Class II Carbonyl Compounds Naturally occurring aldehydes and ketones

Ketosis in diabetes patient Small change in the structure bring forth a large difference in bioacitivity

(alcohol + dehydrogenation) Alkan(e)al ---(ic acid), ---(oic acid)  ---aldehyde

Naming multifunctional compounds

Use Formyl- or keto- if a group of higher priority exists alkenal

Alkan(e)one

-ic acid  -ophenone Use oxo- if a group with higher priority exists

Carbonyl C is a target of nucleophilic attack

Factors affecting reactivity of class II compounds Inductive effect Steric factor

In overall…. Basicity Resonance electron donation Leaving groups are strong base Leaving groups are weak base

cf. Nucleophilic acyl substitution reaction Nucleophilic addition 3 pathways

1. Irreversible nucleophilic addition reaction when Z - is strong base 2. reversible nucleophilic addition reaction when Z - is weak base

3. nucleophilic addition–elimination reaction when Z - has a lone pair and there is sufficient acid water can be eliminated from the addition product

a carbon nucleophile

Polarity in Grignard reagent cf. alkyl halide Grignard reagent is very basic: Reacts with –OH, -NH 2, -SH, -COOH

Grignard reagent can form new C-C bond Reactions of Aldehydes and Ketones with Grignard Reagents

More examples Carboxylation with CO 2

Reactions of Class I Carbonyl Compounds (esters and acyl chlorides) with Grignard Reagents two equivalents

Section 6.10

Reduction of aldehyde and ketone Use of sodium borohydride, NaBH 4

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives with Hydride Ion

Sodium borohydride is not strong enough to reduce esters, carboxylic acid, and amide. Instead, use lithium aluminum hydride, LiAlH 4

Ester, carboxylic acid  alcohol: use LAH Ester  aldehyde: use DIBALH

LiAlH 4 reduces amides into amines

Formation of Cyanohydrin

Cyanohydrin is stable in neutral and acidic condition. However, unstable under basic condition.

Further reactions of cyanohydrin Formation of  -hydroxy carboxylic acid Formation of primary amine

Reaction with 1 o amine  imine (= Schiff base)

Reaction with 2 o amine  enamine

Addition of Primary Amine: Formation of Imine

Nucleophilic addition-elimination reaction

Imine formation is H + -catalyzed, pH-dependant reaction Must be enough acid for this… But too much acid destroys free amine for the reaction

Carbinolamine is a unstable compound because…. Imine is readily hydroyzed back to the C=O and amine

The reaction is reversible

Enamine is also hydroyzed back to C=O and amine by acid catalysis

Preparation of primary amine

Secondary amine Tertiary amine

General for ketone

Addition of Water: Hydrate Extent of equilibrium depends on the reactivity of carbonyl compound % hydrate Formaldehyde99.9 Acetaldehyde58 Acetone 0.2

Hydrate at equilibrium depends on both electronic and steric effects - Bulky, e-donating group decreases stability of hydrate - small, e-withdrawing group increases stability of hydrate

How mechanism was unraveled? 18 O labelling experiment

Aldehyde  acetal Ketone  ketal (currently, a subset of acetal)

Acetal or ketal can be hydrolyzed back to aldehyde or ketone

How to prosecute the following reaction? Reaction with LAlH4 would reduce both keto and ester groups.

Use of protecting groups: Protects a functional group from a synthetic operation that it would not otherwise survive.

Ketal as a protecting group

More example 1 discrimination aldehyde from keto group More example 2 protection of alcohol as TMS ether

More example 3 protection of carboxyl group as ester More example 4 protection of amino group by acetylation ?

Formation of thioketal

Use of thioketal

Overall Formation of alkene ylide from alkyl halide Ylide a compound that has opposite charges on adjacent covalently bonded atoms a phosphorane CH 3 CH 2 -Br (CH 3 ) 2 CH-Br

How to prepare a ylide? Strong base

If more than 2 routes are available… choose the one that involves less hindered alkyl halide

Wittig reaction is very regioselective. Compare with…

Stereoselectivity of Wittig reaction depends on kinds of ylide EZ

Prochiral carbonyl group Two different groups Re and Si faces 1  2  3, clockwise, Re

Attack on the faces creates enantiomers Equal probability Equal probability

Retrosynthetic analysis Disconnection: an important tool in retrosynthetic analysis Synthetic equivalent

Another example 1

Another example 2 Unuseful disconnection

Conjugate addition or 1,4-addition Two nucleophilic sites for attacking  -unsaturated carbonyl compounds Direct addition or 1,2-addition

1.Nature of Nu - 2.Reactivity of Carbonyl compound 3.Reaction condition Thermodynamic vs kinetic control More stable

Weaker base prefers conjugate addition (more stable product)

Reactivity of carbonyl compound? Reactive carbonyl  direct addition is faster Less reactive carbonyl  conjugate addition is faster

Reactive carbonyl (ie. aldehyde) + strong base  direct addition Less reactive carbonyl (ie. ketone) + strong base  conjugate addition A Lewis acid (Ce 3+ ) activates carbonyl group

Grignard (strong base) with aldehyde (reactive carbonyl) with sterically hindered ketone (less reactive carbonyl) Gilman reagent always conjugate addition

Hard/Soft Nucleophile/electrophile Hard/Soft ~ degree of polarization Hard reacts with hard and soft with soft Hard C-Mg (highly polarized) reacts with polarized C=O Soft C-Cu (less polarized) reacts with less polarized C=C

Conjugate addition or nucleophilic acyl substitution (as a result of direct addition) Highly reactive derivatives (acyl halide)  substitution

Less reactive derivatives (amide, ester)  conjugate addition

Examples of biological conjugate addition

2008 Nobel Prize in Chemistry Osamu Shimomura, Marine Biological Laboratory (MBL), Woods Hole, MA, USA and Boston University Medical School, MA, USA, Martin Chalfie, Columbia University, New York, NY, USA Roger Y. Tsien, University of California, San Diego, La Jolla, CA, USA Green Fluorescent Protein (GFP)

Fin