Cathedrals of science“There are ancient cathedrals which, apart from their consecrated purpose,

inspire solemnity and awe. Even the curious whisper reverberatesthrough the vaulted nave, the returning echo seems to bear a message ofmystery. The labor of generations of architects and artisans has beenforgotten, the scaffolding erected for the toil has long since beenremoved, their mistakes have been erased, or have become hidden bythe dust of centuries. Seeing only the perfection of the completed whole,we are impressed as by some superhuman agency. But sometimes weenter such an edifice that is still partly under construction; then the soundof hammers, the reek of tobacco, the trivial jests bandied from workmanto workman, enable us to realize that these great structures are but theresult of giving to ordinary human effort a direction and purpose.

Science has its cathedrals, built by the efforts of a few architects and manyworkers…..

Gilbert Lewis, from the preface toThermodynamics and the FreeEnergy of Chemical Structure

LangmuirLewis

Early experiments designed to describethe transition states of reactions

Eschenmoser Dunitz Baldwin

Trajectory ofattack during SN2

Experimentalevidence that

clarifies shape ofσ*

Trajectory of attackon carbonylsExperimentalevidence that

clarifies shape of π*

Rules to predictwhen

intramolecularattack occurs

When is HOMO-LUMO overlap

possible?

How do we know that trajectory of attack duringan SN2 reaction is 180o?

R3N Br nN !*C-Br

Early experiments designed to describethe transition states of reactions

Trajectory of attackon carbonylsExperimentalevidence that

clarifies shape of π*

Dunitz

The Bürgi-Dunitz Angle: Experimental Evidence from CrystalStructures of 1,8-Disubstituted Naphthalenes

OCCH3CH3O

Procter, G.; Britton, D.; Dunitz, J.D. Helv. Chim. Acta 1981, 64, 471-477.

The Bürgi-Dunitz Angle (105o ± 5)

“…a decrease in N-C=O distance beingaccompanied by an increase innonplanarity at the carbonyl carbonand a slight lengthening of the C=Odistance.”

Bürgi, H.B; Dunitz, J.D. Acc. Chem. Res. 1983, 16, 153-161.

ORR

N

α

A reminder of Bürgi and Dunitz en route to a mitosane…

Papaioannou, N.; Blank, J.T.; Miller, S.J J. Org. Chem. 2003, 68, 2728-2734.

in the crystal structure of an intermediate (12):

Early experiments designed to describethe transition states of reactions

Baldwin

Rules to predictwhen

intramolecularattack occurs

When is HOMO-LUMO overlap

possible?

Baldwin’s Rules for Ring Closure

Baldwin, J.E. J.Chem. Soc., Chem. Comm. 1976, 734-736.Enolates: Baldwin, J.E.; Lusch, M.J. Tetrahedron 1982, 38, 2939-2947.

Favored: exo-tetexo-trigendo-dig

Disfavored: 3,4-exo-dig5-, 6-, 7-endo-tet3-, 4-, 5-endo-trig

✔✔✖✔✔✔7

✔✔✖✔✔✔6

✔✖✖✔✔✔5

✔✖✖✔✔4

✔✖✖✔✔3

Dig (sp)Trig(sp2)

Tet(sp3)

Dig(sp)

Trig(sp2)

Tet(sp3)

RingSize

ENDOEXO

✔✔✔✔7

✔✔ ✔✔✔6

✖✖✔✔5

✖✖✔✔4

✖✖✔✔3

Trig(sp2)

Tet(sp3)

Trig(sp2)

Tet(sp3)

RingSize

(ENOLENDO)-EXO

(ENOLEXO)-EXO (Enolendo) - ketone is IN the ring

(Enolexo) - ketone is OUT of the ring

(Remember Eschenmoser’s examples)

Baldwin’s Rules - the Endo-Dig preference

Computational studies suggest that geometry of attackof π* should be similar for alkynes and alkenes:

Attacking σ* Attacking π*(the Bürgi-Dunitz angle)

?!?! Not attacking π* ???

Strozier, R.W.; Caramella, P.; Houk, K.N. JACS 1979, 101, 1340-1343

OCCH3N

As do crystal structures:“…not only does the nitrile group appear to becomparable in strength to the carbonyl group as anelectrophile in these compounds, but also thepreferred approach angle Nu. . . C-X must be verysimilar in the two classes of molecules.”

Procter, G.; Britton, D.; Dunitz, J.D. Helv. Chim. Acta 1981, 64, 471