Encapsulated hydrogen-bonded dimers of amide and carboxylic acid Demeter Tzeli a , Ioannis D. Petsalakis a , Giannoula Theodorakopoulos a,⇑ , Dariush Ajami b , Wei Jiang b , Julius Rebek Jr. b a Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou, Athens 116 35, Greece b Skaggs Institute for Chemical Biology & Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA article info Article history: Received 2 July 2012 In final form 13 August 2012 Available online 18 August 2012 abstract A theoretical DFT study on benzamide and benzoic acid dimers in the gas phase and encapsulated in two cages of different size has been carried out in order to explain experimental observations regarding the % distributions of the different dimers formed in these cages. The results show that the % distribution of encapsulated dimers in the larger cage is similar to the gas-phase distribution. In the smaller cage inter- action of amide with the cage leads to lower dimerization energy and a reduced % fraction of the corre- sponding encapsulated dimers, compared to the large cage % distribution, in agreement with experiment. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction The importance of hydrogen bond interactions in many chemi- cal, biochemical, and biological processes leads to a constant inter- est in the description of the nature and strength of the hydrogen bond [1–3]. Whereas observation of the individual donor and acceptor hydrogen bond pairs in solution is difficult because their weak interactions result in nanosecond lifetimes and rapid ex- change of partners, reversible encapsulation provides temporary isolation of the dimers by mechanical barriers in very small spaces for milliseconds to hours and allows their characterization by NMR methods [4]. In fact, the capsule is considered to act as the solvent, fixed in place around the solute during the synthesis and assembly of the complex [4,5]. Recently, the relative stability of encapsulated homodimeric and heterodimeric hydrogen bonding in p-ethylene- benzoic acid, p-ethylene benzamide and p-ethylenephenylboronic acid in the 1.2 4 .1 capsule has been examined both experimentally by NMR [4], and theoretically via DFT methodology [6,7]. The the- oretical % distribution of the encapsulated dimers, taking into ac- count statistical factors as well as the calculated dimerization energies are in good agreement with the experimental % distribu- tion [4,6,7]. Furthermore, the calculated % distribution of the encapsulated dimers is similar to those calculated for free dimers in a solvent as well as in the gas phase, indicating negligible effect of encapsulation on the % distribution of the dimers formed. How- ever, this does not seem to be the case when a smaller capsule is employed, according to recent experimental work on benzoic acid and benzamide dimers and the 1.1 cage where different % distribu- tion of the dimers from that of the larger cage is obtained [8]: Whereas, in the larger cage the carboxylic acid–amide heterodimer has the largest % fraction, in the smaller cage the carboxylic acid dimer predominates. Given that the different dimers are of similar size, hydrogen bonding interactions with the walls of the small cage need to be considered. In the present study, the relative stability of encapsulated homodimers and the heterodimer of benzoic acid and benzamide in the 1.1 and 1.2 4 .1 [4] cages has been examined theoretically via DFT methodology, in order to determine the origin of the observed differences in the % distributions of the encapsulated di- mers in the two cages. 2. Calculations The two capsules employed are 1.1 which consists of two cavit- ands 1, and 1.2 4 .1 [4], which consists of two cavitands 1 with four glycoluril spacer molecules 2 (see Figure 1). Both capsules are large enough to accommodate the possible dimers formed by benzoic acid (C) and benzamide (A) molecules. It should be noted that the A and C monomers are of similar size. The geometry of the encapsulation complexes, which include 230–296 atoms, were optimized by DFT calculations employing the M06-2X [9] functional in conjunction with the 6-31G(d,p) basis set [10]. The M06-2X functional is a hybrid meta exchange correla- tion functional, it is highly-nonlocal with double the amount of nonlocal exchange [9] and has been shown previously to lead to good predictions of the dimerization energies of dimers of carbox- ylic acids and amides compared to corresponding quantities at the MP2/aug-cc-pVQZ and CCSD(T)/aug-cc-pVTZ levels of theory [7]. For all structures determined, basis set superposition error (BSSE) corrections to the dimerization energy have been taken into account using the counterpoise procedure [11]. All calculations were performed using the GAUSSIAN 09 program package [12]. 0009-2614/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cplett.2012.08.024 ⇑ Corresponding author. Fax: +30 210 7273794. E-mail address: ithe@eie.gr (G. Theodorakopoulos). Chemical Physics Letters 548 (2012) 55–59 Contents lists available at SciVerse ScienceDirect Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett