hapter 17 Aldehydes and Ketones arbonyl Groups polarized (1) Aldehydes and Ketones ' aldehydes ketones : and : are poor leaving groups (2) arboxylic Acid Derivatives l ' ' 2 carboxylic acid substituent could be a leaving group (, l,, 2 ); provides for similar reactivity as aldehydes and ketones but sometimes different reactivity; we saw a glimpse of this difference already
1) LiAl 4, Et 2 2) 2 3 1) LiAl 4, Et 2 2) 2 LiAl 4 2 LiAl 4 3 omenclature: prefix - parent - suffix (1) Aldehydes: need the longest chain that contains the () group
3 butanal 3 3 3 1 4 3 2 2,4-dimethylpentanal 1 2 3 4 5 6 3 5-hydroxy-4-methylhexanal 3 (2) Ketones: -one as suffix 3 3 2-propanone (acetone) 6 3 5 4 3 2 3 1 4-chloro-5-hydroxy-3-hexanone l There are a number of common carbonyl groups: 3
Synthesis of Aldehydes (1) From alcohols (oxidation) P 2 l 2 P 2 l 2 (2) From alkenes (oxidation) 1) 3, 2 l 2 2) Zn, Ac 3 Ac
(3) From alkynes disiamylborane B 1) 2), 2 2 2 (4) From esters via partial reduction ' 1) DIBA, toluene 2) 3 + ( 3 ) 2 2 Al 2 ( 3 ) 2 3 1) LiAl 4, Et 2 2) 2 LiAl 4 2 LiAl 4 3
Synthesis of Ketones (1) xidation of alcohols Jones' reagent P 2 l 2 (2) zonolysis of alkenes (oxidation): can also use KMn 4 with acid 3 3 3 2 1) 3, 2 l 2 2) Zn, Ac 3 3 3 + (3) ydration (addition of 2 ) to terminal alkynes 2, 2 S 4 gs 4 3 (4) Friedel-rafts Acylation l All 3
(5) rgano-opper (uprate) oupling l 1) ( 3 ) 2 uli, Et 2 2) 2 xidation of Aldehydes and Ketones r 3, 2 S 4 2, acetone 3 r 3, 2 S 4 2, acetone ne can also use the Tollens reagent (Ag 2, 4 ) to oxidize aldehydes, and it is a very gentle method for the selective oxidation of aldehydes xidation of aldehyde () takes place via the hydrate 2 r 3 3 +
ucleophilic Addition eactions u δ + δ u is sp 2 is sp 3 --' ~ 120 --' ~ 109 What about the nucleophile? (1) ucleophile can be (2) ucleophile can be 2 -- - 2 3 (3) Steric effects when nucleophile adds to carbonyl carbon Which is more reactive: aldehydes or ketones? Aldehydes (): (i) nucleophile can easily approach carbonyl carbon (ii) addition product is less sterically hindered (iii) transition state is less crowded: low G (iv) greatest polarization of the = bond with being most δ+ since cannot stabilize the positive charge on carbon very well Ketones (() ): (i) groups can stabilize the partial positive charge on the carbonyl carbon
Let us consider a simple nucleophile such as 2 2 ' ' hydrate (gem diol) geminal = "same carbon" an equilibrium: position of equilibrium depends on and (on stability of aldehyde and ketone vs the hydrate product) K eq 3 3 3 l 2 l 3 l 2 l 2 F 3 F 3 (1) addition of water is more favorable for aldehydes than for ketones (2) electronegative groups attached to carbonyl carbon make addition more favorable δ δ + Why is this useful? The more a compound favors addition at equilibrium, the more rapidly it will react in addition reactions -- the transition state has similar preferences as the addition intermediate (ammond postulate again...)
transition state E n erg y G G G rxn eaction oordinate The equilibrium can be established with either base or acid catalysis: Base: δ δ + + Acid: 3 2 2 2 (a) If nucleophile is strong enough, there is (b) If nucleophile is not strong enough, need to by coordination to a Bronsted acid (+) or a Lewis acid
addition (1) is a weak acid pk a ~ 9.1 (not much at equilibrium) (2) δ δ + + catalyzed by base (in order to make ) or by direct addition of + 3 + heat ( ) 1) LiAl 4, TF 2) 2 2 2 2 Grignard addition δ Mg X δ + Et 2 so not an equilibrium magnesium coordinates carbonyl oxygen (Mg is Lewis acidic) and makes carbonyl carbon even more electrophilic -- magnesium helps to activate the carbonyl carbon
ydride Addition: reduce aldehydes and ketones to alcohols are sources of : and both reagents can 1) ab 4, Et 2) 3 + not reversible so not an equilibrium Amines: nucleophiles with attached hydrogens (good nucleophiles) 2 primary amines secondary amines ' 2 ' ' 2 ' 3 + 3 2 + 2
(1) Primary Amines (product is an imine): p of the reaction is very important (best at about p = 4.5) δ δ + 2 2 3 + 2 2 imine protonation to yield a good leaving group
3 3 2 2 2 2 2 2 2 2 2 2 all are - 2 for formation of
(a) all are equilibria 3 + 3 2 + 2 (b) equilibrium favored to reactants for imine so need to (c) oximes, semicarbazones, and hydrazones are (reaction can even be done in 2!) (2) Secondary amines 2 : enamines 2 2 2 3 + 2 2 2 -- -- there is no proton to lose on when you start with a secondary amine ( 2 )
3 3 ( 3 ) 2 3 ( 3 ) 2 3 3
Wolff-Kishner eaction ' ' 2-2 2 2 ' ' + 2 + 2 2 ' ' ' 1) 2 2, K 2) 3 +
Acetal Formation + ' acid ' " " 2 " (1) equilibrium so: (a) lots of - and also remove 2 then favor equilibrium to the (b) lots of 2 then favor equilibrium to the (2) protection of ketone? 3 for ester reduction: LiAl 4 is needed but ketone would be reduced at the same time so need to protect (mask, hide) the ketone group 3 3 + 3 3 3 1) LiAl 4, Et 2 2) 2 2 + 3 3 3 2 3, +
Equilibrium: G = T S = Acetal formation has an unfavorable entropy (3 moles <=> 2 moles), so use diol 3 + + 2 + 1) Mg, Et 2 3 + 2) 3 Br Br Br 3 3 ow? (a) hemiacetal formation: acidic or basic conditions are fine ' 3 + ' 3 ' 3 3 ' 3 ' 3 ' 3 3 ' 3
(b) hemiacetal conversion to acetal works in ' 3 3 + ' 3 3 ' 3 ' 3 3 ' 3 acetal 3 ' 3 3 Thioacetals ' S + S aney i 2, Et ' same mechanism as for acetal formation 3 S S S S + 3 aney i 2, Et 3
Wittig eaction 2 P ylid Ph Ph Ph Ph = + P Ph Ph Ph triphenylphosphine oxide Ph 3 P 3 Br Ph 3 P 3 a Et 2 Ph 3 P 2 acidic hydrogens PPh 3 2 P Ph Ph Ph betaine PPh 3 oxaphosphatane P + Ph Ph Ph 2 1) Ph 3 P 2 TF 2) 2 + Ph 3 P= 2 1) Ph 3 P 2 TF 2) 2 + Ph 3 P=
annizzaro eaction: + + (a) : as a leaving group (b) reaction is driven by the formation of stable carboxylate anion (irreversible) Similar action as ADP in biology: 2 2 ' not aromatic some aromatic character
1,2-Addition to arbonyl Group: 2 + u 1 u 2 u addition of u and to 1 and 2 1,4-Addition to α,β-unsaturated Enone: 4 3 2 u 2 1 (a) final step is a u u (b) overall reaction is addition of u- to 1 and 4 of enone u (c) need the carbonyl group (=) to have 1,4-addition to the = double bond 1) u 2) 2 no reaction 1) u 2) 2 u What kinds of nucleophiles work?
(1) Amines 3 Et 2 Et 3 Et 2 3 2 Et 3 (2) addition 1) Et 2 Al-, toluene 2) 3 + agata reaction (3) rgano-copper (uprate) eactions 1) 2 uli 2) 3 +
ow to make 2 uli? -X 2 Li pentane -Li + Li-X ui 2 -Li 2 uli + LiI Et 2 1) ( 3 ) 2 uli 2) 3 + 1) ) ) uli 2 3 2) 3 + 3 3 1) 3 MgBr, Et 2 2) 3 + 3 1) 3 Li, Et 2 2) 2 1) ( 3 ) 2 uli, Et 2 2) 3 + 3