methodologies. Since NMR chemical shifts are very ef®cient monitors of the stereochemistry of such molecules, their d ( 13C) spectroscopic parameters were recorded and were also calculated using the continuous set of gauge transformations (CSGT) method, implemented with the B3LYP exchangecorrelation DFT-HF hybrid functional. The electronic structures of DTAC and DTAP, characterized by the manifold of four N LPOs, were also investigated by measuring the He(I) photoelectron (PE) spectra, which were interpreted by means of ab initio manybody calculations using the outer valence Green function (OVGF) method.

cis-DTAP 2.03 1.545

trans-DTAP 0 1.550

334.72 337.08 332.85 sp 6.62 sp 5.69 46.06

329.14 334.22

50.38 176.12 75.36

58.84 180

sp 5.89 180

2. Computational and experimental details The equilibrium structures of all conformers were completely optimized with the B3LYP hybrid functional [8] and the standard 6-31G(d,p) basis set, using the gaussian-98 package [9]. The combination of this functional, which takes into account the electron exchange-correlation effects, and the polarized basis set offers a good compromise between the size of the calculations and the accuracy of the theoretical predictions. Localization of the molecular orbitals (MOs) was performed according to the NBO analysis program [10]. The 13C NMR absolute shielding constants (s values) were calculated at the B3LYP-DFT level with the CSGT method [11], using the 63111G(2d,p) basis set. The calculated magnetic shieldings were converted into the d chemical shifts by noting that at the same level of theory the 13C shielding value in TMS is 177.51. The vertical ionization energies (IEs) were calculated at the ab initio level according to Cederbaum's OVGF method [12], which includes the effects of electron correlation and reorganization beyond the Hartree±Fock approximation. The selfenergy part was expanded up to third order and the contributions of higher orders were estimated by

V. Galasso et al. / Journal of Molecular Structure (Theochem) 582 (2002) 187±193

189

Fig. 1. The DFT optimized structures of cis-DTAC (upper) and cisDTAP (down).

Fig. 2. The DFT optimized structures of trans-DTAC (upper) and trans-DTAP (down).

means of a renormalization procedure. In order to calculate the self-energy part, all occupied valence MOs and the 71 and 81 lowest virtual MOs were considered for DTAC and DTAP, respectively. The double-z plus polarization [4s2p1du2s1p] basis set [13] was used. The tetraamines were synthesized as previously described [4,6]. The He(I) spectra were recorded on a Perkin Elmer PS-18 photoelectron spectrometer connected to a Datalab DL4000 signal analysis system. The bands, calibrated against rare-gas lines, were located using the position of their maxima, which were taken as corresponding to the vertical ionization energy values (^0.05 eV). The 13C NMR spectra of cis- and trans-DTAP were measured in CDCl3 solution on a Brucker DRX500 Avance spectrometer at 400 MHz and 25 8C.

3. Results and discussion A selection of the most relevant structural parameters of all molecules (bond lengths, sum of the valence angles at bridging carbons and nitrogens, torsion angles, and hybridization of N LPOs) are presented in Table 1; a full listing of the atomic coordinates may be obtained from the authors on request. The main aspects of the experimental information and present DFT conformational analysis are summarized below. First, it must be stressed that, according to the DFT calculations, not only does the known cis-DTAC of C2 symmetry have a static structure, but so also does the as yet unsynthesized trans-isomer of C2h symmetry: harmonic frequency calculations, indeed, gave no imaginary vibrational frequencies. From the

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Table 2 Observed vs. calculated carbon chemical shifts (d ) for DTAC and DTAP Nucleus

C1 C3 C4 C5 C6 C1 C3 C4 C5 C6 C7 a b

cis-DTAC

trans-DTAC

Theor.

Expt.

76.6 48.1 50.9 51.2 47.0 cis-DTAP Theor. 76.5 52.6 19.8 55.1 53.2 44.4

77.5 50.0 52.4 51.5 49.2

a

Expt. b 77.0 52.5 19.6 56.0 54.4 44.8

Theor.

Expt.

81.8 49.7 49.5 trans-DTAP Theor. 79.8 52.8 24.2

Expt. b 83.6 54.1 24.2

51.8

52.7

From Ref. [5]. This work.

theoretical standpoint, such a free tetraamine is therefore perfectly feasible and remains a challenging synthetic target. It is, however, predicted to be less stable than the cis-isomer by 9.8 kcal mol 21. The distinctive structural feature of both the cisand trans-DTAC isomers is the marked stretching of the peripheral C±C bonds in the two ®ve-membered rings. Upon formal conversion from cis to trans conformation the most important structural modi®cations are: (1) the shortening of the central C±C bridge Ê ); (2) the more acute pyrami(from 1.514 to 1.477 A dalization of the central carbons, which is measured P by the sum of the three C±C±C angles (from a ˆ 333:0 to 324.78); and (3) the shortening of the distance Ê ). between adjacent nitrogens (from 2.309 to 2.272 A In both isomers, the two six-membered rings are chair-shaped. The two ®ve-membered rings, instead, are half-chairs in the cis- (Fig. 1) and envelopes in the trans-conformation (Fig. 2): the envelope arrangement is characterized by one small dihedral angle (98), which doubles in the half-chair arrangement (198). The consequence of the presence of two fully eclipsed ethano units, a shorter central bridge and a closer proximity of the adjacent N LPOs, positioned in the same face of the molecule, is a severe steric strain in trans-DTAC. The dif®culty encountered in the synthesis of trans-DTAC, as opposed to the ready

availability of the cis-isomer, can therefore be traced to its peculiar bonding situation. No experimental X-ray structure has been reported for unsubstituted cis-DTAC. Recently, Rohovec et al. [7] have determined the X-ray structures of two mono- and bis-quaternary ammonium salts of cisDTAC and Rojas-Lima et al. [5] have established the X-ray structure of a diborane adduct of cisDTAC. However, the positive charges on the nitrogens as well as the N ! B bonds dramatically perturb the molecular arrangement around the nitrogens and therefore no direct comparison is possible. In contrast to DTAC, the trans conformer (C2h symmetry) of DTAP is predicted to be more stable than the cis conformer (C2 symmetry) by 2 kcal mol 21. It should also be noted that the present DFT energy order for the isomers of DTAP is the opposite of that previously determined by Okawara et al. [14] with semiempirical AM1 calculations. The principal structural feature that distinguishes the cis and transisomers of DTAP is the diamond-lattice geometry. In both isomers, the four six-membered rings are all regular chairs, assembled as a saddle-type array in cis (Fig. 1) and a ¯attened ladder-type array in trans (Fig. 2). Common to both isomers is the length of the Ê ), which is quite similar to central C±C bond (1.55 A the normal length of a strain-free single bond between two saturated tetravalent (nominally sp 3 hybridized) Ê , as is observed, e.g. for the carbons atoms of 1.54 A central bond in butane [15]. The theoretical structural parameters are consistent with those obtained from Xray data by Gluzinski et al. [3]. In particular, the length of the central P bond, the shortest intraring N´ ´ ´N distance, and a of the central carbons are: Ê , and 334.78 (theoretical) vs. 1.52, 1.54, 2.43 A Ê 2.43 A, and 332.78 (experimental) for cis-DTAP; Ê , 329.18 (theoretical) vs. 1.53, 2.40 A Ê, 1.55, 2.40 A 327.78 (experimental) for trans-DTAP. The orbital composition of the N LPO is mainly governed by the degree P of pyramidalization, measured by the relevant a reported in Table 1. Accordingly, in all conformers the N LPOs have a marked p-character. As expected, these relative hybridizations closely resemble that computed for the related monocyclic system, N,N 0 -dimethyl-hexahydropyrimidine (sp 5.76). As a consequence of their peculiar stereochemistry, the patterns of the spectroscopic properties of the

V. Galasso et al. / Journal of Molecular Structure (Theochem) 582 (2002) 187±193

191

Fig. 3. Photoelectron spectra of cis-DTAC, cis-DTAP, and trans-DTAP.

present molecules exhibit important analogies and differences. Among the various spectroscopic observables, the NMR chemical shifts and ionization energies are very ef®cient monitors of the complex interplay of structural and electronic effects operating in a molecule. Therefore, we report here on these properties. The 13C chemical shifts calculated by the CSGT formalism with the B3LYP/6-3111G(2d,p) model are collected in Table 2. It must be noted that highly accurate predictions of the d ( 13C) observables require very large basis sets and high orders of perturbation theory or coupled-cluster methods, but for the present medium-sized molecules these requirements are computationally severe. However, the CSGT theoretical results are in substantial accord with the available experimental values. In particular, the high deshieldings of the carbons C1 and C2 in the aminal bridge and the large differences …Dd . 25† between their chemical shifts and those of the other secondary NCH2 carbons are well accounted for. According to both observation and theory, the N±C±N signal moves down®eld on passing from cis to transDTAP, and a similar displacement is also predicted for DTAC. For DTAP, the down®eld shift …Dd ˆ 4:5† of the C±C±C resonance on going from the cis to the trans conformer is reproduced accurately. Finally, it is worth mentioning that the CSGT estimate of the deshielding of the aminal proton of cis-DTAP relative to that in trans-DTAP …Dd ˆ 0:94† is in good agreement with experiment …Dd ˆ 0:78†: An effect of similar magnitude …Dd ˆ 1:07† is also predicted in the case of the corresponding isomers of DTAC. All

these data manifest the large and long-range effects of the four N LPOs. Unfortunately, the open-chair precursor, tetrakis(dimethylamino)ethano, has not yet been synthesized and characterized, which precludes an estimate of the relevant polycyclization effects on the ring carbons of DTAC and DTAP. The most remarkable aspects of the PE spectra of the investigated molecules concern the location and splitting of the manifold of the photoionizations originating from the four N LPOs. The adjacent LPOs are arranged with the syn con®guration in the trans-isomer and with the anti con®guration in the cis-isomer. In each conformer, the two sets point in opposite directions. From a qualitative standpoint, the LPOs generate four semilocalized n MOs, which under the C2 point group of the cis-isomer are:

c 1 …a† ˆ …n1 1 n3 † 1 …n2 1 n4 †; c 2 …a† ˆ …n1 1 n3 † 2 …n2 1 n4 †; c 3 …b† ˆ …n1 2 n3 † 1 …n2 2 n4 †; c 4 …b† ˆ …n1 2 n3 † 2 …n2 1 n4 †; while for the trans-isomer of C2h symmetry:

c 1 …ag † ˆ n1 1 n2 1 n3 1 n4 ; c 2 …au † ˆ n1 1 n2 2 n3 2 n4 ; c 3 …bg † ˆ n1 2 n2 1 n3 2 n4 ; c 4 …bu † ˆ n1 2 n2 2 n3 1 n4 :

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Table 3 Vertical ionization energies (eV) of DTAC and DTAP. Molecular orbital symmetry (MO), Koopmans' theorem value (KT), and ionization energy (IE) cis-DTAC

trans-DTAC

MO

KT

IE

26b(n) 27a(n) 26a(n) 25b(n) 25a(s ) 24a 24b 23b 23a 22a 22b 21b

9.22 9.62 9.83 9.88 12.07 12.51 12.53 12.98 13.07 13.45 13.74 13.92

7.95 8.30 8.55 8.56 11.01 11.44 11.45 11.88 11.89 12.32 12.58 12.75

cis-DTAP MO KT 30b(n) 9.13 31a(n) 9.23 29b(n) 9.67 30a(n) 9.78 29a(s ) 11.53 28a 12.31 28b 12.39 27b 12.74 27a 13.00 26b 13.06 26a 13.24 25b 13.40 25a 13.81 24b 13.87

IE 7.88 7.93 8.32 8.50 10.46 11.25 11.27 11.63 11.84 11.96 12.08 12.27 12.58 12.69

IEexp 8.4 10.7

IEexp. 7.8 8.4 10.3 11.2

MO

KT

IE

12au(n) 14bu(n) 16ag(n) 11bg(n) 15ag(s ) 10bg 15ag 11au 13bu 14ag 10au 9bg

9.27 9.42 9.50 9.70 12.21 12.49 12.72 12.78 13.17 13.32 13.51 13.93

7.94 8.10 8.29 8.35 11.16 11.41 11.54 11.68 12.08 12.18 12.38 12.73

trans-DTAP MO KT 17bu(n) 9.30 19ag(n) 9.43 9.59 13au(n) 12bg(n) 9.97 18ag(s ) 11.47 11.89 11bg 12au 12.15 17ag 12.80 16bu 13.01 13.25 16ag 15bu 13.42 11au 13.58 10bg 13.69 13.71 10au

IE 8.01 8.23 8.24 8.59 10.41 10.82 11.02 11.74 11.92 12.06 12.32 12.40 12.49 12.54

IEexp

IEexp. 7.9 8.5 10.3 10.7 11.0

These MOs are energetically split by a mediated interplay of through-space and through-bond interactions. In the present molecules, formally built by two directly linked N±CH2 ±N units, both 1,3- and 1,4interactions are operative. The low-energy regions of the He(I) PE spectra of cis-DTAC, cis- and trans-DTAP are shown in Fig. 3. The ®rst broad band with a complex envelope is attributed to emissions from the N LPOs. After a gap as large as 1 eV, there is the onset of a prominent, congested band system, which is associated with the series of the s-photoionizations. The ab initio Koopmans' theorem (KT) values, i.e. orbital energies, OVGF ionization energies (IEs), and assignments are given in Table 3. The pole strengths

calculated for all photoionizations are about 0.9, which indicates the reasonable validity of the one-particle model for these processes. It should be stressed that highly accurate predictions of the IEs require very large basis sets and exhaustive treatment of the particle space. However, the theoretical results provided by the nonempirical OVGF formalism allow a correct interpretation of the observed spectroscopic features of DTAC and DTAP. For each compound, the composite lowenergy band is associated with the four closely spaced n levels. Both the theoretical average value nÄ of these IEs (8.34, 8.16, and 8.27 eV) and their overall separation D (0.61, 0.52, 0.58 eV) for cis-DTAC, cis-DTAP, and trans-DTAP, respectively, are in substantial agreement with the corresponding spectroscopic bands, which are centered at 8.4, 8.1, and 8.2 eV and have a width of 1.2 eV (FWHM). For trans-DTAC nÄ is predicted to lie at 8.15 eV, with a D of 0.41 eV. According to theory, the remaining features in the spectra of all conformers are generated by subsets of many near-lying s-photoionizations. The nÄ and D of the present tetracyclic tetraazacompounds are similar to those of the simple related monocyclic diaza-compound, N,N 0 -dimethyl-hexahydropyrimidine (8.31 and 0.40 eV [16]). A further correlation can be made with the highly symmetrical molecule 1,4,7,10-tetraazatetracyclo[5.5.1.0 4,13.0 10,13]tridecane, which displays the unusual C(NC2)4 framework of D2 symmetry. Its PE features (experimental: nÄ 8.20 and FWHM 1.0 eV; theoretical: nÄ 8.10 and D 0.61 eV) [17] also closely resemble those of DTAC and DTAP, which indicates a similar balance of competing stereoelectronic factors within these tetracyclic molecular frameworks, pivoted upon a central carbon atom or an ethano bridge, respectively. Finally, it is worth mentioning that, upon formal breakage of the central bridge bond in DTAP, the related system 1,4,8,11-tetraazatricyclo[9.3.1.1 4,8]hexadecane is formed. Comparison of its nÄ and D values, 7.80 and 0.40 eV [18], with those of DTAP reveals a slight stabilization of 0.6 eV brought about by the central ring closure. 4. Concluding remarks The equilibrium structures of the cis- and transisomers of the cyclen and cyclam condensation

V. Galasso et al. / Journal of Molecular Structure (Theochem) 582 (2002) 187±193

products with glyoxal have been studied by the DFT method B3LYP/6-31G(d,p). The theoretical results for the various diamond-lattice conformations are in agreement with the available X-ray structural data. The still elusive trans-DTAC has been con®rmed to be a stable species. The electronic structures of these macrocyclic tetraamines have also been investigated through their 13C NMR and PE spectroscopic properties. On the whole, the correspondence between experimental data and theoretical values, obtained by high-level calculations, is satisfactory. In particular, the stereodependence of the variations in the 13C NMR chemical shifts is correctly accounted for by the DFT±CSGT predictions. The ab initio OVGF results have yielded a consistent description of the main features in the PE spectra, i.e. location and splitting of the four n ionization energies. Acknowledgements The ®nancial support from M.I.U.R. of Italy is gratefully acknowledged by V.G. References [1] G.R. Weisman, S.C.H. Ho, V. Johnson, Tetrahedron Lett. 21 (1980) 335. [2] Zbiec, M.A. PhD Thesis, Institute of Organic Chemistry, Polish Academy of Sciences Warszawa, Poland, 1980. [3] P. Gluzinski, J.W. Krajewski, Z. Urbanczyk-Lipkowska, J. Bleidelis, A. Kemme, Acta Crystallogr. Sect. B 38 (1982) 3038.

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