Chapter 23. Carbonyl Condensation Reactions
As a result of the large dipole of the carbonyl group: 1. The carbonyl carbon is electrophilic and is the site of addition reactions by nucleophiles;
O OH O + H3O C C C Chapters 19 & 20 Nu Nu Nu: Ketone/aldehyde (electrophile)
2. The α-protons are acidic and can be deprotonated by strong bases to give an enolate, which are nucleophiles and react with electrophiles.
B O O E O C H C C E Chapter 21 C C C
Enolate anion (nucleophile) 256
23.1 Mechanism of Carbonyl Condensation Reactions An enolate of one carbonyl (nucleophile) reacts with the carbonyl carbon (electrophile) of a second carbonyl compound (1,2-addition reaction) resulting in the formation of a new C-C bond General mechanism (Fig. 23.1, page 855):
Nucleophilic carbonyl: aldehydes, ketones, esters, amides and nitrile Electrophilic carbonyl: aldehydes, ketones, α,β-unsaturated 257 ketones, and esters
130 23.2 Condensations of Aldehydes and Ketones: The Aldol Reaction The base-catalyzed self-condesnation reaction of acetaldehyde gives 3-hydroxybutanal (aldol)
O NaOEt OH O
2 H3C C H H C CH CH C H EtOH 3 2 acetaldehyde 3-hydroxybutanal (!-hydroxy aldehyde) General mechanism of the aldol reaction (Fig. 23.2, page 857)
The base-catalyzed aldol reaction (NaOEt, EtOH) is reversible 258
The position of the equilibrium for the aldol reaction is highly dependent on the reaction conditions, substrates, and steric considerations of the aldol product.
O H O NaOEt HO H aldol reactions involving R C C H R C C α-monosubstituted aldehydes EtOH C C H H H H H R are generally favorable
O H O NaOEt HO H aldol reactions involving -disubstituted aldehydes R C C H R C C α,α EtOH C C H are generally unfavorable R R H R R
O H O NaOEt HO R aldol reactions involving R C C R R C C ketones are generally EtOH C C R H H H R H unfavorable
259
131 23.3 Carbonyl Condensation Reactions versus Alpha-Substitution Reactions
O HO O O
CH2R + RCH2X
How do you suppress carbonyl condensation during an α-alkylation reaction??
O O Li O LDA, THF, -78 °C RCH2X CH2R
The enolate is discretely and quantitatively generated with LDA at low temperature, then the alkyl halide is added to the solution of the enolate.
260
23.4 Dehydration of Aldol Products: Synthesis of Enones The β-hydroxy carbonyl product of the aldol reaction can undergo dehydration to yield a conjugated enones; this step is irreversible and is catalyzed by either acid or base.
Mechanisms (p. 859)
261
132 The aldol reaction can be driven toward products by dehydration
O R O H O NaOEt HO R - H2O R C C R C C R C C R C C R EtOH C C R H H H R H H H R
O NaOH O EtOH HO
22%
O NaOH O O EtOH HO
D 92%
The π-orbitals of the C=C and C=O are in conjugation, which is a stabilizing influence of α,β-unsaturated carbonyls • • • C • O C C
262
Synthesis of α,β-unsaturated carbonyl compounds
MgBr + then H3O R C N O α,β-unsaturated ketones O R C R Cl CuLi 2
O O (H C) CO- K+ O Br2, AcOH 3 3 α,β-unsaturated R R R ketones and aldehydes Br
Br , PBr (H C) CO- K+ O O 2 3 O 3 3 α,β-unsaturated acids, then H O, or HO 2 Y Y esters and amides ROH, or R2NH R
R2 O -unsaturated ketones, H O NaOEt, EtOH α,β 1 1 2 R C C R C C R C C R2 aldehydes and esters - H2O H H H R1 263
133 23.6 Mixed Aldol Reactions Aldol reaction between two different carbonyl compounds
Four possible products HO H O HO H O C C C C O O EtONa, H3CH2CH2CH2C C H H3CH2C C H EtOH H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C H C H H H H H HO H O HO H O C C C C C 5 C3 H3CH2C C H H3CH2CH2CH2C C H H3C H H H3CH2CH2C Aldehydes with no α-protons can only act as the electrophile
EtONa, O HO H O O EtOH C C H3C C (H C) C C H H3CH2CH2C C C H 3 3 C H + H C CH H CH CH C H H H 3 3 3 2 2
O O EtONa, HO H O EtOH C C C + H3C C H C H C H H H H3C H 264
One of the carbonyl compounds is significantly more acidic
EtONa, O O O EtOH H O H3CH2CH2C C C C H3CH2CH2C C C H + H3C C OEt C C CH3 H H H H H H CO2Et
Discrete (in situ) generation of an enolate with LDA
O
H3C C HO H O O O Li+ C H LDA, THF, -78°C C C H CH CH C C H H 3 2 2 H3CH2CH2C C H3CH2C C H C H C H H then H2O H CH CH C H H H 3 2 2
O
H3CH2CH2C C O O Li+ C H HO H O LDA, THF, -78°C H H C C H3C C H3C C C H C H H3CH2CH2CH2C C H H C H H H H then H2O 3
265
134 23.7 Intramolecular Aldol Reactions Treatment of a dicarbonyls compound can lead to an intramolecular aldol condensation. Formation of five- and six-membered rings are favorable.
O O O O EtONa, EtOH EtOH - H2O
O O OH
O O O O
EtONa, EtOH EtOH - H2O O O OH
266
More favorable ring sizes (less strained) are made from intramolecular reactions
O O O
- H2O O O OH
O O O O H - H O 2 less favored O OH pathway
O O O - H2O O O OH
O
O O O H less favored - H2O O pathway OH 267
135 Figure 4.8 (page 111)
!Hcomb !Hcomb per -CH2- Total Strain Cycloalkane Ring Size (n) KJ/mol KJ/mol Energy Strained 3 2090 698 115 rings 4 2744 686 110
5 3220 664 27 Common rings 6 3952 659 0
7 4637 662 27
8 5310 664 42 Medium rings Cyclononane 9 5981 665 54
Cyclodecane 10 6636 664 50 < 12 Large rings Cyclopentadecane 15 9985 659 0 Alkane reference 659 0 268
23.5 Using Aldol Reactions in Synthesis Very important C-C bond forming reaction. Readily make large carbon skeletons from smaller ones
aldol OH O O O reaction O + -or- aldol R1 R1 H H R1 H products H R R1 R1 1
H2, Pd/C
R2 O -or- O Wittig !-alkylation reaction + R1 R1 R1 H H X R 1 R1 R1 Grignard addition OH
R1 R2
R1
Robert B. Woodward (Harvard): 1965 Nobel Prize in Chemistry "for his outstanding achievements in the art of organic synthesis" 269
136 OH
2-ethyl-1-hexanol O
H O O O OH H H H
two n-C4 units
O
X H
270
Problem 23.5: Which of the following are aldol condensation products? a. 2-hydroxy-2-methylpentanal b. 5-ethyl-4-methyl-4-hepten-3-one
HO CH3 O CHO
Problem 23.8: Which of the following can probably be prepared by a mixed aldol reaction? a. b. O c. O O
271
137 23.8 The Claisen Condensation Reaction Base catalyzed condensation of two esters to give a β-keto-ester product NaOEt O O O
2 H3C C OEt EtOH H3C CH CH2 C OEt + then H3O Ethyl acetate Ethyl 3-oxobutanoate (Ethyl acetoacetate) Mechanism: has features of the aldol and nucleophilic acyl substitution reactions (Fig. 23.5, page 866)
272
The product β-keto ester product of the Claisen condensation is more acidic than the reactants; deprotonation of the product drives the reaction forward. One full equivalent of base must be used in the Claisen condensation.
23.9 Mixed Claisen Condensation Strategies are similar to that of the mixed aldol reaction.
Four possible products O O O O C C C C O O EtONa, H3CH2CH2CH2C C OEt H3CH2C C OEt EtOH H3C H H H3CH2CH2C C + H3C C H3CH2CH2C C OEt C OEt + H H H H then H3O O O O O C C C C C 5 C3 H3CH2C C OEt H3CH2CH2CH2C C OEt H3C H H H3CH2CH2C Esters with no α-protons can only act as the electrophile
O O O EtONa, O EtOH C C C + H3C C OEt C OEt C OEt H H then H O+ H3C H 3 273
138 Discrete (in situ) generation of an ester enolate with LDA O
H3C C O O O O Li+ C OEt LDA, THF, -78°C H H C C H3CH2CH2C C H3CH2CH2C C H3CH2C C OEt C OEt C OEt + H then H2O H CH CH C H H H 3 2 2 O
H3CH2CH2C C O O Li+ C OEt O O LDA, THF, -78°C H H C C H3C C H3C C C OEt C OEt H3CH2CH2CH2C C OEt + H C H H H H then H3O 3 Mixed Claisen condensations with a ketone enolate and esters O EtONa, O O EtOH O CH CH + C 2 3 H3CH2C OEt + then H3O
EtONa, O O O O EtOH C H + H OEt + then H3O
EtONa, O O O O EtOH C OEt + EtO OEt 274 + then H3O
23.10 Intramolecular Claisen Condensations: The Dieckmann Cyclization Dieckmann cyclization is an intramolecular Claisen condensation. Mechanism: same as the Claisen (Fig. 23.6, page 879)
275
139 Dieckmann Cyclization works best with 1,6-diesters, to give a 5-membered cyclic β-keto ester product, and 1,7-diesters to give 6-membered cyclic β-keto ester product.
OEt OEt EtO O O EtONa, EtOH - EtO O CO2Et O CO2Et OEt OEt
O O
O O EtONa, EtOH O EtO O OEt OEt CO2Et - EtO CO2Et O OEt
OEt O
O O
OEt H O O
OEt H
276
O O O O EtONa, EtOH EtONa, EtOH OEt CO2Et C O + EtO OEt + + then H3O then H3O OEt Dieckmann cyclization Claisen Condensation
The product of a Claisen condensation or Dieckmann cyclization is an acetoacetic ester (β-keto ester)
O O O O EtONa, + EtONa, EtOH H3O OEt CO Et EtOH 2 CO2Et O ! then H O+ Br 3 acetoacetic OEt ester Dieckmann cyclization
EtONa, NaOEt O O O EtOH O O + O H H3O H CH C C HC C OEt 2 H CH C C OEt 3 2 C OEt H3CH2C C C CH2CH=CH2 3 2 EtOH Br H3CH2C C C ! + CH3 CH then H3O acetoacetic CH3 3 ester Claisen condensation
277
140 23.11 The Michael Reaction The conjugate (1,4-) addition of a enolate with an α,β−unsaturated ketone
Recall from Chapter 19.14
O O O
R R R
1,2- O OH + addition H3O C C C C R C R C Nu Nu O :Nu C C R C O Nu Nu: O Nu O Nu + H3O C C C C C 1,4- R C R C R C addition H enolate
278
The Michael reaction: works best with enolates of β-dicarbonyls.
EtONa, O O O O H H O EtOH C CH2 + C C C C C H C C 3 EtO C CH3 H3C C C CH3 H H H H H H CO2Et electrophile nucleophile
Mechanism (Fig 23.7, page 872) This Michael addition product can be decarboxylated
O H H O + O H H O H3O , ! C C C C C C H3C C C CH3 - EtOH, H3C C C CH3 -CO2 H H H CO2Et H H H H 279
141 A Michael addition product is a 1,5-dicarbonyl compound
O EtONa, O O O H H O + O H H O EtOH H3O , ! C CH2 + C C C 4 C 2 C C 4 C 2 C H3C C EtO C CH3 H3C 5 C 3 C 1 CH3 - EtOH, H3C 5 C 3 C 1 CH3 -CO2 H H H H H H CO2Et H H H H 1 α,β-unsaturated ketone ethyl acetoacetate
O EtONa, O H H O + O H H O O O H3O , ! EtOH C C C C C C C CH2 C C EtO C C OEt - EtOH, EtO C C OEt EtO C + EtO C OEt CO Et -CO2 H H H H H H H H 2 H H
α,β-unsaturated ester diethyl malonate O EtONa, O H H + O H H O N H3O , ! N N EtOH C C C C C C C CH2 C C H N C C - EtOH, H N C C H2N C + EtO C 2 2 CO Et -CO2 H H H H H H H H 2 H H α,β-unsaturated amide β-cyano ester O H H O O EtONa, N N EtOH N C C N CH2 C C O C O C C + H3C C CH H H H H H H 3 O nitro ethylene β-cyano ketone O N O O N H H C CH EtONa, 2 + C C C C C C EtOH CH3 H3C C CH3 C C H H H H H H C CH3 O 280 α,β-unsaturated nitrile β-diketone
23.12 The Stork Enamine Reaction recall enamine formation from Chapter 19.9
O N N H+ - H+ + N -H2O H ketone Iminium ion Enamine or aldehyde 2° amine w/ !-protons Enamines are reactive equivalents of enols and enolates
N N
H H O O
Enamines undergo α-substitution with electrophiles 281
142 Reaction of enamine with α,β-unsaturated ketones (Michael reaction). Mechanism: Page 875
O O N O + CH 3 then H2O
Enamines react on the less hindered side of unsymmetrical ketones O O O O N CH 3 H C H3C 3 + H3C then H2O N H 282
23.13 Carbonyl Condensation Reactions in Synthesis: The Robinson Annulation Reaction annulation: to build a ring onto a reaction substrate. Robinson annulation: two stage reaction involving a Michael reaction followed by an intramolecular aldol reaction.
EtONa, CO Et CO2Et CO Et 2 EtOH -H2O 2 + O O O O O
Michael reaction Intramolecular aldol condensation and dehydration
283
143 O OH H3C H3C
H H3C H
H H H H HO HO HO O
Lanosterol Cholesterol Estrone Testosterone
O O O H C H3C H3C O Robinson 3 OH O O HO Li(0), NH3 H3C annulation + H+ tBuOH O O O O H O
O O O H C H C 3 O 3 O H3C H3C-I NaBH4 A-B ring precursor of steroids
O HO P-O H H H
O O H3C Robinson annulation O + H3C O H3CO O H3CO 284
23.14 Biological Carbonyl Condensation Reactions (please read) Aldolase enzyme: involved in carbohydrate biosynthesis
H2N Lys O O H Lys H Lys H2N Lys N 2- N O PO OH 2- H H OPO 2- 3 O3PO 2- 3 O3PO H OH OH OH H Lys N OH O OH 2- O3PO 2-O PO OPO 2- 3 2- 3 OPO3 Type I aldolase OH OH OH OH in mammals fructose-1,6-phosphate
HIs HIs
N NH N N Zn2+ H Type II aldolase O H O O in yeast and bacteria 2- O3PO OH 2-O PO OH 3 H OPO 2- H H 3 enzyme-B: H OH enzyme-B:H
Enzymatic Claisen condensations in Chapter 27 285
144