ARTICLE IN PRESS

Journal of the Franklin Institute 342 (2005) 586–591

0016-0032/$3

doi:10.1016/j

�Tel.: +1 3E-mail ad

www.elsevier.com/locate/jfranklin

The 2004 Benjamin Franklin Medal in Chemistrypresented to Harry B. Gray

Klaus H. Theopold�

Department Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA

Abstract

The Franklin Institute, Philadelphia, Pennsylvania, awarded the 2004 Benjamin Franklin

Medal in Chemistry to Harry B. Gray for his pioneering contributions in the field of electron

transfer in metalloproteins. In a series of elegant and challenging experiments beginning in the

late 70s, Gray and his coworkers have shown that the transfer of electrons in metalloproteins

can proceed over long distances (~ 20 A) and at fast rates. These experiments have involved the

regiospecific functionalization of structurally characterized electron transfer proteins with

ruthenium complexes, coupled with laser excitation and transient spectroscopy. Probing the

effects of thermodynamic driving force, temperature, donor–acceptor distance and electronic

coupling, Gray has shaped our detailed current understanding of the principles governing

biological electron flow. The mechanism of electron transfer has been identified as electron

tunneling mediated by the molecules separating donor and acceptor. Tunneling timetables

have been established for various intervening media. Important biological processes like

respiration and photosynthesis depend on facile electron transfer, and Gray’s contribution

serves as the fundamental basis for understanding these and many related reactions.

r 2005 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.

Keywords: Electron transfer; Proteins; Franklin medal

0.00 r 2005 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.

.jfranklin.2005.04.015

02 831 1546; fax: +1 302 831 6335.

dress: theopold@udel.edu.

ARTICLE IN PRESS

K.H. Theopold / Journal of the Franklin Institute 342 (2005) 586–591 587

1. Introduction and background

Redox reactions, i.e. reactions involving reduction (addition of electrons) andoxidation (removal of electrons), are among the most important and fundamentalchemical transformations. Beyond the obvious thermodynamic constraints, whichare readily understood in terms of the redox potentials of electron donors andacceptors, there also arise kinetic considerations. Rates of electron transfer reactionsspan a wide range, and the investigation of the mechanisms and rates of electrontransfer — in particular between metal complexes—has been an active area ofresearch in the second half of the twentieth century [1].Two major classes of reactions have been identified, namely ‘inner sphere’ and

‘outer sphere’ electron transfer processes. The former involve facilitation of theelectron transfer through bridging ligands; they are exemplified by the classicreaction of two coordination compounds in aqueous solution shown in Eq. (1) [2]:

CIIIo ðNH3Þ5Cl� �2þ

þ CrIIðOH2Þ6� �2þ

! CoIIðOH3Þ6� �2þ

þ CrIIIðOH2Þ5Cl� �2þ

þ 5 NH3.

(1)

Outer sphere electron transfer, on the other hand, merely relies on momentaryclose approach of the reactants by diffusion. Much effort has been expended on thedetermination of rates of ‘degenerate self exchange reactions’ [3], such as the onegiven in Eq. (2), an acknowledged outer sphere electron transfer.

FeIIðOH2Þ6� �2þ

þ FeIIIðOH2Þ6� �3þ

! FeIIIðOH2Þ6� �3þ

þ FeIIðOH2Þ6� �2þ

,

ketð22�CÞ ¼ 3:3M�1s�1;DGz ¼ 16:7 kcal=mol. ð2Þ

Such thermoneutral reactions ðDG0 ¼ 0Þ provide intrinsic activation barriersunaffected by a thermodynamic driving force. In 1983 Henry Taube won the NobelPrize in Chemistry for his experimental work in the area of electron transferreactions [4].In parallel to the experiments, a theoretical treatment of outer sphere electron

transfer was developed by Marcus [5]. His theory, summarized in expressions such asEq. 3, allowed the calculation of activation barriers and absolute rate constants fromfirst principles, taking into account reorganization energies (l), thermodynamicdriving forces ðDGoÞ, and electronic coupling between donor and acceptor (HAB) [6]:

ket ¼ 4p3=h2lkBT� �1=2

H2AB exp �ðDGo þ lÞ2=4lkBT

� �. (3)

Rudi Marcus won the 1992 Nobel Prize in Chemistry for the development of thetheory that carries his name [7].Electron transfer processes play a vital role in biology [8]. Life sustaining processes

such as respiration, photosynthesis, nitrogen fixation, and many others rely on thetransfer of electrons between biomolecules. However, biological electron donors andacceptors — typically metal complexes — are often shrouded in proteins, preventingthem from attaining close contact. Based on the established notions about electrontransfer reactions, such long transfer distances should lead to extremely slowelectron transfer rates. And yet, electrons are apparently transferred, over distances

ARTICLE IN PRESS

K.H. Theopold / Journal of the Franklin Institute 342 (2005) 586–591588

up to 20 A, and with rates on the millisecond time scale. In order to resolve thisapparent contradiction, Gray initiated a series of experiments in the 70s thatconfirmed and ultimately explained the feasibility of rapid long-distance electrontransfer in proteins.A quote from a 1974 paper by Hopfield may serve to put Gray’s achievement into

the historical context [9]: ‘‘Since electron-transfer proteins play a specific chemicalrole, one should be able to explain in quantitative physical terms how the observedfunctional properties are related to aspects of molecular structure. There are twomajor obstacles to attempting such an explanation at present. First, very little isknown about the relative geometry of the donor and acceptor during the electrontransfer process. Second, even when a geometry is known or surmised, themechanism of electron transfer is unsure.’’ It will be shown that Gray’s work hassupplied the sought explanation in quantitative physical terms.

2. Rates of electron transfer in metalloproteins

To begin, Gray and his coworkers were the first to show that electron transferfrom a ruthenium complex affixed to the outside of the iron containing proteincytochrome indeed proceeded with a rate constant of 20(75) s�1 over a distance of15 A [10]. Several aspects of this experiment were groundbreaking and noteworthy.Thus, the regioselective functionalization of a protein of known molecular structure(determined by single crystal X-ray diffraction) with a redox active and substitutioninert metal complex created a situation in which the distance of the electron transferwas rigorously fixed and known. It also simplified matters by making the electrontransfer an intramolecular event, removing any interference from bimolecularprotein — protein binding steps. The experiment itself was carried out by acombination of photoinduced electron transfer, fluorescence quenching, andtransient absorption spectroscopy; Gray’s extensive prior work in the photochem-istry of transition metal complexes proved instrumental for carrying out thesestudies. While this experiment was only the first of many to come, it has been called a‘‘milestone’’ and having ‘‘revolutionized the field’’.The distance dependence of electron transfer rates was an obvious next issue, and

Gray designed and carried out experiments with various proteins (i.e. cytochrome c,azurin, plastocyanin, myoglobin, cytochrome b562, HiPIP) that had beenfunctionalized with ruthenium complexes in different locations, thus setting upcomparisons between electron transfer reaction equal in all respects except for thedonor — acceptor distance [11]. A fundamental discovery emerging from theseexperiments was the observation that the matter intervening between the donor andacceptor had a profound effect on the electron transfer rates and — moreimportantly — their distance dependence. In the limit of infinitely small directelectronic coupling (HAB) between the two redox partners, the electron transfer wasdescribed as tunneling through a barrier, the height and shape of which is determinedby accessible states of atoms along the electron transfer path [12]. This model leadsto an exponential decrease of rate with distance, but with varying distance decay

ARTICLE IN PRESS

K.H. Theopold / Journal of the Franklin Institute 342 (2005) 586–591 589

constants (b, see Eq. (4)).

ketH2AB exp �bðd � doÞ½ �, (4)

Whereas b is estimated as 3 – 4 A�1 in vacuum and ca 1.7 A�1 in water, theaforementioned experiments are consistent with b ¼ 1:0 (A

�1for electron tunneling

through a b-strand and b ¼ 1:3 (A�1for electron transfer through an a-helix

(b-strands and a-helices are common structural motifs of proteins). One of theobvious consequences is that electrons can be transferred over much longer distancesin proteins than in water.Of course, proteins have complicated and varied structures, and consequently each

specific electron transfer path is unique. Indeed, Gray’s experiments with rutheniummodified wild-type and mutant cytochrome c showed that the measured electrontransfer rates did not correlate with the simple exponential distance decay model.They are better rationalized by a ‘‘tunneling pathway model’’ developed by Beratanand Onuchic [13]; this model accounts for the structural complexity of the protein byrecognizing different kinds of contacts along the tunneling path of the electron. Itallows searching for optimal coupling pathways between fixed donor/acceptor pairs.The tunneling pathway model is now widely accepted as providing the bestdescription of long-distance electron transfer in proteins.

3. Conclusions

Harry Gray and his coworkers carried out the first definitive experimentdemonstrating long-range electron transfer at rates consistent with metabolicprocesses. Through an extended series of related measurements in which thermo-dynamic driving force, temperature, and donor/acceptor distance were system-atically varied and their effects probed, he has established our current detailedunderstanding of this class of reactions. While others have added to the developmentof the field, Gray was the pioneer and the most prolific and consistent contributor.He is universally recognized as having made the greatest impact in the area ofbiological electron flow.

4. Medal legacy for the 2004 Benjamin Franklin Medal in Chemistry

1914

Edgar F. Smith (Cresson) Leading work in electrochemistry

1920

Svante A. Arrhenius (Franklin) Distinguished services to mankind in the field of physical chemistry

1923

Joseph J. Thomson (Scott) For development of the physics of the electron and the identification of itas the atom of negative electricity

1926

Niels Bohr (Franklin)

ARTICLE IN PRESS

K.H. Theopold / Journal of the Franklin Institute 342 (2005) 586–591590

Contribution to the mechanics of atomic structures and theory of theorigin of spectrum lines

1928

Walther Nernst (Franklin) Contributions to exact methods of thermodynamics to electro- andthermochemistry

1930

William H. Bragg (Franklin) Development of method of determining molecular and crystal structureby reflection of X-rays

1937

Robert A. Millikan (Franklin) Measurement of the charge of an electron; and description of Planck’sconstant and the study of cosmic radiation

1937

Peter J. W. Debye (Franklin) Theory that molecules possess permanent dipole moments

1969

Henry Eyring (Cresson) Quantum mechanical calculations of activation energies

1972

George B. Kistiakowsky (Franklin) Thermodynamics and kinetics of organic reactions

1979

Richard G. Brewer (Michelson) Study of the interaction of laser light with molecules

1982

E. Bright Wilson Jr. (Cresson) Contributions to the understanding of molecular structure and dynamics

2003

Robin M. Hochstrasser (Franklin) Pioneering the development of ultrafast and multi-dimensionalspectroscopies, and their applications to gain fundamental molecular-level understanding of the dynamics in complex systems (condensedphases and biomolecules), including energy transfer in solids, reactionmechanisms in liquid solutions, the binding of small molecules onhemoglobin, and the observation of structural changes in proteins

5. Laureate biography

Harry B. Gray is the Arnold O. Beckman Professor of Chemistry at the CaliforniaInstitute of Technology. He received his B.S. in Chemistry from Western KentuckyUniversity in 1957 and his Ph.D. in Chemistry from Northwestern University in1960. After a year as a postdoctoral fellow with Carl Ballhausen at CopenhagenUniversity, he joined the faculty of Columbia University in New York in 1961, andconcurrently held an adjunct appointment at Rockefeller University. In 1966 hemoved to the California Institute of Technology. Gray’s honors include the E. C.Franklin Memorial Award (1967), the Fresenius Award (1970), the ShoemakerAward (1970), the Bailar Medal (1984), the Centenary Medal (1985), the NationalMedal of Science (1986), the Linderstrøm-Lang Prize (1991), the Basolo Medal(1994), the Gibbs Medal (1994), the Chandler Medal (1999), the Harvey Prize (2000),the National Academy of Sciences Award in Chemical Sciences (2003), the

ARTICLE IN PRESS

K.H. Theopold / Journal of the Franklin Institute 342 (2005) 586–591 591

Centennial Nichols Medal (2003), as well as several national awards of the AmericanChemical Society (most notably the Priestley Medal (1991). He is a member of theNational Academy of Sciences, the American Academy of Arts and Sciences, theAmerican Philosophical Society, the Royal Danish Academy of Sciences and Letters,the Royal Swedish Academy of Sciences and the Royal Society of Great Britain. Heholds honorary doctorates from Northwestern University, the University ofChicago, the University of Rochester, the University of Florence, the Universityof Goteborg, Columbia University, and the University of Pennsylvania. Shortly afterbeing awarded the 2004 Benjamin Franklin Medal in Chemistry, he won the 2004Wolf Foundation Prize in Chemistry.

6. Sponsor biography

Klaus H. Theopold was born in Berlin, Germany and grew up in Hamburg, wherehe received his ‘Vordiplom’ in chemistry from the Universitat Hamburg. He thenmoved to the US for graduate school, receiving his Ph.D. from UC Berkeley in 1982.After a year as a postdoctoral associate at MIT he began his academic career asassistant professor at Cornell University. Since 1990 he has been on the faculty of theUniversity of Delaware, where he is currently professor of chemistry and anassociate director of the Center for Catalytic Science and Technology. Theopold haspublished 90 papers and holds two patents. He was named a Presidential YoungInvestigator in 1985, an Alfred P. Sloan Research Fellow in 1992, and a Fellow ofthe American Association for the Advancement of Science in 1995.

References

[1] M.L. Tobe, J. Burgess, Inorganic Reaction Mechanisms, Addison Wesley, Longman, New York,

1999, p. 376.

[2] H. Taube, H. Myers, J. Am. Chem. Soc. 76 (1954) 2103.

[3] T.J. Meyer, H. Taube, in: G. Wilkinson (Ed.), Comprehensive Coordination Chemistry, vol. 1,

Pergamon Press, Oxford, 1987, p. 331.

[4] H. Taube, Angew. Chem. Int. Ed. Engl. 23 (1984) 329.

[5] R.A. Marcus, Ann. Rev. Phys. Chem. 15 (1964) 155.

[6] R.A. Marcus, N. Sutin, Biochim. Biophys. Acta 811 (1985) 265.

[7] R.A. Marcus, Angew, Chem. Int. Ed. Engl. 32 (1993) 1111.

[8] S.J. Lippard, J.M. Berg, Principles of Bioinorganic Chemistry, University Science Books, Mill Valley,

CA, 1994, p. 231.

[9] J.J. Hopfield, Proc. Nat. Acad. Sci. USA 71 (1974) 3640.

[10] J.R. Winkler, D.G. Nocera, K.M. Yocom, E. Bordignon, H.B. Gray, J. Am. Chem Soc. 104 (1982)

5798.

[11] H.B. Gray, J.R. Winkler, in: V. Balzani (Ed.), Electron Transfer in Chemistry, vol. III, Wiley–VCH,

Weinheim, 2001, p. 3.

[12] J.R. Winkler, A.J. Di Bilio, N.A. Farrow, J.H. Richards, H.B. Gray, Pure Appl. Chem. 71 (1999)

1753.

[13] J.N. Onuchic, D.N. Beratan, J. Chem. Phys. 92 (1990) 722.