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Winner of the IUPAC Prize
for Young Chemists - 2003

Roman Boulatov wins one of the 5 IUPAC Prize for Young Chemists, for his Ph.D. thesis work entitled "Synthesis and Reactivity of Metalloporphyrins in (A) Biomimetic Studies ofTerminal Oxidases and (B) the Preparation of Novel Heterodinuclear Multiple Metal-Metal Bonds."

Current address (at the time of application)

Stanford University
PO box 12615
Stanford, CA 94309, USA

E-mail: boulatov@stanford.edu

Academic degrees

  • Ph.D. in Chemistry, Stanford University, July 2002
  • MS in Organic Chemistry, Stanford University, June 2001
  • Summa Cum Laude diploma in chemistry, University of St.-Petersburg, Russia, June 1996

Ph.D. Thesis

Title Synthesis and Reactivity of Metalloporphyrins in (A) Biomimetic Studies of Terminal Oxidases and (B) the Preparation of Novel Heterodinuclear Multiple Metal-Metal Bonds.
Adviser Prof. James P. Collman
Thesis Committee Prof. Gordon Braun, Dep. of Geology; Prof. Edward Solomon, Dep. of Chemistry; Prof. Chris E. D. Chidsey, Dep. of Chemistry; and Prof. T. Daniel P. Stack, Dep. of Chemistry

Essay

The unique properties of porphyrins as transition metal ligands underlie their prevalence as cofactors in the biosphere and also make them valuable components of artificial chemical systems based on d-block elements. My Ph. D. work in the Collman lab at Stanford used porphyrins in both contexts. For example, I utilized porphyrins to stabilize and isolate a MoRe5+ core [ref. 1], which contains the first ever quadruple bond between elements from different groups [ref. 2]. I also studied monomeric RhII porphyrins, which cleave C-H bonds in methane and other hydrocarbons. Yet to be useful as hydrocarbon activation catalysts, the RhII center must survive in the presence of nucleophiles: something that was thought to be impossible before I realized it in a judicially chosen nucleophile/porphyrin system [ref. 3]. But most of my Ph. D. research was devoted to biomimetic studies of the O2-reduction site in terminal oxidases.
Heme/Cu terminal oxidases (e.g., cytochrome oxidase, CcO) make possible terrestrial life as we know it. At their bimetallic heme/Cu site (Figure 1A) these enzymes catalyze the final step in the respiratory electron transfer chain: 4-electron, 4-proton reduction of O2 to H2O. This highly exergonic reaction is coupled to proton translocation against the transmembrane electrochemical gradient, which drives ATP synthesis. Because terminal oxidases are so complex and their isolations are often heterogeneous, biomimetic work can invaluably complement biochemical studies of the enzyme. I chose biomimetic chemistry to understand the possible roles of the distal Cu ion in steady-state O2 reduction by terminal oxidases. This question is one of the more contentious issues of these enzymes’ biochemistry since it can not be probed by studying terminal oxidases themselves and prior biomimetic studies lead to several contradicting hypotheses [ref. 4].

Figure 1. The O2 reducing site of cytochrome oxidase (A) and the biomimetic analogs synthesized and studied as a part of my Ph.D. work (B).

To arrive at biologically-relevant conclusions a biomimetic chemist must synthesize a molecule that faithfully reproduces both the stereoelectronic properties and the reactivity of the target enzymatic site, and study its properties under conditions as close as possible to the ones under which the enzyme operates. I synthesized a series of metalloporphyrin complexes that are the closest structural analogs of the heme/Cu site ever reported (Figure 1) [refs. 5,4] and established that these biomimetic catalysts reproduce the catalytic reactivity of the heme/Cu site toward O2 and H2O2 [refs. 6,7,8]. My catalysts reduce O2 at physiologically-relevant pH and electrochemical potentials,
with high selectivity (>98%) and stability (>104 turnovers), and at maximum rates comparable to those reported for CcO. This catalysis proceeds via turnover-limiting generation of a formally ferric-hydroperoxo intermediate, pFeIII-OOH (Figure 2). This is significant because the most likely source of H2O2 in metalloporphyrin-catalyzed O2 reduction is hydrolysis of pFeIII-OOH [ref. 4]. Because the steady-state concentration of the intermediate produced in the turnover-determining step is minimal, the flux of H2O2 is minimized as well [ref.6]. Indeed, reduction of O2 by cytochrome oxidase is thought to proceed analogously: a slow generation of the ferric-hydroperoxo intermediate followed by its
rapid reduction.

In order the study catalytic O2 reduction under physiologically-relevant diffusion-limited electron flux, I developed a system wherein isolated mobile catalyst molecules are dispersed in a lipid matrix at the electrode surface [ref. 7]. In contrast to the electrode-adsorbed FeCu and Cu-free catalysts, which catalyze O2 reduction under fast electron flux and manifest similar kinetics, mechanism and stability (Figure 2), with slow electron flux the FeCu catalyst is notably superior to the Cu-free analog, displaying higher stability, turnover frequency and selectivity. These findings suggest that the puzzling inactivity of the CuB-free mutants of CcO may be due to rapid degradation of the catalytic site rather than an intrinsic inability of the heme alone to reduce O2. In the absence of an intramolecular electron source, such as CuI , reduction of O2 by the Cu-free catalyst results in oxidation of the porphyrin or imidazoles to chemically-unstable cation-radicals,
thereby leading to rapid catalyst degradation and loss of activity.

The totality of my findings suggests that in a stereoelectronic environment similar to that of the heme/Cu site, the distal Cu ion is an electron storage site. Apparently, O2 reduction at this bimetallic site requires an activation energy that is not significantly lower than that needed at the heme alone, provided electrons are available from elsewhere.

While Cu may seem to be just a “spectator” in O2 reduction under the excess of electrons, it has pronounced physiological benefits by modulating the heme’s reactivity. Without affecting
the kinetics or the mechanism of O2 reduction in this regime, distal Cu decreases the amount of toxic partially-reduced oxygen byproducts generated by the O2-reducing catalyst, by suppressing superoxide-releasing autooxidation of oxyheme, (por)FeO2 [ref. 6]. Cu also makes the FeCu catalyst less susceptible to CO and CN- inhibition [ref. 8], particularly at physiologically-relevant potentials. CN- is cytotoxic because CN-ligated oxidized CcO can not be reduced in vivo, which shuts down respiration and leads to death. My studies suggest that with only a monometallic catalytic site at CcO, 5-times lower concentrations of CN- would cause such shutdown. Cu decreases the susceptibility by increasing the FeIII/II potential and by destabilizing (probably sterically) CN- binding to both the reduced (FeIICuI) and (unexpectedly!) oxidized (FeIIICuII) catalysts.

Figure 2. The kinetic mechanism of catalytic O2 reduction by the biomimetic CcO analogs under physiologically-relevant conditions and rapid electron flux, when Cu does not affect the mechanism. Kinetics and/or thermodynamics of every step other than those generating the pFeO2- and pFeO2H intermediates were studied independently. The broken arrows indicate essentially irreversible steps, which do not affect the overall turnover frequency (TOF).

I was fortunate to work with biomimetic catalysts that are unique in how closely they reproduce both the structure and some key reactivity of CcO. Such fidelity makes it much more likely that the effects of Cu observed in my studies, however unexpected, also influence the reactivity of CcO. More generally, my work has demonstrated that biomimetic studies of a complex enzyme can yield a well-supported and self-consistent hypothesis regarding an aspect of enzymatic reactivity that could not be unraveled by studying the enzyme itself. This work also extends our fundamental understanding of an important but deceptively simple reaction (reduction of O2 to H2O) by demonstrating facile heterolysis of the O-O bond in H2O2 and its
derivatives by a molecular catalyst. This undermines the dominant paradigm in the field of catalytic O2 reduction that O-O bond heterolysis is intrinsically the most difficult part of the O2 reduction cycle. Finally, the techniques I developed, such as electrode-confined lipid films to model diffusion-limited electron fluxes in biological environments and the use of O2- and H2O2 scavengers to identify primary partially-reduced oxygen byproducts, should be valuable to other areas of chemistry.

References
1. Collman, J. P.; Boulatov, R.; Jameson, G. B. The First Quadruple Bond Between Elements of Different Triads. Angew. Chem. Int. Ed. 2001, 40, 1271–1274.
2. Collman, J. P.; Boulatov, R. Heterodinuclear Transition Metal Complexes with Multiple Metal-Metal Bonds. Angew. Chem. Int. Ed. 2002, 41, 3948-3961.
3. Collman, J. P.; Boulatov, R. Synthesis and Reactivity of Porphyrinatorhodium(II)-Triethylphosphine Adducts: The Role of PEt3 in Stabilizing a Formal Rh(II) State. J. Am. Chem. Soc. 2000, 122, 11812-11821.
4. Collman, J. P.; Boulatov, R.; Sunderland, C. J. Functional and Structural Analogs of the Dioxygen-Reduction Site in Terminal Oxidases. In The Porphyrin Handbook; Kadish, K. M.; Smith, K. M.; Guilard, R.; Eds. Academic Press: 2003, Vol. 11, pp. 1-49.
5. Collman, J. P.;. Sunderland, C. J.; Boulatov, R Biomimetic Studies of Terminal Oxidases: Trisimidazole Picket Metalloporphyrins. Inorg. Chem. 2002, 41, 2282-2291.
6. Boulatov, R.; Collman, J. P.; Shiryaeva, I.; Sunderland, C. J. Functional Analogs of the Dioxygen-Reduction Site in Cytochrome Oxidase: Mechanistic Aspects and Possible Effects of CuB. J. Am. Chem. Soc. 2002, 124, 11923-11935.
7. Collman, J. P.; Boulatov, R. Electrocatalytic Dioxygen Reduction by Synthetic Analogs of the Heme/Cu Site of Cytochrome Oxidase Incorporated in a Lipid Film. Angew. Chem. Int. Ed. 2002, 41, 3487-3489.
8. Collman, J. P.; Boulatov, R.; Shiryaeva, I.; Sunderland, C. J. Distal Cu Ion Protects Synthetic Heme/Cu Analogs of Cytochrome Oxidase against Inhibition by CO and Cyanide. Angew. Chem. Int. Ed. 2002, 41, 4139-4142.

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