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Iron chelates such as ethylenediamine-N,N'-bis(2-hydroxyphenyl)acetic acid (EDDHA) and their analogues are the most efficient soil fertilizers to treat iron chlorosis in plants growing in calcareous soils. EDDHA, EDDH4MA (ethylenediamine-N,N'-bis(2-hydroxy-4-methylphenyl)acetic acid), and EDDCHA (ethylenediamine-N,N'-bis(2-hydroxy-5-carboxyphenyl)acetic acid) are allowed by the European directive, but also EDDHSA (ethylenediamine-N,N'-bis(2-hydroxy-5-sulfonylphenyl)acetic acid) and EDDH5MA (ethylenediamine-N,N'-bis(2-hydroxy-5-methylphenyl)acetic acid) are present in several commercial iron chelates. In this study, these chelating agents as well as p,p-EDDHA (ethylenediamine-N,N'-bis(4-hydroxyphenyl)acetic acid) and EDDMtxA (ethylenediamine-N,N'-bis(2-metoxyphenyl)acetic acid) have been obtained following a new synthetic pathway. Their chemical behavior has been studied to predict the effect of the substituents in the benzene ring on their efficacy as iron fertilizers for soils above pH 7. The purity of the chelating agents has been determined using a novel methodology through spectrophotometric titration at 480 nm with Fe(3+) as titrant to evaluate the inorganic impurities. The protonation constants were determined by both spectrophotometric and potentiometric methods, and Ca(2+) and Mg(2+) stability constants were determined from potentiometric titrations. To establish the Fe(3+) and Cu(2+) stability constants, a new spectrophotometric method has been developed, and the results were compared with those reported in the literature for EDDHA and EDDHMA and their meso- and rac-isomers. pM values have been also determined to provide a comparable basis to establish the relative chelating ability of these ligands. The purity obtained for the ligands is higher than 87% in all cases and is comparable with that obtained by (1)H NMR. No significant differences have been found among ligands when their protonation and stability constants were compared. As expected, no Fe(3+) complexation was observed for p,p-EDDHA and EDDMtxA. The presence of sulfonium groups in EDDHSA produces an increase in acidity that affects their protonation and stability constants, although the pFe values suggest that EDDHSA could be also effective to correct iron chlorosis in plants.

Israel Ferna ´ndez (Madrid, 1977) enjoyed studying chemistry at the Universidad Complutense of Madrid (UCM). In 2005, he earned his Ph.D. in Chemistry at the UCM under the supervision of Prof. Miguel A. Sierra and received the Prize for the best Doctoral Thesis in Synthetic Chemistry by the Spanish Royal Society of Chemistry and the Lilly-Young Researcher Prize. After that, he joined the Theoretical and Computational Chemistry group of Prof. G. Frenking at the Philipps Universita ¨t Marburg as a postdoctoral researcher studying the bonding situation and reaction mechanisms of organic and organometallic compounds. At the present, I.F. is a Ramo ´n y Cajal fellow at the UCM. His current research includes the computational study of the bonding situation and reaction mechanisms of organic, organometallic, and bioorganic compounds with special interest in C-C bond forming processes.

[Reaction: see text]. Although Staudinger reported the reaction between ketenes and imines 100 years ago (1907), this process is still the most general and useful method for the synthesis of beta-lactams and their derivatives. This reaction is a [2 + 2] thermal cycloaddition in which two chiral centers may be generated in one preparative step. Staudinger reactions involving alpha,beta-unsaturated imines or ketenes have issues concerning the [2 + 2] or [4 + 2] periselectivity of the reaction. This Account discusses how the main factors that determine the regiochemical and stereochemical outcomes of this reaction were elucidated with computational and experimental data. This fruitful interplay between theory and experiment has revealed that the [2 + 2] cycloaddition is actually a two-step process. The first step is a nucleophilic addition of the nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene. This attack forms a zwitterionic intermediate that evolves toward the final beta-lactam cycloadduct. The second step can be viewed as a four-electron conrotatory electrocyclization that is subject to torquoelectronic effects. When alpha,beta-unsaturated imines are used, the zwitterionic intermediates yield either the corresponding 4-vinyl-beta-lactams or the alternative 3,4-dihydropyridin-2(1 H)-ones. In this latter case, the cyclization step consists of a thermal disrotatory electrocyclization. In the context of stereoselectivity, it is usually assumed that the first step takes place through the less hindered side of the ketene. The cis-trans selectivity of the reaction depends on the geometry of the imine. As the general rule, ( E)-imines form cis-beta-lactams whereas ( Z)-imines yield trans-beta-lactams. Most of the experimental results point to the two-step model. The asymmetric torquoselectivity of the conrotatory ring closure of the second step accounts for the stereochemical discrimination in the reaction of chiral ketenes or chiral imines. Nevertheless, recent studies have revealed that isomerization paths in the imine or in the zwitterion may determine the stereochemistry of the reaction. Thus, if the rotation about the N1-C4 bond of the zwitterion intermediate is faster than the cyclization, the formation of trans-beta-lactams from ( E)-imines is biased. Alternatively, in some cases, the ( E)-( Z) isomerization of the starting imines prior to the cycloaddition steps also results in the formation of trans-cycloadducts. Although the main variables that govern the outcome of the reaction have been elucidated, there are still several aspects of the reaction yet to be disclosed. Finally, the discovery of the catalytic version of the reaction is a new and formidable mechanistic challenge and will be a nice playground for forthcoming theoretical-experimental discussions.

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