CARBONYL CHEMISTRY : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 1 CARBONYL CHEMISTRY
CARBONYL CHEMISTRY : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 2 CARBONYL CHEMISTRY I. NUCLEOPHILIC ADDITION TO ALDEHYDES AND KETONES
II. CARBOXYLIC ACID DERIVATIVES AND NUCLEOPHILIC ACYL SUBSTITUTION
III. SYNTHESIS
CARBONYL CHEMISTRY I : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 3 CARBONYL CHEMISTRY I NUCLEOPHILIC ADDITION TO ALDEHYDES AND KETONES
THE CARBONYL FUNCTIONAL GROUP : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 4 THE CARBONYL FUNCTIONAL GROUP The most common and important FG
Two families
aldehydes/ketones (nuc addition)
c. acid derivatives (nuc acyl substitution) LATER
PROPERTIES : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 5 PROPERTIES Electrophilic carbonyl carbon
different than nucleophilic C-C double bond
Weakly basic oxygen lone pairs
Moderately acidic alpha H’s
NUC ADDITION TO ELECTROPHILIC CARBONYL : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 6 NUC ADDITION TO ELECTROPHILIC CARBONYL
AS VERY WEAK BASE : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 7 AS VERY WEAK BASE
MODERATE ACID : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 8 MODERATE ACID
NUC ADDN TO ALDEHYDES & KETONES : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 9 NUC ADDN TO ALDEHYDES & KETONES CHANGING THE NUC
Grignard Rxn
Hydride reductions
Acetals & Ketals
Imines & Enamines
Wittig Rxn
Aldol Rxn
GRIGNARD REACTION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 10 GRIGNARD REACTION
GRIGNARD REACTION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 11 GRIGNARD REACTION RMgX; X = Cl, Br, I
Organometalics (main group; also Li)
DE.N.
carbon group behaves like free carbanion
EXAMPLES (ALCOHOL SYNTHESIS) : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 12 EXAMPLES (ALCOHOL SYNTHESIS)
Slide 13 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 13
DRY CONDITIONS IMPERATIVE : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 14 DRY CONDITIONS IMPERATIVE
COUPLING SIDE REACTION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 15 COUPLING SIDE REACTION
PROBLEM : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 16 PROBLEM
STEREOCHEMISTRY : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 17 STEREOCHEMISTRY Create new chiral carbon
no existing chiral centers
racemic products
one or more existing centers
diastereomeric centers
Slide 18 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 18
Slide 19 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 19
HYDRIDE REDUCTIONS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 20 HYDRIDE REDUCTIONS Similar to Grignards
“Hydride” nucleophile instead of carbanion
Also a reduction
Another alcohol synthesis
SECONDARY ALCOHOLS FROM KETONES; PRIMARY FROM ALDEHYDES : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 21 SECONDARY ALCOHOLS FROM KETONES; PRIMARY FROM ALDEHYDES “sodium borahydride”
a hydride delivery reagant
ACETALS AND KETALS; USEFUL “PROTECTING GROUPS” IN SYNTHESIS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 22 ACETALS AND KETALS; USEFUL “PROTECTING GROUPS” IN SYNTHESIS
REVERSIBLE….UNDER AQUEOUS ACID : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 23 REVERSIBLE….UNDER AQUEOUS ACID
APPLICATIONS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 24 APPLICATIONS Hydride reduction of nitriles is a good way to make primary amines: However, for a difunctional reactant with a reactive carbonyl, how do you achieve rxn only at the desired nitrile?
PROTECTING GROUPS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 25 PROTECTING GROUPS Sometimes, a longer synthesis is a better one!
Slide 26 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 26
MECHANISM? : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 27 MECHANISM? Many steps!
Familiar steps
http://www.chem.uic.edu/web1/OCOL-II/WIN/CH19/RXN.HTM
IMINES AND ENAMINES : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 28 IMINES AND ENAMINES 1O 2O
Slide 29 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 29 tertiary amines don’t react
“imines” also called “Schiff bases”
Chemistry of vision!
enamines useful in synthesis
CHEMISTRY OF VISION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 30 CHEMISTRY OF VISION
Slide 31 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 31 protonated Schiff base
imine: Lys from
Rhodopsin with ald.
of retinal
CONTROL OF pH! : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 32 CONTROL OF pH! Why?
PROBLEM: WHY DON’T 3O AMINES REACT? : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 33 PROBLEM: WHY DON’T 3O AMINES REACT?
WITTIG : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 34 WITTIG
WITTIG MECH : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 35 WITTIG MECH an “ylide”
ALDOL CONDENSATION REACTION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 36 ALDOL CONDENSATION REACTION Previously adjust B- for Kab <1
ALDOL CONDENSATION REACTION : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 37 ALDOL CONDENSATION REACTION
Slide 38 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 38 hydroxide (pKa 16 for H2O) pKa a-H’s about 20
REQUIRES AT LEAST TWO a-HYDROGENS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 39 REQUIRES AT LEAST TWO a-HYDROGENS Mechanism
Slide 40 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 40
Slide 41 : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 41 First a-H Second a-H
MIXED ALDOL REACTIONS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 42 MIXED ALDOL REACTIONS
ALDOLS IN SYNTHESIS : David A. Jeffrey, Ph.D. djeffrey@costbenllc.com 43 ALDOLS IN SYNTHESIS