Synthetic studies of novel ninhydrin analogs Richard R. Hark, Diane B. Hauze, Olga Petrovskaia, and Madeleine M. Joullié Abstract: Ninhydrin is an essential tool in the analysis of amino acids, peptides, and proteins, and the preferred re- agent for the detection of latent fingerprints on porous surfaces. The goal of this investigation was to prepare ninhydrin analogs with enhanced chromogenic and fluorogenic properties. Target compounds included structures with extended conjugation and (or) with the presence of sulfur-containing moieties. We have devised general convergent routes for novel heterocyclic and aryl-substituted ninhydrin analogs for use as reagents for amino acid detection. Key words: ninhydrin analogs, synthesis, ketals, Suzuki cross-coupling reactions, Stille cross-coupling reactions. Résumé : La ninhydrine est un outil essentiel pour l’analyse des acides aminés, des peptides et des protéines ainsi que le réactif privilégié pour la détection d’empreintes digitales latentes sur des surfaces poreuses. Le but de ce travail était de préparer des analogues de la ninhydrine ayant des propriétés chromogènes et fluorogènes accrues. Les composés ci- bles incluaient des structures avec conjugaison accrue et/ou comportant la présence de portions contenant du soufre. On a mis au point des voies générales convergentes permettant de préparer de nouveaux analogues hétérocycliques de la ninhydrine ainsi que d’autres portant des substituants aryles pour utiliser comme réactifs de détection des acides aminés. Mots clés : analogues de la ninhydrine, synthèses, cétals, réaction de couplage croisé de Suzuki, réactions de couplage croisé de Stille. [Traduit par la Rédaction] 23 Hark et al. Introduction Ninhydrin or 2,2-dihydroxy-1,3-indanedione (1, Fig. 1) has earned a prominent place in chemistry, biochemistry, and forensic science due to its color-forming reaction with amino acids and amines found in fingerprint residues (1). The chemistry of this interesting compound has been the subject of several reviews (2–6). Since its serendipitous discovery by Ruhemann (7), ninhydrin (1) has been a widely used reagent in several areas of chemistry. Although 1 reacts with a plethora of reagents to give a wide variety of structures (5), it is best known for its reactions with amines and amino acids to give the colored compound known as Ruhemann’s purple (8, 9). These com- plex reactions have been a subject of prolonged investiga- tions (5) and are still of current interest (10). Of particular relevance is the work of Grigg and co-workers (11–13), who established the intermediacy of 1,3-dipoles in the formation of Ruhemann’s purple and the studies of the transition-metal complexes of Ruhemann’s purple by Davies et al. (14, 15). Our interest in the synthesis of novel ninhydrin analogs to be used in the detection of latent fingerprints has led us to investigate previously reported approaches to ninhydrin to prepare new reagents with enhanced optical properties. Dur- ing the course of these investigations, we have examined several chemical and physical properties of substituted ninhydrin analogs and have devised new synthetic ap- proaches to some of these compounds. Ninhydrin (1) is the forensic specialist’s top choice for la- tent print detection on porous surfaces (1). It is affordable and easy to apply. The developed dark purple fingerprints are easy to detect by the naked eye and do not require spe- cial viewing conditions. The ninhydrin reaction has the ad- vantage of forming a product with a high molar extinction coefficient under very mild reaction conditions. However, despite its obvious advantages for forensic ap- plications, the fluorogenic and chromogenic properties of ninhydrin can be improved. For example, Herod and Menzel (16) reported that fingerprints which were developed with ninhydrin could be made to fluoresce after treatment with zinc chloride. Formation of fluorescent complexes resulted in enhanced sensitivity and improved contrast between the fingerprint and the background but at the expense of intro- ducing an extra step in processing the prints. An ideal re- agent should display high sensitivity as both a chromogen and a fluorogen without secondary treatment. The high polarity of ninhydrin does not allow much versa- tility in choosing solvent formulations. The choice of sol- vents presents a serious challenge (17) since the solvent has Can. J. Chem. 79: 1–23 (2001) © 2001 NRC Canada 1 PROOF/ÉPREUVE Pagination not final/Pagination non finale Received March 14, 2201. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on November xx, 2001. Dedicated to Professor Victor Snieckus with appreciation for his many contributions to organic synthesis. R.R. Hark, 1 D.B. Hauze, 2 O. Petrovskaia, 3 and M.M. Joullié. 4 Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104–6323, U.S.A. 1 Department of Chemistry, Marietta College, Marietta, OH 45750. Current address: Juniata College, Huntingdon, PA 16652, U.S.A. 2 Chemical Sciences, Wyeth-Ayerst Research, 145 King of Prussia Road, Radnor, PA 19087, U.S.A. 3 PPG Industries, 400 College Park Drive, Monroeville, PA 15146, U.S.A. 4 Corresponding author (telephone: (215) 898-3158; fax: (215) 898-5129; e-mail: mjoullie@sas.upenn.edu).