Stephen J. Lippard

In many respects, synthesis is the heart ofchemistry. The creativity involved in com-bining the elements of the periodic table

into unprecedented molecules and materialsdistinguishes chemists from other scientists.But wielding the chemical paintbrush in acontrolled manner is a challenge.

Consider the synthesis of natural prod-ucts. In assembling a complex organic mol-ecule such as an antiviral or anticancer agent,the synthetic chemist must plan and executemultiple reactions, typically in a stepwisemanner, until the desired compound isobtained. Success often requires the ability toreact a single part of a molecule to the exclusion of others. Such ‘chemoselectivity’ istypically achieved with a protecting group thatcan later be removed without destroying anyof the product. The labour-intensity of thisprocess is analogous to being dressed in med-ieval armour and having to wash with a firehose, cleaning the face by raising the visor, thehands by removing the gauntlets, and so on.

A key goal in synthetic organic chemistryis the design of reagents to achieve chemicaltransformations at specific sites in a mol-ecule without protection and deprotectionsteps. To achieve one stereoisomer to theexclusion of its mirror image is a further,often more difficult, challenge, as is thedevelopment of catalysts that promote anefficient chemical transformation.

The synthetic inorganic chemist faces adifferent but equally formidable task of con-trol. Consider the goal of preparing a catalystfor a chemical transformation that occurs inliving organisms at ambient temperatureand pressure, such as the conversion of

atmospheric nitrogen to ammonia, naturalgas to methanol, or water to hydrogen. Thefirst of these catalysts would significantlyassist in the fertilizion of crops; the secondwould allow methane to be transportedmuch more economically from remote gaswells to urban areas; and the third wouldprovide a key ingredient for fuel cells from anon-carbon, replenishable fuel source.

The enzymes that catalyse such reactionsin nature typically operate at kilohertz fre-quencies: many biological chemical reactionsconvert substrates to products at rates ofroughly 1,000 per second. Almost half of theseenzymes require metal ions to achieve theircatalytic functions — usually Mg, Ca, Mn, Fe, Co, Ni, Cu and Zn — typically embeddedin a three-dimensional protein matrix thatensures tightly controlled alignment of thereactants to achieve the desired formation andrelease of the product molecule(s). Outsidethe protein milieu, these metals in their typical &2 and &3 oxidation states formcomplexes that exchange their ligands rapidly— they are kinetically labile.

These ions seem, therefore, to have beenadopted by living organisms precisely becausethey can bind to substrates and release products on a timescale commensurate withbiological requirements. Notably absent fromthe list are second- and third-row transitionmetals, such as Ru, Pd and Pt. Complexes containing these metal ions are important asindustrial catalysts, but their rates of ligandexchange are much lower than those of theirfirst-row counterparts. With a few exceptions,such as Mo and W, such elements have there-fore not been selected for biological functions.

A great challenge for the synthetic inorganic chemist who is attempting tomimic an enzymatic transformation is to create an environment that stabilizes the ligand composition at the metal ion, whileoffering labile sites for catalysis. In a biologi-cal molecule, ligands are typically supplied byamino-acid side chains and are therefore heldin relatively fixed positions. Disassembly orrearrangement to thermodynamically morestable entities is kinetically prohibited byenergy supplied by the folding of the proteininto its specific three-dimensional shape. Increating a functional synthetic analogue ofthe protein’s active site, however, the chemistis faced with the daunting task of overcomingthe tendency of the desired target molecule torearrange or react with components of thesolution to form a thermodynamically stable,undesired side product with no functionalcapability. The system is thus under thermo-dynamic rather than kinetic control, becauseof the labile nature of the metal ions involved.

Yet in organic chemistry, one more

frequently has kinetic control of the mol-ecule. For example, in preparing a catalystwith a phenyl (C6H5) ring as the frameworkon which a reactive moiety is appended, theorganic chemist does not have to worryabout undesired transformations involvingthe spontaneous cleavage of C–C and C–Hbonds in the phenyl unit, because thesebonds are kinetically stable. The use ofdesigned peptides is one approach to theproblem of creating new molecules as lig-ands for transition-metal ions that provideparallel kinetic stability for inorganic catalysts but allow for functional sites.

On occasion, the inability to control adesired chemical transformation gives rise tonew molecules that can be objects of aestheticbeauty as well as potential usefulness. Oneexample is the serendipitous synthesis of carboxylate-bridged polyiron compounds(see figure), including the ‘molecular ferricwheel’, the ‘molecular 18-wheeler’ and anopen-shell Keggin ion. I have not seriouslypursued the rational design of such moleculesbecause I do not understand the principles of control involved. In cases in which manyinteractions are possible, particularly manynon-covalent, subtle interactions working inconcert, the chemical paintbrush can seem tohave a mind of its own. It is often impossible topredict the factors that will dominate and dictate the nature of the product.

With the use of kinetically more inert tran-sition-metal ions in conjunction with bridg-ing ligands, however, it is possible to assemblemolecular squares, cubes and other polygonsand polyhedra, as well as porous solids withpotential for a range of applications. Possibleexamples include new materials for cleaningwaste water, smart detectors for chemical andbiological warfare agents, and componentsfor molecular electronics devices. ■

Stephen J. Lippard is in the Department ofChemistry, Massachusetts Institute of Technology,Cambridge, Massachusetts 02139, USA

FURTHER READINGLippard, S. J. Chem. Eng. News 78, 64–65 (2000).DeGrado, W. F., Summa, C. M., Pavone, V., Nastri, F. &Lombardi, A. Annu. Rev. Biochem. 68, 779–819 (1999).Taft, K. L. et al. J. Am. Chem. Soc. 116, 823–832 (1994).Watton, S. P. et al. Angew. Chem. 36, 2774–2776 (1997).Leininger, S. et al. Chem. Rev. 100, 853–907 (2000).

The art of chemistryconcepts

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Chemical revolution: (from inside) the open-shellKeggin ion, ferric wheel and molecular 18-wheeler.

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ChemicalsynthesisSuccess in the synthesis of naturalproducts often requires the ability to react a single part of a moleculeto the exclusion of others.

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