Structural features of neutral and cationic cyclams Luis G. Alves, M. Teresa Duarte, Ana M. Martins * Centro de Química Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais 1,1049-001 Lisboa, Portugal article info Article history: Received 18 March 2015 Received in revised form 27 May 2015 Accepted 29 May 2015 Available online 2 June 2015 Keywords: Cyclam Hydrogen bonds Tetraaza rings Macrocycles Supramolecular structures abstract Dicationic compounds of general formula [1,8-R 2 -1,4,8,11-tetraazatricyclo[9.3.1.1 4,8 ]hexadecane]X 2 , where R ¼ H, Me or Bn' and X is a halogen counterion were obtained by reactions of 1,4,8,11- tetraazatricyclo[9.3.1.1 4,8 ]hexadecane with different electrophiles. The solid-state molecular structures of the compounds reveal that the hydrogen, methyl or benzyl groups are located on the nitrogen atoms that are not only the less sterically hindered but also have the electron lone pair pointing out of the macrocycle backbone. In all compounds it is observed a bond shortening between the N-C aminal and the two other CeN bonds that may be attributed to an inductive effect. These compounds afford the cor- responding trans-N,N'-disubstituted cyclams upon hydrolysis in basic medium. © 2015 Elsevier B.V. All rights reserved. 1. Introduction The growing interest in the design and synthesis of poly- azamacrocycles during the past years is mainly associated to their ability to form stable complexes with a plethora of metal ions [1] and also with a variety of anions [2], if used in their protonated forms. Several synthetic approaches to prepare sophisticated pol- yazamacrocycles were recently developed with the focus on the optimization and widening of their properties. For cyclam, in particular, numerous methods for the synthesis of poly-N-func- tionalized derivatives have been used [3]. Tetra- and mono-N- functionalized cyclams are the most widely described as these types of compounds may be obtained by straightforward pro- cedures [4]. Even though, the syntheses of mono-N-functionalized cyclams are non-efficient procedures concerning atomic economy requiring a large excess of cyclam. The direct preparation of N,N'- difunctionalized cyclam rings faces several problems mainly because the reaction of cyclam with two equivalents of alkyl or aryl halides yield mixtures of mono-, di-, tri- and even tetrasubstituted macrocycles [3b,5]. Moreover, disubstituted cyclams display several isomers depending on the relative positions of the pendant arms, namely, two different cis-disubstituted and one trans-disubstituted isomers. Guilard et al. developed a convenient three-step proce- dure that relies on the formation of 1,4,8,11-tetraazatricyclo [9.3.1.1 4,8 ]hexadecane, 1, by reaction of cyclam with formaldehyde providing exclusively the trans-disubstituted isomer [6]. This methodology was used by us for the preparation of several trans- H 2 (R 2 Cyclam) compounds whose molecular and supramolecular structures are discussed here (Scheme 1). In this work we also explore the solid-state molecular structure of 1,4,8,11-tetraazatricyclo[9.3.1.1 4,8 ]hexadecane either in anhy- drous and hydrated forms (1.4H 2 O and 1.6H 2 O). The role of the stereochemical conformation on its protonation is addressed. 2. Experimental 2.1. General considerations Cyclam [7], 3,5-di-tert-butylbenzyl bromide [8], 1,4,8,11- tetraazatricyclo[9.3.1.1 4,8 ]hexadecane, 1 [6], 1,8-benzyl-1,4,8,11- tetraazacyclotetradecane, 12 [6], 1,8-(4-tert-butylbenzyl)-1,4,8,11- tetraazacyclotetradecane, 14 [9], 1,8-(4-trifluoromethylbenzyl)- 1,4,8,11-tetraazacyclotetradecane, 16 [9], 1,8-(3,5-di-tert-butylben- zyl)-1,4,8,11-tetraazacyclotetradecane, 17 [8], 1,8-(3,5-dimethylben zyl)-1,4,8,11-tetraazacyclotetradecane, 18 [8], and 1,8-methyl- 1,4,8,11-tetraazacyclotetradecane, 20 [6], were prepared according to general described procedures. All other reagents were com- mercial grade and used without further purification. The NMR spectra were recorded in a Bruker AVANCE II 300 or 400 MHz spectrometers at 296 K. 1 H and 13 C NMR spectra were referenced internally to residual solvent resonances and reported relative to tetramethylsilane (0 ppm). 19 F NMR was referenced to external * Corresponding author. E-mail address: ana.martins@tecnico.ulisboa.pt (A.M. Martins). Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc http://dx.doi.org/10.1016/j.molstruc.2015.05.037 0022-2860/© 2015 Elsevier B.V. All rights reserved. Journal of Molecular Structure 1098 (2015) 277e288