Chemistry 125: Lecture 73April 28, 2010

Benzoin, Claisen, Robinson(Ch. 19)

Two Un-Natural Products This

For copyright notice see final page of this file

The Benzoin Condensation (prob. 19.90)

Ph C

OH

C N

C N

CH 3OH

H C N

nucleophile

like C=O an

-activatorleaving

groupH C Ph

O

also an -activator(benzylic)

Ph C

O

C N

H

H C Ph

OH

N Cbase

- HCN

CN “reverses thepolarity” of O=C+

to C- (“umpolung”)

need Ph-CO

to attack O=CH-Ph

H+

C N

where we’re going:

what we have:

not basic enough pKa > 30

The Claisen Condensation (sec 19.8)

The Claisen Condensation (sec 19.8)Driving Force

Nature’s Claisen (sec 19.6)

Fatty Acids have even numbers of C atoms!

Driving Force

Robinson Annulation (sec 19.11)

REVIEW 1:The Synthesis of Two

Unnatural Products

(in order to settle a question in the theory of organic chemistry)

Is cyclobutadiene antiaromatic (4n)?

Diels-Alder

OO

OO

+ O=C=O

h

h

(must be disrotatory)

Make it and see.

(2 +2 forbidden thermally)

very strained

(2 +2 forbidden thermally, but it happens anyway)

Presumptive Evidence.Spectroscopy?

Make one moleculeper cage

Making & Studying“antiaromatic”Cyclobutadiene

(for solubility)

O

CH

CH2

CH2

Ph

mouth

Cram, Tanner, and Thomas (1991)

Preparing Dihydrocinnamaldehyde

O

CH

CH2

CH2

Ph

O

CH

CH

CH

Ph

O

CH

CH3

O

CH

Ph

(as mixture with tetra- substituted and two

disubstituted analogues)

Start with Hemisphere

OH

+

H +

etc. etc.

The electrophilic aromatic substitution is reversible, and

ultimately the desired “tetramer” stereoisomer precipitates from the equilibrating mixture in 69% yield based on hydrocinnamaldehyde.

O-CH2 bonds by SN2

Ar-O- with CH2BrCl

How to form the C16 ring?

1) “Br+” / -H+ (3 moles)

Br Br Br

2)

--BrCH2

Cl

Hydrocinnam-aldehyde

(from benzaldehyde

see above)

Resorcinol

Lucky!

H+

(OH activating o,p-directing)

(by chromatography; 5% from tetramer)

Joining Hemispheres1) Br+/-H+ (3 moles)

Br Br Br

3) BuLi

4) B(OR)3

5) HOO-

Li Li LiB(OR)2 B(OR)2 B(OR)2OH OH OH

O-CH2 bonds by SN2

Ar-O- with CH2BrCl2)

--

~40%(1% overall)HO

O-

O-B(OR)2

HO-

-O-

6) O-CH2 bonds by SN2

Ar-O- with CH2BrCl

(add “Ar- ” to B ; lose RO-)

(insert O between C and B. Cf. hydroboration/oxidation;

(halogen-metal exchange

more stable “Ar- anion”)

Note: the purpose of 1,3,4,5 is to “hide” an OH group between the OH groups of resorcinol, and then reveal it.

HO-

lose most stable ArO- anion)

CHCl3CHCl3

CHCl3CHCl3

CH3CNCH3CN

CH3CNCH3CN

HC-N(CH3)2 held within molecule.

O

Stereo PairX-Ray View

JACS, 113, 7717 (1991)(easier to see without a

viewer if you make it small)

CHCl3 &CH3CN are

held between molecules in

crystal

but lost with t1/2 = 34 hrs

at 140°C.

.

. . ... .. .

as guestBenzene

Antiaromaticupfield shift?

Most shift comes fromother rings, still ~1.5ppm above benzene

Normal

Replace DMF by -Pyranone

above center of 8 benzene rings

.

... O

O

O

O

.

... O

O

.

...

Proton NMR

End of Lecture 73April 28, 2010

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These last six frames are left over from a previous year

(and a different textbook).

Instead of discarding them, I left them here in case they

might be useful as you review.

Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis

(Cf. p. 1068)

,-unsaturated carbonyl Aldol

H

acetaldehyde

H

Cinnamaldehyde(prepared by this

method in 1884)

Ph-CH2-CH2-CHO

H2 / cat (see frame 13)

Ester Enolate (Ch. 22)C nucleophile

*

*

“Claisen” or “Acetoacetic Ester” Condensation (pp. 1072-1075)

substitution at ester

Why not use OH-?

Equilibrium position?

Biological Claisen X = SR = coA(sec. 22.6, pp. 1081-1083)

Biological Claisen X = SR = coA(sec. 22.6, pp. 1081-1083)

Acid Derivatives :A/D Substitution at C=O

How to go “wrong” way? (e.g. R-CO-OH R-CO-Cl)

S

O

ClClO-

O

SO-

ClCl

O

O

Cl-

O

S

O

Cl

O SO2Cl

Cl-

O

Cl

O-

Trick with SOCl2.

X = Cl ; Y = Cl + stable SO2

O-

XY

Y-

X

O

X-

Y

O

ROHO-

O

Equilibrium favors the more stable anion:

Cl- > -O-C-R > -OR > NR2-

O

pKa -2.2 4.8 16 35