1508 Research Article Received: 4 August 2008 Accepted: 13 March 2009 Published online in Wiley Interscience: 27 May 2009 (www.interscience.wiley.com) DOI 10.1002/jrs.2306 IR/Raman spectroscopy and DFT calculations of cyclic di-amino acid peptides. Part III: comparison of solid state and solution structures of cyclo(L-Ser-L-Ser) Andrew P. Mendham, a Trevor J. Dines, b M. J. Snowden, a Robert Withnall c * and Babur Z. Chowdhry a* B3-LYP/cc-pVDZ calculations of the gas-phase structure and vibrational spectra of the isolated molecule cyclo(L-Ser-L-Ser), a cyclic di-amino acid peptide (CDAP), were carried out by assuming C 2 symmetry. It is predicted that the minimum-energy structure is a boat conformation for the diketopiperazine (DKP) ring with both L-seryl side chains being folded slightly above the ring. An additional structure of higher energy (15.16 kJ mol -1 ) has been calculated for a DKP ring with a planar geometry, although in this case two fundamental vibrations have been calculated with imaginary wavenumbers. The reported X-ray crystallographic structure of cyclo(L-Ser-L-Ser), shows that the DKP ring displays a near-planar conformation, with both the two L-seryl side chains being folded above the ring. It is hypothesized that the crystal packing forces constrain the DKP ring in a planar conformation and it is probable that the lower energy boat conformation may prevail in the aqueous environment. Raman scattering and Fourier-transform infrared (FT-IR) spectra of solid state and aqueous solution samples of cyclo(L-Ser-L-Ser) are reported and discussed. Vibrational band assignments have been made on the basis of comparisons with the calculated vibrational spectra and band wavenumber shifts upon deuteration of labile protons. The experimental Raman and IR results for solid-state samples show characteristic amide I vibrations which are split (Raman: 1661 and 1687 cm -1 , IR: 1666 and 1680 cm -1 ), possibly due to interactions between molecules in a crystallographic unit cell. The cis amide I band is differentiated by its deuterium shift of ∼30 cm -1 , which is larger than that previously reported for trans amide I deuterium shifts. A cis amide II mode has been assigned to a Raman band located at 1520 cm -1 . The occurrence of this cis amide II mode at a wavenumber above 1500 cm -1 concurs with results of previously examined CDAP molecules with low molecular weight substituents on the C α atoms, and is also indicative of a relatively unstrained DKP ring. Copyright c  2009 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article. Keywords: cyclic di-amino acid peptides (CDAP); X-ray crystallography; ab initio calculations; vibrational spectra Introduction Cyclic di-amino acid peptides (CDAPs), i.e. diketopiperazine (DKP) and its derivatives, continue to be of long-standing interdis- ciplinary scientific interest. They have attracted considerable scientific attention in relation to their biological activity. [1] Re- cent publications have highlighted research into the use of DKPs as potential antibiotic and anticancer drugs, as well as for the treatment of cardiovascular disease. [1–4] In fact, suitable phar- maceutical delivery systems for these molecules are also being investigated. [5] The diverse occurrence, isolation and identification of these molecules in nature, e.g. in marine fungi [6] and marine sponges, [7] have also been reported. DKPs have been discovered in foods [8] and beverages [9] and are, in certain cases, claimed to impart a metallic bitter taste to the palate. Since the early 1980s the energetics (e.g. heats of transfer between the gas, water and/or crystal phases, heats of dilution, etc.) of CDAPs have been exam- ined from both theoretical and practical perspectives, especially in relation to their perceived theoretical importance to the protein folding problem. [10] X-ray crystallography, [11 – 15] NMR, [16,17] CD [18] and gas-phase microwave [19] spectroscopic techniques have hith- erto been used in investigating the structure and conformation of a number of symmetrically substituted CDAPs. Theoretical spec- troscopic investigations [20] have also played a part in structural analysis. [21] Despite the foregoing comments, detailed experimen- tal vibrational spectroscopic experiments on CDAPs have, to date, been less common except for, e.g., the studies on the parent DKP (i.e. cyclo(Gly-Gly)) and cyclo(D-Ala-L-Ala) reported by Cheam and Krimm. [22,23] ∗ Correspondence to: Babur Z. Chowdhry, School of Science, University of Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK. E-mail: b.z.chowdhry@gre.ac.uk Robert Withnall, Wolfson Centre for Materials Processing, Brunel University, Uxbridge, Middlesex UB8 3PH, UK. E-mail: Robert.Withnall@brunel.ac.uk a School of Science, University of Greenwich at Medway, Chatham Maritime, Kent ME4 4TB, UK b Division of Electronic Engineering and Physics, University of Dundee, Dundee DD1 4HN, UK c Wolfson Centre for Materials Processing, Brunel University, Uxbridge, Middlesex UB8 3PH, UK J. Raman Spectrosc. 2009, 40, 1508–1520 Copyright c  2009 John Wiley & Sons, Ltd.