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NORTH

EASTERNSECTION • AMERIC

AN

CHEM

ICAL

SOCIETY

FOUNDED 1898

NESACS

March 2002 Vol. LXXX, No. 7

MonthlyMeetingRichards Medal to Stephen J. Lippard

MeetingReportWhat Is Different aboutFluorocarbons? by David M. Lemal

SummerScholarReportToward a Small-MoleculeActivated Protein Splicing System

Book ReviewHaving Faith, an ecologist’sjourney to motherhood by Sandra Steingraber

2 The Nucleus March 2002

The Nucleus March 2002 3

The Nucleus is distributed to the members of the Northeastern Section of the American Chemical Society, to the secretaries of the Local Sections, and to editors of all local A.C.S. Section publications.Forms close for advertising on the 1st of the month of the preceding issue. Text must be received by theeditor six weeks before the date of issue.Editor: Arno Heyn, 21 Alexander Rd., Newton, MA 02461,

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Tel: 781-837-0424; FAX: 781-837-8792Contributing Editors: Mukund Chorghade, Patricia Hamm, Features; Edward Atkinson, History of

Chemistry; Maryann Solstad, Health; Dennis Sardella, Book Reviews; Marietta H.Schwartz, Software Reviews; E. Joseph Billo, Puzzles.

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Copyright 2002, Northeastern Section of the American Chemical Society, Inc.

Monthly Meeting _______________________________________5Richards Medal to Stephen J. Lippard ( M.I.T.): Three Avenues in BioinorganicChemistry: Cisplatin, Methane Monooxygenase, and Metalloneurochemistry

Who Was Theodore William Richards?______________________6Pictures on pp. 24-25

Meeting Report ________________________________________8January 2002 Meeting Address:What Is Different About Fluorocarbons? By David M. Lemal

ACS Short Course_____________________________________13Interpretation of Mass Spectra, May 2 and 3, 2002

Section Business _____________________________________14Candidates for 2003, Board of Directors Meeting of December 6, 2001

Summer Research Report_______________________________16Toward a Small-Molecule Activated Protein Splicing System, by Ravi V. Shah, Joshua M. Finkelstein, and Gregory L. Verdine (Harvard)

Book Review _________________________________________22Having Faith, an Ecologist’s Journey to Motherhood, by Sandra Steingraber;reviewed by Dennis Sardella

Puzzle Column _______________________________________23Solution to the February Puzzle: p. 21

Cover: Stephen J. Lippard in the Saddle

Deadlines: May 2002 issue: March 14, 2002Summer Issue: June 28, 2002 (National Meeting Issue)

The Northeastern Section of the AmericanChemical Society, Inc.Office: Marilou Cashman, 23 Cottage St., Natick, MA 01760. 1-800-872-2054 (Voice or FAX) or 508-653-6329. e-mail: [email protected] Section business may be conducted via the business office above.NESACS Homepage:http://www.NESACS.orgFrank R. Gorga, WebmasterWashington, D.C. ACS Hotline: 1-800-227-5558Officers 2002Chair:Morton Z. HoffmanChemistry Department, Boston UniversityBoston, MA 02215-2507; 617-353-2494 [email protected]:John L. NeumeyerHarvard Medical School/McLean Hospital115 Mill St., Belmont, MA 02478; 617-855-3388 [email protected] Past Chair:Timothy B. FrigoAdvanced Magnetics, Inc.61 Mooney St., Cambridge, MA 02138617-497-2070x3007 [email protected]:Michael SingerSigma RBI3 Strathmore Rd. Natick, MA [email protected]:James PiperSimmons College, 300 The FenwayBoston, MA 02115,617-521-2722 [email protected]:Anthony RosnerArchivist:Myron Simon20 Somerset Rd.Newton, MA 02465; [email protected]:Michael E. Strem, Joseph A. Lima, Esther A.H. HopkinsCouncilors: Alternate Councilors:Term Ends 12/31/2002 Term Ends 12/31/2002Mary T. Burgess Michael J. DubeMichaeline F. Chen Jean Fuller-StanleyDoris I. Lewis Patrick M. GordonJulia H. Miwa John L. NeumeyerTerm Ends 12/31/2003 Term Ends 12/31/2003Catherine E. Costello Wallace J. GleekmanWilliam Klemperer Arno H.A. HeynDorothy J. Phillips Howard R. MayneBarbara G. Wood Alfred ViolaTerm Ends 12/31/2004 Term Ends 12/31/2004Thomas R. Gilbert Timothy B. FrigoPatricia H. Hamm Morton Z. HoffmanMichael J. Hearn Truman S. LightArlene W. Light Donald O. Rickter

All Chairs of standingCommittees, the editor of THE NUCLEUS, and the Trustees of SectionFunds are members of theBoard of Directors. AnyCouncilor of the American Chemical Societyresiding within the section area is an ex officiomember of the Board of Directors.

Stephen J. Lippard isthe Arthur AmosNoyes Professor ofChemistry and Headof the ChemistryDepartment at theMassachusetts Insti-tute of Technology.He was born in Pitts-burgh, Pennsylvaniaand educated in thePittsburgh publicschools. He studied atHaverford College(B.A., magna cumlaude, 1962) and theMassachusetts Insti-tute of Technology (Ph.D, 1965). Aftera postdoctoral year at MIT during1965-66 he joined the f aculty ofColumbia University as an AssistantProfessor of Chemistry, being pro-moted to Associate Professor withtenure in 1969 and to Professor in1972. In January of 1983 he moved toMIT. He has taken sabbatical leaves atthe University of Göteborg in Sweden,the MRC Laboratory of MolecularBiology in Cambridge, England, theAnorganisch-Chemisches Institut derTechnischen Universität München,Garching, Federal Republic of Ger-many, and the University of California,San Diego.

Professor Lippard has held fellow-ships from the Woodrow Wilson Foun-dation, the National ScienceFoundation, The Alfred P. Sloan Foun-dation, The Camille and Henry Drey-fus Foundation, the GuggenheimFoundation, and the John E. FogartyInternational Center.

He is a member of the AmericanChemical Society, The Royal

Society of Chemistry, The AmericanCrystallographic Association, The Bio-physical Society. He was elected to Phi Beta Kappa (junior year), SigmaXi, and the American Society of Bio-logical Chemists, and a Fellow of the American Association for theAdvancement of Science.

He was editor of the well-known

series “Progress inInorganic Chem-istry” from Volume11 to 40, w as anAssociate Editor ofthe journal InorganicChemistry, is now anAssociate Editor ofthe Journal of theAmerican ChemicalSociety, was aFounding member ofthe Editorial Advi-sory Board forChemical Researchin Toxicology, andserves or has served

on the editorial boards of Accounts ofChemical Research, Anticancer DrugDesign, Bioorganic & MedicinalChemistry, Bioorganic & MedicinalChemistry Letters, ChemBioChem,Chemical and Engineering Ne ws,Chemical Research and Technology,Chemistry & Biology, Inorganic Chem-istry, Inorganic Chemistry Concepts,Inorganica Chimica Acta, Journal ofBiological Inorganic Chemistry, Jour-nal of Inorganic Biochemistry, andTopics in Biological Inorganic Chem-istry. He is the author or co-author ofover 550 publications in the fields ofinorganic and coordination chemistry,organometallic chemistry, and biologi-cal chemistry.

He has co-authored a book withJeremy Berg entitled “Principles ofBioinorganic Chemistry.” He holdsseveral US. and foreign patents. He haschaired several symposia at AmericanChemical Society national meetings,was Alternate Councilor for the Divi-sion of Inorganic Chemistry, wasChairman of the Bioinorganic Subdivi-sion, and Chairman of the InorganicDivision. He has given over 50 namedlectureships at universities both in thiscountry and abroad, served as a panelmember of the Medicinal ChemistryStudy Section B and BMT Study Sec-tion of the National Institutes ofHealth, and has been a consultant forEngelhard Corporation, Exxon Corpo-

ration, Johnson Matthey Co., Procept,Smith Kline & Beckman, Suntech andJohn Wiley & Sons, Inc. He is cur-rently Chairman of the Scientific Advi-sory Board of N AXCOR He w asChairman of the 1985 Gordon


Corporate PatronsAlfa Aesar, a Johnson Matthey Com-

panyHoechst Marion Roussel Co.Pharm-Eco Laboratories, Inc.Physical Sciences, Inc.Polaroid CorporationStrem Chemicals, Inc.Corporate SponsorsAerodyne Research, Inc.AstraZeneca R&DBorregaard Synthesis, Inc.Bristol-Myers SquibbCambridge Isotope LabsConsulting Resources CorporationDike, Bronstein, Roberts &

Cushman, LLPHoughton Chemical Corp.JEOL, USA, Inc.MassTrace, Inc.New England BiolabsOrganix, Inc.Pfizer, Inc.Research Biochemicals Int’lZymark Corporation

NewMembersIncludes members relocated to theNortheastern SectionInvitation to attend a SectionmeetingYou are cordially invited to attend oneof our upcoming Section meetings asguest of the Section at the Social hourand Dinner Meeting.Please call Marilou Cashman at 800-872-2054, 508-653-6329, or:[email protected] by noon of thefirst Thursday of the month, to acceptthis invitation, letting her know thatyou are a new member. ◆◆

continued on page 6

Stephen J. Lippard (Photo by Bachrach)

Biography

AbstractThree Avenues in BioinorganicChemistryThe interface between inorganic andbiological chemistry is broad and ex-panding. Metal ions are extensivelyapplied in diagnostic and therapeuticmedicine. The simple coordinationcompound cis-diamminedichloroplat-inum(II), also known as cis-platin, hascontributed significantly to the man-agement of testicular cancer, formerly

a leading cause of death of youngmales. This and related platinum anti-cancer drugs kill cancer cells through amultifactorial mechanism. The firststep is activation to facilitate DNAbinding. Structures of the major plat-inum-DNA adduct reveal distortions ofthe double helix that trigger the inter-action of proteins involved in geneactivation. Inhibition of the key cellularprocesses of transcription andnucleotide excision repair ensues. Thediscovery of a means of applying thisinformation has afforded a new treat-

ment for ovarian cancer, currentlyundergoing a phase I clinical trial inBoston.

Metal ions are also key compo-nents of enzymes. In methanotrophicbacteria, which use methane as theirsole source of carbon and energy, ahydroxylase enzyme (MMOH) hous-ing a carboxylate-bridged non-hemediiron unit activates dioxygen for theselective conversion of methane intomethanol. This remarkable reactionproceeds in a stepwise fashion, thedetails of which have been delineatedthrough structural studies of theenzyme and its partner proteinsrequired for activity, mechanistic stud-ies of intermediates, and experimentaland theoretical analyses of the C-Hbond activation step. The transitionstate involves a bound radical thatevolves products through both con-certed insertion and recoil /reboundsteps. Analogs of the active site havebeen synthesized that afford insightinto the structures and chemistry ofMMOH.

Neurochemistry is similarlyreplete with inorganic ions essential forfunction. New fluorescent sensors forzinc and nitric oxide ha ve beenobtained that have the potential to mapneural networks in the hippocampus,the center of learning and memory. ◆◆


Monthly MeetingThe 832nd Meeting of the Northeastern Section of the AmericanChemical Society Richards Medal Award Meeting Thursday, March 14, 2002Harvard UniversityHarvard Faculty Club, 20 Quincy St., Cambridge, MA5:30 pm Social Hour; a table of Career Services Literature and Aids will be

available 6:30 pm Dinner8:15 pm Award Meeting, Mallinckrodt Building, 12 Oxford St., Pfizer

Lecture Hall (MB23, ground floor)Dr. Morton Z. Hoffman, NESACS Chair, presidingReflections on T.W. Richards-Dr. Patricia A Mabrouk, Chair, Richards Medal Award CommitteeIntroduction of the Award Recipient-Dr. Daniel G. Nocera, Mass.Institute of TechnologyPresentation of the Medal to Prof. Stephen J. Lippard, Mass. Insti-tute of Technology-Dr. Morton Z. HoffmanThree Avenues in Bioinorganic Chemistry: Cisplatin, MethaneMonoxygenase, and Metalloneurochemistry-Dr. Stephen J. Lippard,Mass. Institute of Technology

Dinner reservations should be made no later than noon, March 7, 2002. Pleasecall or f ax Marilou Cashman at (800) 872-2054 or e-mail [email protected]. Reservations not cancelled at least 24 hours inadvance must be paid. Members, $30.00; Non-members, $35.00; Retirees,$20.00; Students, $ 8.00. THE PUBLIC IS INVITED.Anyone who needs special services or transportation, please call MarilouCashman a few days in advance so that suitable arrangements can be made.Free Parking: in the Broadway St. Garage (3rd level or higher), enter fromCambridge St. via Felton St.Next Meeting: April 18, 2002, Gustavus J. Esselen Award to Dr. Ronald Bres-low, Columbia University. 5:30 Reception and Dinner, Harvard Faculty Club;8:15 Award Meeting, Pfizer Lecture Hall, Mallinckrodt Building, 12 Oxford St.Dr. Breslow: ”Chemistry Lessons from Biology and Vice-versa”

Section NewsJanuary Section Meeting speaker DavidM. Lemal, as announced earlier, willbe receiving the 2002 ACS Award forCreative Work in Fluorine Chemistryat the Orlando Meeting. There is anextensive write-up about his work inC&ENews 2002, Jan. 21, 54.

The following students will bereceiving Fellowships of the OrganicDivision, ACS (name of the mentorand institution in parentheses):David J. Guerin (Scott J. Miller,Boston College)Rebecca T. Ruck (Eric N. Jacobsen,Harvard Univ.)Jennifer V. Schaus (James S. Panek,Boston Univ.)Our congratulation and best wishes tothese Award/Fellowship recipients. ◆◆

The presentation of the TheodoreWilliam Richards Medal to Stephen J.Lippard this month recognizes ‘con-spicuous achievement in the advance-ment of chemistry’, and we can takepride not only in the choice this year,but also in the many distinguishedchemists who have won this honor inpast years. [See the listing in THENUCLEUS, 1998 (2) 24]. But as wehonor Prof. Lippard, we are also hon-oring the memory of Richards himself.Who was this. man?

The first award of what, at thattime; was known as the TheodoreWilliam Richards Gold Medal (themedal is still gold, with a silv er replicafor informal display) was made toArthur Amos Noyes in 1932. The Sec-tion Chairman, William Ryan, intro-duced the occasion with the followingquotation by Henry Watterson:A mound of earth a little higher gradedPerhaps upon a stone a c hiselled

name,A daub of printer’s ink soon blurred

and fadedAnd then — oblivion. That — that is

fame.Ryan went to point out that Wat-

terson, as an observer in national poli-tics, had developed a cynical attitudetoward self-seeking politicians, andRyan contrasts the impermanence ofreputation of such with the seekers oftruth for truth’s sake for whom truefame is imperishable. With reference toRichards he said, “True fame ... liveson, not merely to perpetuate the nameof the individual and his accomplish-ments, but rather to inspire and encour-age others who are serving similarends.”

But in our age, when only “fifteenminutes” of f ame are allo wed, itbehooves us to keep alive the namesand accomplishments of our predeces-

sors in chemistry. The NortheasternSection has many great chemists, butthe earliest of the internationallyrenowned was Theodore WilliamRichards. His Nobel Prize in Chem-istry, awarded in 1914, was the firstgiven an American chemist.

He was born in Germantown in1868, was educated at home by hismother, a poet, and his f ather a marineartist. He became interested in scienceat the age of six when he was shownthe rings of Saturn through a four inchtelescope by Professor Josiah ParsonsCooke, Jr. of Harvard while the familywas at Newport, R.I. At ten he wasmaking Pharaoh’s Serpents with mer-curic thiocyanate and coloring flameswith various salts.. He obtained moneyto set up a chemistry laboratory whenhe was 13 by printing on a hand press,copywriting, and selling an edition ofhis mother’s sonnets. He was allowedto attend chemistry lectures at the Uni-versity of Pennsylvania, and at 14entered and studied chemistry atHaverford. He received the Bachelor ofScience at 17. He went to Harvard tostudy under Cooke and received aBachelor of Arts and, at 20, after a yearof very difficult research in which hedemonstrated exceptional experimentalskills in determining the atomic weightratio of oxygen to hydrogen in water,earned the Ph.D. degree. A year inEurope on a Harvard fellowship gavehim the opportunity of studying analyt-ical techniques at Göttingen and visit-ing important laboratories in Germany,France, England, and Switzerland. Hereturned to Harvard in 1889 as anassistant and remained there for therest of his years. When Cooke died, in1892, Richards, already an assistantprofessor, was sent to Ostw ald atLeipzig and Nernst at Göttingen to pre-pare himself to become the instructor

Who was TheodoreWilliam Richards? by M.S. SimonAdapted from The NUCLEUS, 1996 (3) 4 ff


Research Conference on InorganicChemistry and was Chair of the 1996Gordon Research Conference on Met-als in Biology.

His awards include the Henry J.Albert Award of the International Pre-cious Metals Institute for his work onplatinum metals and their interactionswith nucleic acids, the AmericanChemical Society Award in InorganicChemistry sponsored by MonsantoCompany, the Remsen Award spon-sored by the Maryland Section of theAmerican Chemical Society , theAlexander van Humboldt Senior US.Scientist Award, the John C. Bailar, Jr.Medal of the University of Illinois, theAmerican Chemical Society Award forDistinguished Service in InorganicChemistry sponsored by MallinckrodtCompany, the William H. Nicholsmedal sponsored by the New York Sec-tion of the American Chemical Society,the Frontiers in Biological ChemistryAward from the Max Planck Institutfür Strahlenchemie, honorary D. Sc.degrees from Haverford College andTexas A&M University, an HonoraryMembership in the Italian ChemicalSociety, and Scientific Membership inthe Max-Planck-Gesellschaft. He hasbeen elected to the American Academyof Arts and Sciences, the NationalAcademy of Sciences, and the Instituteof Medicine.

Professor Lippard’s research activ-ities span the fields of inorganic, bio-logical chemistry, and neurochemistry.Included are mechanistic studies ofplatinum anticancer drugs, the synthe-sis of dimetallic complexes as modelsfor non-heme iron enzymes and metal-lohydrolases, structural and mechanis-tic investigations of methanemonooxygenase, and novel sensors forneurotransmitters. ◆◆

BiographyContinued from page 4


in physical chemistry. His rise to fullprofessorship at Harvard in 1901 camequickly, when Göttingen attempted torecruit him.

His early work centered one whatat the time was one of the major sci-entific problems, that of determiningexact atomic weights. He explained hischoice, “not merely because I felt morecompetent in that direction than in an yother, but also because atomic weightsseemed to be one of the primal myster-ies of the universe. They are valueswhich no man by taking thought canchange. They seem to be independentof place and time. They are silent wit-nesses of the very beginnings of theuniverse, and the half-hidden, half-dis-closed symmetry of the periodic sys-tem of the elements only enhancesone’s curiosity about them. Moreover,among the many properties possessedby an element, the atomic weightseems one of the most definite and pre-cise. Hence in trying to satisfy a desirewhich had as its object the discovery ofmore knowledge concerning the funda-mental nature of thing’s, one naturallyassigns to the atomic weights animportant place.”

In the following years Richardsand his students (if we include inde-pendent work of Baxter andHönigschmid, who had been trainedby him) determined the atomic weightof 55 of the 92 known elements, inmany cases in parts per ten thousand,in some, parts per hundred thousand.All of the elements whose atomicweights were the basis for determiningthe atomic weights of other elementswere determined. His work on leadfrom uranium and from non-radioac-tive sources advanced acceptance ofthe theory of isotopes, the onlyconclusive evidence until the develop-ment of the mass spectrograph.

He was always respectful to thoseon whose shoulders he was standing,J.J. Berzelius and J.S. Stas, pioneers inatomic weight determination, but whenhis superior methods showed that theStas values had to be revised, he took

the mantle on his own shoulders. Amodest man, only after searching dili-gently for his own possible errorswould he conclude that the Stas workhad to be superseded.

He was guided to success by “hisability to foresee all sources of errorand possible calamities which the aver-age investigator would have over-looked completely”, reported hisson-in-law, James B. Conant.

Richards put it thus, “Every sub-stance must be assumed to be impure,every reaction must be assumed to beincomplete, every method of measure-ment must be assumed to contain someconstant error, until proof to the con-trary can be obtained. As little as possi-ble must be taken for granted.”

It is illuminating to consider thatmuch of his work was conducted inBoylston Hall, where his laboratoryhad been a stockroom, where the ironsashes of the fume hood rained rust,and a flood on the floor above causedthe ceiling to collapse on him; wherefumes from elsewhere in the buildingcould ruin his experiments. Finally, theWolcott Gibbs Memorial Laboratory, agift of Dr. Morris Loeb, was built in1912 and Richards had the facilities hiswork deserved.

The concentration on atomicweights suggests that Richards wassolely an analytical chemist. Indeed, hewas a superb analytical experimental-ist, but his work in other areas of phys-ical chemistry formed an importantpart of the total picture. His workbegan at the period when physicalchemistry was aborning; van’t Hoff,Arrhenius, Ostwald, Nernst were thenew names and the Zeitschrlft fürPhysikalische Chemie was founded in1887. Richards’ first student in physi-cal chemistry was G.N. Lewis, towhom he assigned the study of theelectrochemistry and thermochemistryof amalgam cells. Richards rejected thebelief of that day that atoms wereincompressible, developed evidencethat atomic volumes change, and,according to Lewis, very nearly dis-covered the third law of thermodynam-ics in his studies of the relationship ofchanges in free energy and total energyaccompanying a reaction. His inven-

tion (with G.S. Forbes and L.J. Hen-derson) of an adiabatic calorimeter ledto studies of specific heats of acids,bases and salts, heats of solution anddilution, heats of neutralization and thethermochemistry of organic com-pounds.

His laboratory attracted studentsfrom many other countries to learn themethods of the Harvard school. Hisability to devise methods which couldgive superb results in the hands of stu-dents led to volumes of publishedresearch. The list of his studentsincludes many of the most capablephysical chemists of the first half ofthe twentieth century.

At his death in 1928 the North-eastern Section appealed for funds toset up a memorial and, with ‘gratifyingresponse’, raised a sum of ten thousanddollars in a few months. The TheodoreWilliam Richards Gold Medal wasdesigned by Cyrus Dallin, a distin-guished sculptor and friend ofRichards. A more complete account ofthe career of Richards may be found ina lecture delivered by Sir Harold Hart-ley and recorded in the Journal of theChemical Society (London), 1930,1930-1968, from which much of thisarticle was taken. Other sourcesinclude the Encyclopedia Britannicaand The NUCLEUS. The ScientificWork of Theodore William Richards isthe title of a Ph.D. dissertation by Shel-don J. Kopperl, U. Wisconsin, Madi-son, 1970, 333-359. ◆◆

(For pictures of T.W. Richards see p. 24 and 25) ◆◆

Who Was TWR?Continued from page 6

Have you looked at the NESACS

website?

WWW.NESACS.org


Meeting ReportWhat Is Different About Fluorocarbons?An address delivered at the January 10, 2002 meeting of the Northeastern Section by David M. Lemal, DartmouthCollegeOf all the elements in the Periodic Table, only fluorine canfully replace the hydrogens in virtually every kind oforganic molecule.1 The properties and chemical reactivityof the resulting fluorocarbons and fluorocarbon derivativesare dramatically different from those of the parent com-pounds. From the inert, uniquely slippery polymer Teflon®

to the liquids that carry oxygen in blood substitutes andbreathing liquids, perfluorinated substances enjoy an abun-dance of uses, for many of which they are without equal.Fluorinated drugs and agrochemicals are also very impor-tant, but these compounds generally contain at most a fe wfluorines. The account that follows is focused on fundamen-tal aspects of fluorocarbon chemistry, with emphasis on therelationship between perfluorinated compounds and theirhydrocarbon counterparts.

Contrasts between these classes of compounds aretraceable principally to three key differences between hydro-gen and fluorine. The great disparity in electronegativity isof central importance, and fluorine’s ~20% greater van derWaals radius and bond length to carbon give rise to largesteric effects in highly fluorinated molecules. In addition,lone pairs give fluorine π donor ability that hydrogen lacks.

The remarkable volatility and low refractive indices offluorocarbons are attributable to fluorine’s status as the mostelectronegative element, for its tightly bound electrons resistpolarization. The consequently weak London forcesbetween fluorocarbons are largely responsible for theirpeculiar solubility properties. Immiscibility of fluorocarbonliquids with many other solvents forms the basis for fluo-rous biphase technology,2 which facilitates the separation ofreaction mixtures.

Fluorine’s schizophrenic character as π donor but �acceptor is clearly revealed in relative acidities. For exam-ple, pentafluorocyclopentadiene 13 (13 < pKa < 16) differsin acidity only modestly from the parent hydrocarbon (pK a= 164) because of opposing � and π effects; but the perfluo-ropentamethyl derivative 25, with no lone pair-π repulsion inits anion, is at least 18 orders of magnitude more acidic thanthe parent (pKa ≤ -2). Further illustration of the interplaybetween � and π effects is found in the relative gas phasestabilities of CHnF3-n

+ ions. The most stable of the fourcations, and therefore the best compromise between stabiliz-ing π and destabilizing � effects. is CHF2

+. 6

Call For PapersNortheast Student ChemistryResearch Conference 2002Open to undergraduates, graduates, and postdoctoral fellowsin all areas of chemical researchSaturday, April 27, 2002Boston University, Science BuildingVisit the NESACS YCC website athttp://people.bu.edu/nsycc for details.

Abstracts will be accepted on this site. There is noregistration fee.Students are invited to present a poster or a 15 minute oralpresentation.

Deadlines:Oral presentations: April 5, 2002Poster presentations: April 12, 2002

Undergraduate Research PosterSession224th National Meeting of the American Chemical Society Boston, Massachusetts, August 18–22, 2002The ACS invites undergraduate students to submit abstractsof their research papers for presentation at the Under gradu-ate Research Poster Session, which will be part of the pro-gram for undergraduates at this national meeting.Abstracts must be submitted electronically:• Go to the meeting web site:

<http://chemistry.org/portal/Chemistry?PID=acsdisplay.html&DOC=meetings%5Cboston2002%5Cindex.html>

• Click on “Submitting a Paper”• Click on “CHED” (Division of Chemical Education)• Go to “Undergraduate Research Posters”For further information, contact:

LaTrease E. Garrison, Undergraduate Programs American Chemical Society1155 Sixteenth Street, NWWashington, DC 20036Tel: (202)872–6166; Fax: (202)833–7732e–mail: [email protected]

Deadline for receipt of abstracts: April 8, 2002 ◆◆


Electron withdrawal by fluorine tends to lower inenergy all of the molecular orbitals in a fluorocarbon, butthe effect is much greater on σ-type than on π-type orbitalsbecause of the compensating π donor effect of the fluorinelone pairs (the “perfluoro effect”7). Whereas the first ioniza-tion potentials (π) of ethylene and tetrafluoroethylene arevirtually identical, the second (σ) differ by more than 3 eV.Another manifestation of the perfluoro ef fect is found in thehexafluorobenzene radical anion (3), wherein the half-filledLUMO is a σ* instead of a π* orbital.8

Perfluoroalkyl substituents markedly stabilize strainedcarbon skeletons (the “perfluoroalkyl effect”9), making pos-sible the isolation and study of ring systems whose parentmolecules are unknown or extremely unstable. Steric pro-tection is responsible in part for the ef fect, but strengtheningof skeletal C-C bonds is apparently also signif icant. As anexample, Dewar thiophene (4) has been observed only incryogenic matrices,10 but perfluorotetramethyl Dewar thio-phene (5) has a half-life for aromatization of 5.1 hours at160 oC.11 Isomerization of hexamethyl Dewar benzene (6)to the benzene is highly e xothermic (∆H = ca. -57kcal/mol12), yet at 400 oC perfluorohexaethylbenzene istransformed in good yield into its Dewar isomer 7.13 Thisamazing reversal illustrates the importance that steric effects

can assume in fluorocarbons, as the reaction is driven byrelief of nonbonded repulsion in the benzene.

Ketones are strongly destabilized by fluorine substitu-tion because of electron withdrawal from an already elec-tron-deficient carbonyl carbon. In contrast to typical enols,perfluoroenols are strikingly stable kinetically, resistingketonization even in the presence of powerful acids.14 Insome cases they are thermodynamically stable as well.15

Heptafluorocyclopentenol (9) is a case in point, as K enol forits formation from the cyclopentanone 8 is ~130 even in car-bon tetrachloride (cf. cyclopentanone itself, Kenol = 1.1 x 10-8

in H2O16). Equilibrium constants for enolization of 2 H-per-fluoroketones are far higher in Lewis basic solvents such asether, THF and acetonitrile than in carbon tetrachloridebecause of the powerful hydrogen bond donor ability of per-fluoroenols.

Meeting ReportContinued from page 8

Continued on page 10


The strain energy of hexafluorocyclopropane is greaterthan twice that of the parent hydrocarbon (~70 vs. 27.6kcal/mol).17 The large amount of s character in the exo-cyclic carbon orbitals results in especially strong bonds tohydrogen, thus lowering the energy of cyclopropane, butelectronegative fluorine atoms prefer bonding to carbonorbitals with more p character (Bent ’s Rule18). Destabiliza-tion of 3-membered rings by fluorine is e vident in the con-trasting behavior of quadricyclane (10) and its perfluorocounterpart. The hydrocarbon has a half-life of 4 hours at154 oC for ring opening to norbornadiene, 19 but octafluoro-quadricyclane (11) rearranges to a tricy-cloheptene at temperatures just above0oC.20 Incidentally, the 19F NMR spec-trum of octafluoroquadricyclane spansmore than 100 ppm, thus illustrating thegreat dispersion available in fluorineNMR that enhances its value as a struc-tural tool.21

Other evidence for fluorine’s preference for sp3 over sp2

hybridization at carbon includes the much greater heat ofpolymerization of tetrafluoroethylene as compared with eth-ylene: ∆H = -37.2 vs –22.7 kcal/mol.22 It is apparent as wellin the thermal cyclization of perfluorodienes and –trienes.For example, decafluorohexa-1,5-diene (12) rearranges

cleanly to the strained bicyclo[2.1.1]hexane 13,23 a reactionthat proceeds completely in the opposite direction with theparent hydrocarbons.24 Cope rearrangement of perfluoro-1,5-dienes takes place via biradical transition states,25 notconcertedly as with hydrocarbon dienes,26 again in large partbecause of fluorine’s preference for p-rich carbon orbitals.

In contrast to cyclopropanes, fluorine substitution sig-nificantly stabilizes cyclobutanes, presumably because itreduces repulsion between nonbonded carbons by diminish-ing electron density in the center of the ring. 27 This helps toexplain why the highly strained and reactive alkene 14 isstable at elevated temperatures28 while the parent hydrocar-bon dimerizes or polymerizes rapidly below 0 oC,29 and why[2.2.2]propellane 1530 ring opens a great deal slower atroom temperature than the only previously isolated deriva-tive of this very strained ring system (16).31

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Meeting ReportContinued from page 9


Whereas the fragile central bond of 16 is cleaved elec-trophilically in an instant by bromine at –70 oC, 15 is stableeven to sulfuric acid in acetonitrile at room temperature.The electron withdrawal by fluorine that makes 15 stoutlyresistant to electrophilic attack renders it v ery susceptible toattack by nucleophiles, for all of the halide ions clea ve itscentral bond under gentle conditions.32

We hope the above catalog of contrasts, though hardlycomplete, serves to highlight the special nature of fluorocar-bons and their derivatives, and to help the reader understandwhy they continue to fascinate the researchers who studythem.Acknowledgement. The author is greatly indebted to thecoworkers whose names appear in the references, and to theNational Science Foundation, the Air Force Office of Scien-tific Research and the donors of the Petroleum ResearchFund of the American Chemical Society for support of thework carried out in our laboratory. References1 Chemistry of Organic Fluorine Compounds II: A Critical

Review; Hudlicky, M.; Pavlath, A.E., Eds.; American Chemi-cal Society: Washington, D.C., 1995. Fluorine at the Millen-nium. Fascinated by Fluorine; Banks, R.E., Ed.; Elsevier:Oxford, 2000. Organofluorine Chemistry, Principles andCommercial Applications; Banks, R.E.; Smart, B.E.; Tatlow,J.C., Eds.; Plenum: New York, 1994.

2 Curran, D.P. Pure Appl. Chem. 2000, 72, 1649. Horvath, I.T.Acc. Chem. Res. 1998, 31, 641.

3 Paprott, G.; Lentz, D.; Seppelt, K. Chem. Ber. 1984, 117,1153. Paprott, G.; Seppelt, K. J. Am. Chem. Soc. 1984, 106,4060.

4 Streitwieser, A., Jr.; Nelson, L.L. J. Am. Chem. Soc. 1976, 98,2188.

5 Laganis, E.D.; Lemal, D.M. J. Am. Chem. Soc. 1980, 102,6633.

6 Blint, R.J.; McMahon, T.B.; Beauchamp, J.L. J. Am. Chem.Soc. 1974, 96, 1269.

7 Brundle, C.R.; Robin, M.B.; Kuebler, N.A.; Basch, H. J. Am.Chem. Soc. 1972, 94, 1451. Brundle, C.R.; Robin, M.B.;Kuebler, N.A. J. Am. Chem. Soc. 1972, 94, 1466.

8 Yim, M.B.; Wood, D.E. J. Am. Chem. Soc. 1976, 98, 2053.9 Lemal, D.M.; Dunlap, L.H., Jr. J. Am. Chem. Soc. 1972, 94,

6562.10 Rendall, W.A.; Clement, A.; Torres, M.; Strausz, O.P. J. Am.

Chem. Soc. 1986, 108, 1691. Rendall, W.A.; Torres, M.;Strausz, O.P. J. Am. Chem. Soc. 1986, 107, 723.

11 Kobayashi, Y.; Kumadaki, I.; Ohsawa, A.; Sekine, Y. Tetrahe-dron Lett. 1975, 1639.

12 Oth, J.F.M. Angew. Chem. Int. Ed. Engl. 1968, 7, 646. Adam,W.; Chang, J.C. Internat. J. Chem. Kinetics 1969, 1, 487.

13 Dabbagh, A.-M.; Flowers, W.T.; Haszeldine, R.N.; Robinson,P.J. J. Chem. Soc., Chem. Commun. 1975, 323. Clifton, E.D.;Flowers, W.T.; Haszeldine, R.N. J. Chem. Soc., Chem. Com-mun. 1969, 1216.

14 For a concise summary of this w ork of Bekker, Knunyants et

al., which encompasses 19 papers, see: Hart, H.; Rappoport,Z.; Biali, S.E. in The Chemistry of Enols; Rappoport, Z., Ed.;Wiley: Chichester, 1990; p 502.

15 Lindner, P.E.; Lemal, D.M. J. Am. Chem. Soc. 1997, 119,3259. See also Lindner, P.E.; Lemal, D.M. J. Org. Chem.1996, 61, 5109; Lindner, P.E.; Correa, R.A.; Gino, J.; Lemal,D.M. J. Am. Chem. Soc. 1996, 118, 2556; Correa, R.A.; Lind-ner, P.E.; Lemal, D.M. J. Am. Chem. Soc. 1994, 116, 10795.

16 Keeffe, J.R.; Kresge, A.J.; Schepp, N.P. J. Am. Chem. Soc.1990, 112, 4862.

17 Zeiger, D.N.; Liebman, J.F. J. Mol. Struct. 2000, 556, 83.18 Bent, H.A. Chem. Rev. 1961, 61, 275.19 Frey, H.M. J. Chem. Soc. 1964, 365.20 Dailey, W.P.; Lemal, D.M. J. Am. Chem. Soc. 1984, 106,

1169.21 Emsley, J.W.; Feeney, J.; Sutcliffe, L.H. High Resolution

Nuclear Magnetic Resonance Spectroscopy; Pergamon:Oxford, 1966; Vol. 2, Chap. 11. The range of 19F chemicalshifts is ~300 ppm for organofluorine compounds and ~1000ppm overall.

22 Joshi, R.M.; Zwolinski, B.J. in Ham, G.E., Ed.; Vinyl Poly-merization; Marcel Dekker: New York, 1967; Vol. 1.

23 Correa, R.A.; Jing, N.; Lemal, D.M. J. Org. Chem. 1993, 58,6406.

24 Srinivasan, R.; Levi, A.A. J. Am. Chem. Soc. 1963, 85, 3363.25 Jing, N.; Lemal, D.M. J. Am. Chem. Soc. 1993, 115, 8481.26 Houk, K.N.; Gustafson, S.M.; Black, K.A. J. Am. Chem. Soc.

1992, 114, 8565. Dupuis, M.; Murray, C.; Davidson, E.R. J.Am. Chem. Soc. 1991, 113, 9756.

27 Liebman, J.; Dolbier, W.R., Jr.; Greenberg, A. J. Phys. Chem.1986, 90, 394. Bauld, N.L.; Cessac, J.; Holloway, R.L. J. Am.Chem. Soc. 1977, 99, 8140.

28 Junk, C.P., Ph.D. Dissertation, Dartmouth College, 2000.29 Wiberg, K.B.; Matturro, M.G.; Okarma, P.J.; Jason, M.E. J.

Am. Chem. Soc. 1984, 106, 2194. Wiberg, K.B.; Matturro,M.G.; Okarma, P.J.; Jason, M.E.; Dailey, W.P.; Burgmaier,G.J.; Bailey, W.F.; Warner, P. Tetrahedron 1986, 42, 1895.

30 Zhang, Y.; Smith, J.R.; Lemal, D.M. J. Am. Chem. Soc. 1996,118, 9454.

31 Eaton, P.E.; Temme, G.E., III J. Am. Chem. Soc. 1973, 95,7508.

32 Smith, J.R., Ph.D. Dissertation, Dartmouth College, 1999 ◆◆

Meeting ReportContinued from page 10 Nominations

Henry A. Hill Award for Outstanding Service tothe Northeastern SectionNominations for the Henry A. Hill Award for OutstandingService to the Northeastern Section are invited. Nomina-tions should be sent by August 8, 2002 to the Administra-tive Secretary, NESACS, Marilou Cashman, 23 Cottage St.,Natick, MA 01760. A resume of professional activities anddescription of the nominee’s service to the NortheasternSection should be included. The Award is to be presented atthe October meeting of the Section.

Michael J. Dube, Chair, Awards Committee ◆◆

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2002


Applications InvitedThe James Flack Norris and Theodore William Richards Undergraduate SummerResearch Scholarships

The Northeastern Section of the American Chemical Society(NESACS) established the James Flack Norris andTheodore William Richards Undergraduate Summer Schol-arships to honor the memories of Professors Norris andRichards by promoting research interactions between under-graduate students and faculty.

Research awards of $3250 will be given for the summerof 2002. The student stipend is $2750 for a minimum com-mitment of ten weeks of full-time research work. Theremaining $500 of the award can be spent on supplies,travel, and other items relevant to the student project.

Institutions whose student/faculty team receives a Nor-ris/Richards Undergraduate Summer Research Scholarshipare expected to contribute toward the support of the facultymembers and to waive any student fees for summerresearch. Academic credit may be granted to the students atthe discretion of the institutions.

Award winners are required to submit a report (~5-7double-spaced pages including figures, tables, and bibliog-

raphy) of their summer projects to the NESA CS EducationCommittee by November 8, 2002 for publication in TheNucleus. They are also required to participate in the North-east Student Chemistry Research Conference (NSCRC) inApril 2003.

Eligibility: Applications will be accepted from student/f ac-ulty teams at colleges and universities within the Northeast-ern Section. The undergraduate student must be achemistry, biochemistry, chemical engineering, or molecularbiology major in good standing, and have completed at leasttwo full years of college-level chemistry by summer, 2002.

Application: Application forms are available on theNESACS web site at http://www.nesacs.org. Completedapplications are to be submitted no later than March 22,2002 to the Chair of the Selection Committee:

Professor Edwin Jahngen, University of Massachusetts LowellChemistry Department, Room 520265 Riverside Street, Olney HallLowell, MA 01854-5047

Notification: Applicants will be notified of the results by e-mail on April 26, 2002. Written confirmation will follow.◆◆


ACS SHORT COURSEDesigned to improve the skills and marketability of practicing B.S., M.S., and Ph.D. chemists.

The NESACS Committee on Continuing Education is pleased to sponsor this newly updated National ACS Two-Day Short Course, at a registration fee less than half of that charged at National and Regional ACS Meetings.

INTERPRETATION OF MASS SPECTRAThis Short Course is designed for chemical scientists who require the knowledge and skill of mass spectral interpretation.

The course does not require expertise in advanced mathematics, physics, or theoretical chemistry. Registrants should have abasic knowledge of chemistry, and course work in organic chemistry is desirable. Participants should bring a basic calcula-

tor to the course.DATES and TIME: Thursday, May 2, 2002; 8:00 a.m. – 5:00 p.m.

and Friday, May 3, 2002; 8:30 a.m. – 5:00 p.m.

PLACE: Snell Library, Room 90, Northeastern University, 360 Huntington Ave., Boston, MAPROGRAM AGENDA:

COURSE BONUS!Bring your own mass spectra to the course for analysis. The instructor will help you to interpret your spectra and usethem as examples for class discussion if appropriate.

INSTRUCTOR: O. David Sparkman is an Adjunct Professor of Chemistry at the University of the Pacific in Stockton, Cal., and a con-

sultant to the National Institute of Standards and Technology Mass Spectrometry Data Center. At the University ofthe Pacific he teaches courses in mass spectrometry and analytical chemistry and manages the mass spectrometryfacility. He is on the Editorial Advisory Boards of the Journal of the American Society for Mass Spectrometry andthe HD Science GC/MS Update – Part B. He is the author of Mass Spectrometry Desk Reference, and with J.Throck Watson developed the Mass Spectral Interpretation Quick Reference Guide. Professor Sparkman is one ofthe highest rated instructors in the ACS Short Course program..

PRE-REGISTRATION REQUIRED – Registration Fees:ACS Members if received before Apr 17………… $450.00; after April 17 ……$525.00Non-ACS Members if received before April 17 ..…$550.00; after April 17 ……$625.00

There will be a limited number of scholarships for unemployed ACS Members on a space-available basis.Parking Fee: about $14.00/day University cafeterias will be available for lunches.

For further information contact: Prof. Alfred Viola at (617) 373 2809

Registration form for Short Course: Interpretation of Mass Spectra. May 2-3, 2002Name: _________________________________________ Business Affiliation:__________________________________Mailing ________________________________________ Telephone:__________________________________Address________________________________________

Mail with remittance to: Prof. Alfred Viola, Chair(Please make checks payable to NESACS. NESACS Committee on Cont. Ed.

Sorry, we cannot accept credit cards or Department of Chemistrypurchase orders.) Northeastern University

Boston, MA 02115

Introduction to Chemical Bonding in Organic Mole-cules as it Pertains to Mass Spectrometry

How the EI Mass Spectrum is Formed – Rules andPrinciples.

Naturally Occurring Stable Isotope Abundances andTheir Role in Peak Intensity

The Molecular IonOdd-electron ions; the nitrogen rule; logical losses.

Fragmentation as it Relates to Structure, ElementalComposition, and Compound Type.

Mass Spectra of High Molecular Weight Compounds. MS/MS Mass Spectra – What Are They and How Do

We Deal With Them? Fragmentation of Specific Compound Types –

Aliphatic and Aromatic Hydrocarbons, Alcohols,Amines, Acids, Aldehydes, and Ketones.

Library Searches and Mixed Spectral DataChemical Ionization and Electron Ionization Spectra

Used Together to Determine the Identity and Struc-ture of an Unknown.


Board ofDirectorsNotes of Meeting of December6, 2001NOTE: Board Meetings are held on themonthly meeting day at 4:30 p.m. Sec-tion members are invited to attend.Officers’ Reports:Chair: T. Frigo announced thatNESACS has received a mini-grant of$500 from the ACS Office of Diversityfor the February 2002 joint meetingwith NOBCChE.T. Frigo relayed Dr. Shakhashiri’sappreciation for having been awardedlifetime membership to NESACS. Healso sent a video-tape of the HolidayLecture, to be kept by D. Lewis and tobe made available on loan.A meeting with officials of the BostonMuseum of Science is to be held forplanning for NCW 2002.He reminded board members thatannual reports are due.Chair-Elect: M. Hoffman stated thatfor the February 14 Meeting (Valen-tine’s Day), in honor of the occasion,members’ “Special Valentines” are tobe invited to the reception and dinneras guests of the Section.Treasurer: J. Piper presented theNovember 2001 Treasurer’s Report.After some discussion, it was MOVEDand VOTED to accept the report.Standing Committees:Bd. Of Publications: MIT is starting aProgram in Science Writing whichmay offer an opportunity for coopera-tion.

The reader survey has been com-pleted and results are being tabulatedfor later presentation.

A revised budget has been pre-sented to the Budget Committee.

Help from YCC is sought for help-ing improving the website appearance.

Editor: The January issue is to be24 pages, with the first summer scholarreport to be in the issue.Membership: M. Chen stated that twonew members will be at tonight’s din-ner. continued on page 15

Chair-Elect:Howard R. MayneJean Fuller Stanley

Treasurer: James U. Piper

Auditor:Anthony L. Rosner

Trustee:Michael E. Strem

Councilor/ Alternate Councilor:Mary BurgessMichaeline ChenMukund S. ChorghadePatrick M. GordonMorton Z. HoffmanDoris I. LewisTruman S. LightDonald O. RickterLawrence T. ScottMichael SingerAmy TapperDavid Warr

Director-at-Large:Ernest V. GromanChu W. JungJulia H. MiwaCarmela C. Amato-Wierda

Nominating Committee:Timothy B. FrigoMichael J. HearnDonald O. RickterDerk A. Wierda

Norris Award Committee:James A. GolenHoward R. MayneMarietta SchwartzJ. Donald Smith

Timothy B. Frigo, Chair, NominatingCommittee

Note: Candidates my be nominated bypetition, accompanied by signatures of130 members, to be submitted to theNESACS office by March 24, 2002. ◆◆

Candidates for 2003

Chemistry Education: R. Tannerstated several issues for next year’s“Connections to Chemistry” meeting:How to accommodate the increasednumber of applicants, how to maintaincurrent costs per person, whether therecan be industrial sponsorship.

Also, Chemmatters has been sentto all attendees of the 2001 “Connec-tions” with a label stating “compli-ments of NESACS.”

Norris Richards Scholar papershave been submitted to theNUCLEUS. Only one of the Scholarshas asked for support to attend theOrlando ACS Spring Meeting. Theother three expect to present papers atthe Boston ACS Fall Meeting.

The issue of section and personalliability was raised. Clarification ofSection responsibility, such as for Sec-tion-supported travel to ACS Meetingsis to be sought by the Chair with helpfrom M. Strem.Esselen Award: J. Koob reported(written report) that four nominationshave been received and a committeemeeting has been scheduled forDecember 18, 2001 to make a finalselection. Six or seven members areexpected to be present, one of them byspeakerphone from California. Waysare to be sought for trimming the costsof the award meeting.Other Committees:Natl. Chemistry Week: D. LewisMOVED as the sense of the Board formaking a $2000 donation to the Bas-sam Shakhashiri Science Foundation inlieu of giving Dr. Shakhashiri an hono-rarium. So VOTED unanimously.Summerthing: D. Lewis stated thatSummerthing 2002 will again be at theBoston Red Sox, with the date to bedetermined after the game schedule isavailable. If it is possible to schedulethis event during the August 25-29,2002 National ACS Meeting in Boston,1000 tickets will be ordered, otherwise200 if the game is in June or July.Younger Chemists: A. Tapperreported that the February 14, 2002Career event is all set with 5 speakersfrom 3:00-5:30 pm, preceding the reg-ular monthly NESACS meeting.

She stated that volunteers are

needed for the April Research Sympo-sium Organizing Committee.Government Affairs: M. Hearn statedthat the National OLGA is planningthe 2002 State House Day. The State’snewest Congressman is to be con-tacted. The ACS Chemistry and PublicAffairs Committee is modifying theGrass Roots Awards to recognize

recipients on both the national andlocal level.New Business: A. Heyn stated that itis time to activate a National MeetingCommittee for the August 2002 ACSMeeting in Boston. M. Hof fmanagreed to chair this committee.From the minutes of M. Singer ◆◆


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At the NESACS MeetingMIT Faculty Clup on December 6, 2001


The ability to perturb the activityof intracellular proteins in a specific,dose-dependent fashion with smallmolecules represents a significant boonto clinical and basic medical research.One general approach, chemical induc-tion of dimerization (CID), uses smallmolecules to dimerize two differentproteins, bringing these proteins in

close proximity to one other. Thisapproach has proven fruitful in themodulation of various important cat-alytic and signaling events, namelyFas-mediated apoptosis, eukaryoticgene transcriptional regulation, andactivation of receptor tyrosine kinases(Belshaw et al., 1996, Amara et al.1997, Rivera et al. 1996). Although

CID’s have been useful in many bio-logical processes, this approach has notbeen extended to the post-translationalmodification of protein levels. In thisresearch, we aim to construct a ligand-activated intein that allows small mol-ecule-dependent induction of proteinlevels using CID technology.

Protein splicing involves the exci-sion of non-coding peptides calledinteins that interrupt the coding exteinsequences of a given polypeptide.This autocatalytic activity has sparkedseveral structural and mechanisticstudies (for review, see Perler, 1998).The intein structure is modular, with conserved N- and C-terminal regions

and nucleophilicresidues at splicejunctions are respon-sible for the ac yltransfer reactionsleading to extein lig-ation (Fig.1 Mills etal., 1998). Recentwork in proteinsplicing has focusedon the use of transsplicing elements,with each e xteinfused to either the

N- or C-terminal half of the minimalintein. Splicing acti vity is thendependent on association between thetwo intein termini to form the activesite (Mills et al., 1998; Evans et al.,2000).

Recently, Ozawa et al. have engi-neered a trans splicing system of theVDE intein from S. cerevisciae that isdependent on protein-protein interac-tions (Figure 2A; Ozawa et al. 2000).The authors split the VDE intein andan EGFP reporter in half (VDE N,VDEC; EGFPN, EGFPC) and coex-pressed protein fusions of EGFPN-VDEN-calmodulin and M13peptide-VDEC-EGFPC in E. coli. Splic-ing was shown to be dependent on theinteraction between calmodulin andM13 peptide in E. coli, as constructslacking these binding partners did notsplice in trans to produce an EGFP sig-nal.

Summer Research ReportToward a Small-Molecule Activated Protein Splicing System Ravi V. Shah† , Joshua M. Finkelstein, and Gregory L. Verdine, Department ofChemistry and Chemical Biology Harvard University

† 2001 Norris/Richards Summer ScholarBoston, MA 02115

Figure 1, Mechanism of trans splicing.InteinN and InteinC associate with one another. Intein byproducts are shaded.


These results suggest that thereconstitution of the intein active site isa proximity-driven process, whereinthe association of the N- and C-termi-nal intein fragments leads to transsplicing. In this research, we sought toapply the CID system to protein splic-ing,by replacing the calmodulin andM13 peptide with FKBP (FK-506-binding protein) and FRB* (FKBP-rapamycin bonding domain), tw oproteins that interact in the presence pfthe macrolide rapamycin (Figure 2B,Liberles et al. 1997).ExperimentalPlasmid construction. Standard PCRcloning methods were used to construct the fusions EGFPN-VDEN-Linker-FKBP and FRB-Linker-VDEC-EGFPC. The mutant EGFP “m125”(E125I, I129C) used by Ozawa et al.(2000) was used in this research.EGFPN (EGFP1-128) was amplifiedfrom the pCI-EGFP plasmid (Clon-tech, Palo Alto, CA) and VDEN

(VMAI1-184) was amplified fromgenomic DNA extracted from strainBY4741 (MATa, his3D1 leu2D0,met15D0, ura3D0, fpr1::kanMX4;Research Genetics, Huntsville, AL)

using the QiaGEN genomic DN Aextraction kit (Qiagen, Inc., Valencia,CA). These two PCR products were

ligated via mutually-primed PCR withexternal primers containing BamHIand XhoI sites, and cloned into theBamHI XhoI sites of the galactose-inducible yeast expression vectorpESC-Leu (Clontech). FKBP (FKBP1-

107) amplified from plasmids availablein the laboratory (Nyanguile et al.1997) was cloned into the XhoI-NheIsites of pESC-Leu (Clontech). (Thefull construct is referred to as pESC-Leu-NTERM.) Similar techniques(mutually primed PCR followed bycloning) were used to clone VDEC

(VMA1389-454) and EGFPC (EGFP129-

239) into the SalI-XhoI sites of thegalactose-inducible yeast expressionvector pESC-His (Clontech). FRB*was amplified from plasmids alreadyavailable in the laboratory (Liberles etal. 1997) was cloned into the BamHI-SalI sites of pESC-His. (The full con-struct is referred to aspESC-His-CTERM.) The “Linker”residues were derived from Ozawa etal. (2000) and incorporated into PCRcloning primers to confer flexibility tothe signal tripartite fusion protein. Theamino acid sequence of the N-terminallinker was ASNLENGRNG; the

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continued on page 18

Figure 2, Experimental paradigm. (A) Ozawa approach: Dimerization of calmodulin andM13 peptide initiates protein splicing. (B) CID approach: Rapamycin induces dimerizationof FKBP and FRB to initiate splicing.


sequence of the C-terminal linker wasGNNCDNNDV. For in vitro studies,the full N-terminal intein construct wassubcloned from pESC-Leu-NTERMinto the BamHI-EcoRI sites of bacter-ial expression vector pET-28b (calledpET-28-NTERM; Novagen, Madison,WI); the C-terminal construct was sub-cloned from pESC-His-CTERM intothe BamHI-XhoI sites of pET-28b(called pET-28-CTERM). Sequenceconfirmation of all constructs was per-formed by Seqwright, Inc. (Houston,TX).Expression and solubility testing.Each pET-28b construct (pET-28b-CTERM and pET28b-NTERM) weretransformed into BL21(DE3) lysogencompetent cells (Novagen). The levelsof expression at 25, 30, and 37°C forboth constructs were assessed by grow-ing one colony from each BL21(DE3)transformation in kanamycin (30µg/mL)-supplemented Luria-Bertanimedium (LB) to an optical density(OD600) of 0.4-0.7, inducing transcrip-tion via addition of isopropyl-ß-D-

thiogalactopyranoside (IPTG, finalconcentration 1 mM; control was unin-duced), and allowing expression for 4h. A 1 mL aliquot of induced and unin-duced cells were pelleted; the super-natant was removed; the cell pellet wasresuspended and lysed by boiling at100°C for 10 min in SDS loadingbuffer (2% SDS, 0.25% bromophenolblue, 10% ß-mercaptoethanol). Theresulting lysates were subjected toSDS-PAGE on a NuPAGE 4-12% Bis-Tris gradient gel in MES electrophore-sis buffer (Invitrogen, Carlsbad, CA).Experiments to assay the solubility ofthe expressed proteins were run in asimilar manner, lysing cells via sonica-tion in Lysis Buffer (500 mM NaCl, 50mM Tris-HCl pH 8.0) and pelleting thelysates. Both the supernatant (soluble)and pelleted cell debris (insoluble)fraction were boiled in SDS loadingbuffer and subjected to SDSPAGE asabove.Protein overexpression. One colony ofthe appropriate BL21(DE3) transfor-mant was inoculated into a 1 L cultureof kanamycin-supplemented LB, andgrown at 37°C (pET-28b-NTERM) or25°C (pET-28b-CTERM) overnight. A

50 mL aliquot of the stationary phaseovernight culture was reinoculated intofresh 1 L kanamycin-supplementedLB, grown to OD 600 0.4-0.7, andinduced at the optimal temperature(25°C for C-terminal, 30°C for N-ter-minal) for 24 hr and 4 hr , respectively.Cells were pelleted, resuspended in 20mL Lysis Buffer, and mechanicallylyzed via French press. Lysates werecentrifuged at 15,000g for 20 min. ThepET28b vector encodes hexahistidinetags at the N- and C-terminal ends ofthe recombinant proteins, and theseHis tags were used to purify the pro-teins via Ni2+ affinity chromatography.As such, the resulting supernatant wasloaded onto an affinity column chargedwith 2 mL Ni2+ TALON resin (Clon-tech) and pre-equilibrated with 20 mLLysis Buffer. The supernatant-contain-ing column was incubated for 1 hr at4°C under gentle shaking. Supernatantwas allowed to flow through the col-umn (“flow through”), and the columnwas subsequently washed 4 x 10 mL ofLysis Buffer (“wash”). The bound pro-teins were eluted from the column byaddition of Elution Buffer (500 mMNaCl, 50 mM Tris-HCl pH 8.0, 100mM imidazole) in 1 mL aliquots. Frac-tions were collected and assayed forprotein using the Bradford assay (Bio-Rad, Hercules, CA), and protein-containing fractions were pooled(“eluant”).Construction of yeast strain. In yeastcells, the FKBP ortholog Fprlp bindsrapamycin to form a complex thatbinds Torlp, ultimately leading togrowth arrest in G1 (Zheng et al.,1995). In order to overcome the prob-lem of rapamycin cytotoxicity in yeastcells, an fprl knock-out yeast strainmutant for Torlp had to be constructed.It is known that a mutation in the non-essential tor1 allele (S1972R) rendersyeast rapamycin-resistant (Zheng et al.1995). The Tor1 wild-type allele wascloned from yeast genomic DNA,appropriately mutated, and gel puri-fied.

We first transformed the FKBP-containing pESC-Leu-NTERM intothe BY4741 strain and selected onLeu-deficient, geneticin (30 µg/mL)-containing agar (Leu- gen) with glu-

Summer ResearchContinued from page 17


cose as a carbon source. Although theyeast fpr1 had been deleted, the FKBPfrom our transformed pESCLeu-NTERM construct will participate in adeleterious FKBP-rapamycin-TORinteraction. A colony from the firsttransformation (BY4741 with pESC-Leu-NTERM) was grown in Leu -

media supplemented with galactose toinduce the expression of the N-termi-nal intein construct containing FKBP.Homologous recombination of ourmutant tor1 allele into the genome ofthese cells is currently being con-ducted, and selection will be per-formed on Leu-, gen agar platessupplemented with galactose and 1µg/mL rapamcyin. Transformationswere completed as described by theS.C. EasyComp Transformation Kit(Invitrogen).Results and Discussion.Protein expression. High levels of pro-tein expression of the N-terminal con-struct were obtained at both 30°C and37°C (Figure 3). The absence of astrong band in the soluble fraction at37°C for the N-terminal construct (Fig-ure 4) indicates that the overexpressedN-terminal intein product is not solu-ble and well-folded at 37°C: We there-fore conducted a large-scale expressionand purifiction of the pET -28b-NTERM at 30°C to yield the ~50kDproduct in reasonable purity (Figure 5).Since our

NTERM and CTERM constructsconsist of several segments of proteins

(EGFP and VDE) that may not foldcorrectly outside the context of the fullpeptide, it is possible that the peptidesco-purifying with our target may bemolecular chaperones responsible forre-folding proteins in E. coli.

The C-terminal intein constructposed more difficulties with respect tosoluble expression and purification.Again, the C-terminal intein express athigh levels at both 30°C and 37°C(Figure 3), but solubility experimentsshowed that a significantly higher frac-tion of the C-terminal fusion proteinwas solubly expressed at 37°C than at30°C (Figure 4). However, attemptedpurification of large-scale preparationsof the fusion protein at 37°C failed(Figure 5). In order to increase solubil-ity, we attempted overexpression at alower temperature, with favorableexpression results (data not shown).Although we did not attempt a solubil-ity test at this temperature, the large-scale preparation of the fusion proteinat 25°C was partially successful, yield-ing small amounts of the impure pro-tein (Figure 6). Interestingly, a similarpattern of bands co-eluted with the C-terminal intein as with the N-terminalintein. This may be a further indicationof a cellular unfolded protein chaper-one response or simply that we areeluting constitutively expressed ubiqui-tous proteins that have affinity for theNi column. We are currently lookinginto other expression systems (forexample, different bacterial cell lines

may increase soluble expression) andmore extensive purification for yield-ing a target free of contaminants for invitro studies.Future goals. The difficulties inherentin soluble expression and purificationof the C-terminal intein fragment haveled us to pursue in vivo studies in yeastand mammalian cells. We are currentlyattempting the Torlp recombinationand yeast transformations as discussed(Zheng et al. 1995), and will select forrecombinants resistant to rapamycin.After transforming the rapamycin-resistant strain containing the N-termi-nal intein construct with ourC-terminal construct, we will induce

Figure 4. Solubility test of N- and C-terminalinteins. (Note: lane for “37 uninduced” notloaded in N-terminal constructs)

Figure 3. N and C-terminal intein fusionexpression. The arrows indicate the bandcorresponding to the overexpressed prod-uct (~50 kD for N; ~30 kD for C).

Figure 5. Purification of N- and C-inteins.FT = flow of lysate through column; WA= wash; EL = elution. Boiled induced cellsand Ni2+ resin also included.


Figure 6. Purification of C-intein. Legend as in Figure 5.


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expression of both N- and C-terminalfragments with galactose and assay forin vivo splicing activity upon additionof rapamycin. We are also in theprocess of subcloning the N- and C-terminal intein fusions into pCMV-Script mammalian expression vector(Stratagene, La Jolla, CA). Instead ofrelying on FKBP and FRB dimeriza-tion with rapamycin, our new systeminvolves a small molecule-dimerizerthat is more orthogonal to cellularfunction. We are constructing fusionproteins of the form EGFPN-VDEN-Linker-FKBP3* and FKBP3*-Linker-VDEC-EGFPC, where FKBP 3*represents three copies of an engi-neered variant of FKBP that selectivelybinds to the small molecule homod-imerizer AP1903 (Clackson et al.1998). AP1903 can selectively dimer-ize FKBP* that is present on both theN- and C-terminal intein fusions in thepresence of endogenous FKBP. Pre-sumably, an increased number ofcopies of FKBP* will force a dimeriza-tion event via cooperative effects. Wewill very shortly complete the cloningand assay of this system in mammaliancells.Implications. The development of thistechnology could make a very largeimpact on expression profiling usingDNA microarrays. The ability to con-trol protein levels in a temporal anddose-dependent fashion would allowus to monitor genome-wide responsesto the increased expression of a partic-ular gene. Current profiling studiesrely on “knocking out” or overexpress-ing genes of interest, which has limita-tions because gene overexpression isnonconditional; transfection perma-nently alters the expression profile of acell. Development of a ligand-activatedintein would allow rapid, liganddependent increases in protein expres-sion, facilitating the study of biologicalevents that occur quickly. Therapeuti-cally, viral-mediated delivery of med-ically relevant proteins (for example,tumor suppressor gene products) intheir “inactive-intein fused” form and

subsequent dose-dependent activationby a ligand allow reversible, temporalcontrol of protein levels appropriate tothe patient. In total, CID protein modi-fication allows the construction of aligand-activated intein with the abilityto titrate intracellular protein levels in adose- and time-dependent manner, giv-ing access to a wide range of novelapplications in genetics and medicine.ReferencesAmara, J., Clackson, T., Rivera, V.M.,

Guo, T., Keenan, T., Natesan, S.,Pollock, R, Yang, W., Courage, N.,Holt, D., Gilman, M. A versatilesynthetic dimerizer for the regulationof protein-protein interactions. PNASUSA 1997 20, 10618-10623.

Belshaw, P.J., Ho, S.N., Crabtree, G.R,Schreiber, S.L. Controlling proteinassociation and subcellular localiza-tion with a synthetic ligand thatinduces heterodimerization of pro-teins. PNAS USA 1996 93, 4604-4607.

Chan, T., Carvalho, J., Riles, L.,Zheng, X. A chemical genomicsapproach toward understanding theglobal functions of the target ofrapamycin protein. PNAS USA 200097(24):13227-13232.

Clackson, T., Yang, W., Rozamus, L.,Hatada, M., Amara, J., Rollins, C.,Stevenson, L., Magari, S., Wood, S..,Courage, N., Lu, X., Cerasoli, F.,Gilman, M., Holt, D. Redesigning anFKBP-ligand interface to generatechemical dimerizer with novel speci-ficity.

Evans, T.C. Jr., Martin, D., Kolly, R,Panne, D., Sun, L., Ghosh, I., Chen,L., Benner, J., Liu, X.Q., Xu, M.Protein trans-splicing and cycliza-tion by a naturally split intein fromthe dnaE gene of Synechocystisspecies PCC6803. J. Biol. Chem.2000 275(13): 9091-9094.

Liberles, S.D., Diver, S.T., Austin,D.J., Schrieber, S.L. Inducible geneexpression and protein translocationusing nontoxic ligands identified bya mammalian three-hybrid screen.PNAS USA 1997 94, 7825-7830.

Mills, K., Lew, B., Jiang, S., Paulus, H.Protein splicing in trans by purifiedN- and C-terminal fragments of the

Mycobacterium tuberculosis RecAintein. PNAS USA 1998 95(7), 3542-3548.

Nyanguile, O., Uesugi, M, Austin, D.,Verdine, G. A nonnatural transcrip-tional coactivator. PNAS USA 199794, 13402-13406.

Ozawa, T., Nogami, S., Sato, M.,Ohya, Y., Umezawa, Y. A fluorescentindicator for detecting protein-pro-tein interactions in vivo based onprotein splicing. Anal. Chem. 200072(21): 5151-5157.

Ozawa, T., Kaihara, A, Sato, M., Tachi-hara, K., Umeza wa, Y. Splitluciferase as an optical probe fordetecting protein-protein interactionsin mammalian cells based on proteinsplicing. Anal. Chem. 2001. 73(21),2516-2521.

Ozawa, T., Umezawa, Y. Detection ofprotein-protein interactions in vivobased on protein splicing. Curr.Opinion in Chem. Biol.2001 5, 578-583.

Perler, F. Protein splicing of inteinsand hedgehog autoproteolysis: struc-ture, function, and evolution. Cell1998 92, 1-4.

Rivera, V., Clackson, T., Natesan, S.,Pollock, R, Amara, J., Keenan, T.,Magar, S., Phillips, T., Courage, N.,Cerasoli, F., Holt, D., Gilman, M. Ahumanized system for pharmaco-logic control of gene expression.Nature Medicine 1996 2, 1028-1032.

Zheng, X.-F., Fiorentino, D., Chen, J.,Crabtree, GR., Schrieber, S. TORKinase domains are required for tw odistinct functions, only one of whichis inhibited by rapamycin. Cell 199582, 121-130. ◆◆

Summer ResearchContinued from page 19

Feb. Puzzle Solution


Book ReviewHaving Faith. An Ecologist’sJourney To Motherhoodby Sandra Steingraber (Perseus Books,2001 288 pp., ISBN 0738204676;$26.00 hardcover} Reviewed by Dennis J. Sardella,Department of Chemistry, MerkertChemistry Center, Boston College,Chestnut Hill, MA 02467Phil Cousineau, in his book The Art ofPilgrimage, says, that “The differencebetween pilgrim and tourist is theintention of attention, the quality of thecuriosity.” From this perspective, San-dra Steingraber’s book, Having Faith.An Ecologist’s Journey ToMotherhood, qualifies as a pilgrimagethrough pregnancy, with Steingraberserving up an enjoyable blend of expe-rience, scientific reflection, and writingthat verges on the poetic.

Now a book chronicling the tenmonths of a pregnancy and the firstyear of infancy may not, admittedly, be

an obvious choice for a review in aperiodical aimed at chemical profes-sionals. Certainly, I would not haveexpected to be interested in reviewingit. When it came across my desk (unso-licited), my initial reaction was “Here’sone that was clearly misdirected,”rather like my reaction when my wifeand I are trolling the aisles of the localvideo store and she picks up a filmwhose jacket blurb describes it as“heartwarming”. For some reason,however, I glanced through the firstfew pages of “Having Faith” and wasdrawn into it, so here I am, recom-mending that you read a book which isnot about chemists, or the chemicalprofession, but which illustrates beauti-fully what can happen when an artistand a scientist inhabit the same body.

Sandra Steingraber, who currentlyteaches at Cornell, can flat out write.Someone, during her scientific appren-ticeship, obviously forgot to tell herabout the importance of writing in thethird person and/or the passive voice.The result is a style that is a kind ofextended meditation on her experimen-

tal observations in the laboratory of herpregnant body.

In the very early stages of herpregnancy, during the time when, toquote Psalm 139, “when I was growingin secret in my mother’s womb”, thereis not much that Steingraber can actu-ally observe. She nonetheless imaginesthe changes taking place, such as theproliferation of blood vessels, in imag-inative parallels between externalobservations as a naturalist with theprocesses taking place within her:

“Plant physiologists still can ’texplain why maple sap runs in thespring. It’s a mystery that secretlypleases me. All trees stockpile sugarduring the winter , and in mostspecies simple capillary action canaccount for its ascent from roots tobranches in the early spring, This isthe same adhesive force that drawsa drop of water through a papernapkin. But this principle cannotaccount for the ten to twelve gallonsof 4 percent sucrose solution thatyour average sugar maple can pullup its trunk and pour into a bucket

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during the month of March. Injureany other tree and sap will merelyooze from the wound. But the com-plex hydraulics of maples somehowgenerates an interior force thatexceeds the outside air pressure.Sap spurts from every gash and bro-ken branch.” (p. 30)“My botanical reverie soon turnsobstetrical. In fact, the internalanatomy of a human placentaresembles a maple grove: the longcolumns of cells sent out by theembryo into the uterine lining dur-ing the first few weeks of pregnancyquickly branch and branch againuntil, by the third month of preg-nancy, the treetops of an entire for-est press up against the deepestlayers of the womb. Meanwhile, theopen taps of the uterus’s spiralarteries send jets of blood spurtingbetween these arboreal structures.”(p. 31)

As the book advances along withher pregnancy, Steingraber’s attentionmoves beyond the confines of her bodyto the interactions linking the mother,the developing fetus and the environ-ment. Along the way, she discusses theeffects of teratogens such as diethyl-stilbestrol (DES), mercury and lead,exploring and challenging some time-honored ideas such as the notions ofthreshold toxicity limits and the pla-cental barrier that supposedly protectsthe unborn child from exogenous con-taminants (both now known to beincorrect). She provides information onthe various ways in which data on birthdefects is (and often is not) cataloguedthroughout the United States. Sheemploys data from the Toxics ReleaseInventory to describe the release oftoxins into the environment as a resultof both natural processes and humanactivity, highlighting the ways in whichgovernment and business have oftenchosen to ignore data far decades. Herdiscussion of lead contaminationranges widely, covering

Across1. Not germ5. Ancient Egyptian creator

deity9. Look for sales

13. Once ____ a time . . . 14. Tree snake15. Rate16. Nothing more 17. Reversed 19. Singing voice 20. Ancient Syria 21. Grow incisors 23. Bog24. Element named after

state it was discovered in 26. Leukotrines alias27. Department in France 28. Go downhill fast? 30. Female fowl33. Baking soda, informally 38. As I was going to

St. _____41. Wraths43. Forearm bones 44. To delete45. Masking or scotch 46. Ore diggers48. Make a lap 49. Summer color 51. Beer container 53. Flightless bird

55. Element 99, named aftera famous scientist

63. Stocking problem64. Garden tool 65. ____ Domini 66. Melody 68. Hindu honorific title 69. Stand in line70. Paul formerly71. Predecessor of KGB 72. Grafted: heraldry 73. Shade trees74. Oxhide strap75. Fishing pole part

Down1. It may be poison 2. Verdi work3. Upright and honest4. Condition resulting from

low iron levels5. Element Important In

nuclear weapons andnuclear energy

6. Copier supply7. Cosmetician Elizabeth 8. Port-au-Prince’s city 9. Mineral spring

10. 163 days for curium, 433years for americium

11. Set of eight12. Menial workers

18. ___’I-hijjah (12th Muslim month)

22. Type sizes25. Lie29. Baby goat 30. Slap31. A long time32. First transuranium ele-

ment discovered 34. 151 to Caesar35. ___ Arbor, Michigan 36. ___ Dawn Chong37. Element named after the

school It was discoveredat

39. Biblical judge 40. Group42. Black or Red 47. Type of whale 50. After taxes52. Rodent, sometimes 53. Rub out54. Large painting56. A taxing gp.57. “It’s ___ __ never”58. Metal-working tool59. Allegro and adagio60. Stupid and trivial61. Join together62. Hotel alternative67. Capone and Hirt

Puzzle ColumnBy permission from the The INDICATOR of the New York/North Jersey Sections,December 2001 Transuranium Elements by Colleen M. Parriott

Book ReviewContinued from page 22



• the known toxicity of lead com-pounds, the introduction oforganolead compounds as antiknockadditives in gasolines and their con-tinued use for decades in the f ace ofincontrovertible evidence of leadtoxicity, arguably because the alter-native, ethanol, was nonpatentable,and therefore less profitable,

• the promotion of lead-based pig-ments by the paint industry, the con-sequence being that their banning inthe United States trailed that inEurope by decades,

• the fact that coal-based power plants,

the single greatest emitters of leadinto the biosphere, were until rela-tively recently exempt from environ-mental regulations governing leademission,

eventually connecting again with herpersonal story linking lead pollution inthe starting point of her and her hus-band’s journey from a leave in herhome state of Illinois (one of the majorUS areas of combustion-based leadrelease) to Somerville, her husband’shome city, where she and her husbandthen resided.

In all the back and forth move-ment between the intricate process tak-ing place within her and the potentialenvironmental assaults that couldderail or terminate it, though, Stein-

graber’s narrative; while informativethought provoking and sobering, neverbecame hysterical. There are evenlaughs along the way, such as whenshe speaks of feeling herself isolated,in transit between two worlds:

“Being pregnant is like walkingover a plank-and-cable bridge.Behind me, on one bank, is the tribeof women who are not mothers.They drink wine, stay up late, skipmeals, change lovers, study San-skrit, and write grant proposals for afive-year study of tropical cloudforests. In front of me, on the otherbank, is the tribe of mothers. Theyarrive at meetings late, leave partiesearly, are badly in need of haircuts,know way too much about the care

Book ReviewContinued from page 23

Pictures of T.W. Richardsfrom Harvard University Archives

T.W.R. in 1888

T.W.R. in 1907

Asst. Prof. T.W.R. with his Harvard Chem 4 Class in 1892 (back row, center)


and feeding of guinea pigs, andhave to hang up now.” (p. 94)

The well-established correlationbetween brain size and gestationalperiod suggests that human pregnan-cies should last about twenty-twomonths. However, the size of thehuman pelvis makes this impossible,the result being that the first year oflife can be regarded as the last twelvemonths of pregnancy. This provides arationale for Steingraber’s devoting thelast third of her book to her first yearof motherhood, and in particular to anextensive discussion of nursing andmother’s milk. Steingraber provides avivid contrast between the extensivebenefits provided by mother’s milk andthe alarming fact that biomagnification

(a process which she links to conserva-tion of mass as one moves up the foodchain) concentrates toxins in mother’smilk, making it among the most con-taminated of foods.

This, in a way, brings me back towhere I began - to the question of whya middle-aged male chemist should beenthusiastically recommending a bookon the pregnancy of an ecologist, andwhy I think you should consider read-ing it. There are, in fact, quite a fewreasons, beginning with the quality andvitality of Sandra Steingraber’s writing, which many scientists could benefitfrom imitating at some level. Next isher ability to integrate the personal andprofessional perspectives in a way thatrespects the integrity of both. Thirdly,

there is simply a lot to learn about theinterlocking nature of biological andbiochemical processes and the way inwhich they are inextricably intertwinedwith the world in which we live andmove. Finally, because the demo-graphic shift in the profession in recentdecades makes it extremely likely thatin the near future (if it has not alreadyhappened) you, or someone in yourlaboratory or department, will be expe-riencing these remarkable changes, orbe married to someone experiencingthem, or working with or supervisingsomeone negotiating them, the abilityto appreciate the magnitude and themajesty of what is happening couldprove very useful. ◆◆

T.W.R. in 1920 (age 52)

T.W.R. in Manchester, England with H.B. Dixon in 1911

Harvard Research Group of T.W.R. in 1905Front row: (L to R): H.H. Willard, F.G. Jackson,T.W.R., Burgess, Grinnel Jones;Back row: Delbrück, Carrol-Thomas, Matthews,Coffin, Frevert, J.H. Wilson, Rowe, Mabes(the names are in indistinct handwriting!Corrections invited)


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Note also the MIT Chemistry DepartmentWebpage calendar:http://web.mit.edu/chemistry/www/temp/seminars/pchemseminars.htmland the Harvard Chemistry web site for updates:http://www-chem.harvard.edu/events/Physical_Seminars.html(which includes the Harvard/MIT joint seminars).

March 1Prof. Jon Sessler (Univ. of Texas)"Novel Porphyrin-inspired Systems: Acyclic,Macrocyclic, and Polycyclic"Boston College, Merkert Chemistry Center,Room 130, 2609 Beacon St. 4:00 pm

March 4Dan Kopp, Lippard Group (MIT)Biochemistry Seminar Series"Electron transfer and C-H Bond Activation inMethane Monooxygenase"MIT, Room 6-120, 4 pm

March 5Prof. John A. Gerlt (Univ. of Illinois, Urbana-Champaign)"Does Sequence or Structure Determine EnzymeFunction? Different Reactions Catalyzed by the'Same' Active Site"Tufts Univ., Pearson Chem. Building, 62 Talbot Ave., Medford, Room 106, 4:30 pm

March 6Prof. Richard Eisenberg (Rochester Univ.)Harvard/MIT Inorganic Chemistry Seminar @HarvardHarvard Univ., MB-23 Pfizer Lecture Hall, 4:15 pm

March 7Prof. Bryan Coughlin (U Mass Amherst)TBADartmouth College, room 101 Fairchild, 10:30 amProf. Ron Shen (Univ. of Calif., BerkeleyPhysics dept) Harvard/MITHarvard Univ., MB-23 Pfizer Lecture Hall, 4:15 pmProf. Alex Pines (Univ. of Calif., Berkeley)Harvard/MIT Physical Chemistry Seminar atMIT

"NMR and MRI at a Distance"MIT, Room 2-105, 4 pm

March 11Prof. David Walt (Tufts Univ.)"Optical Sensor Microarrays; from MolecularBiology to ArtificialOlfaction"Boston Univ., 590 Commonwealth Ave., Science Center Auditorium, SCI 107, 4:00 pm

March 12Prof. Eric Bakker (Auburn Univ. & EcoleNormale Superieure, Paris)"From Extremely Selective Ion Sensors to SmartMicrospheres"Tufts Univ., Pearson Chem. Building, 62 Talbot Ave., Medford, Room 106, 4:30 pm

March 14Prof. Jennifer Doudna (Yale Univ.)"Splicing with a twist: Unexpected structurearound the branch point of a group II intron"Boston College, Merkert Chemistry Center,Room 130, 2609 Beacon St. 4:00 pmProf. Jeff Gelles (Brandeis Univ. Dept. ofBiochemistry)Harvard Univ., MB-23 Pfizer Lecture Hall, 4:15 pmDr. Erik J. Sorensen(Scripps Research Institute)Seminar in Organic Chemistry TBAMIT, Room 6-120, 4 pm

March 15Dr. John E. Blume (Vice President, StrategicTechnologies, Metabolex Inc.)"Genomics as a Viable Approach for TherapeuticTarget Discovery"CURRENT TOPICS IN MEDICALCHEMISTRY -- A DISTINGUISHEDLECTURE SERIES, Boston Univ., 595 Commonwealth Ave., Room 228 Rafik B. Hariri Building, 2:00 pm

March 18Prof. Bill Tolman (Univ. of Minnesota)"Using Synthetic Chemistry to UnderstandCopper and Iron Active Sites in Proteins"Boston Univ., 590 Commonwealth Ave., Science Center Auditorium, SCI 107, 4:00 pmJennifer Stone, Stern Group (MIT)Biochemistry Seminar Series"Molecular Mechanisms of T cell Triggering"MIT, Room 6-120, 4pm

March 19Prof. Erick M. Carreira (ETH, Zurich)Novartis Lecture in Synthetic Organic ChemistryMIT, Room 6-120, 4 pm

March 20Prof. Dev Arya (Clemson Univ.)"Neomycin-Nucleic Acid Interactions"Boston College, Merkert Chemistry Center,Room 130, 2609 Beacon St. 4:00 pmProf. Donald Darensbourg (T.A.M.U)Harvard/MIT Inorganic Chemistry Seminar @MITMIT, Room 6-120, 4 pm

March 22Dr. Barrie J. Carter (Executive Vice President &CSO, Targeted Genetics Corp.)"Developing Therapeutic Applications of GeneDelivery"CURRENT TOPICS IN MEDICALCHEMISTRY -- A DISTINGUISHEDLECTURE SERIES, BostonUniv., 595 Commonwealth Ave., Room 228 Rafik B. Hariri Building, 2:00 pm

March 25Prof. Marina Petrukhina (SUNY-Albany)"Rh2(O2CCF3)4 Adducts with PolycyclicAromatic Hydrocarbons: Discrete Molecules,1D Polymers and 2D Networks"Boston College, Merkert Chemistry Center,Room 130, 2609 Beacon St.4:00 pmProf. Dennis Curran (Univ. of Pittsburgh)"An Introduction to Fluorous Techniques for theSynthesis of OrganicMolecules"Boston Univ., 590 Commonwealth Ave., Science Center Auditorium, SCI 107, 4:00 pm

March 26Prof. William R. Roush (Univ. of Michigan)TBABoston College, Merkert Chemistry Center,Room 130, 2609 Beacon St. 4:00 pmProf. Milan Mrksich (Univ. of Chicago)"A Surface Chemistry Approach to StudyingCell Adhesion"Tufts Univ., Pearson Chem. Building, 62 Talbot Ave., Medford, Room 106, 4:30 pm

March 27Drs. Lijuan Zhang and Robert Rosenberg (MIT)"Heparan Sulfate: A Glycobiology Frontier inthe Post-genomic Era"The Boston Glycobiology Discussion Group,6:00 pm dinner, MIT Faculty Club, 50 Memorial Drive, Cambridge; reservation isrequired: contact David Newburg(781-642-0025)Prof. Allan J. Jacobson (Univ. of Houston)Inorganic Chemistry Seminar TBAMIT, Room 6-120, 4 pm

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