Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 1
Addition to carbonyl compounds (skip 8.25, Me3SiCN, 8.2.7, 8.4.5-7, 8.5, 8.7
1. general properties
HA
O
1.1. significant CO dipole attracts Lewis acids and bases
1.1.1. lone pairs and partial charge at oxygen
H3 C

CH3

1.1.2. polarized  electrons readily displaced toward oxygen
A
1.1.3. planar electrophile (3 sp2 hybridized orbitals), easy access
1.1.4. addition results in rehybridization (4 sp3 orbitals), brings substituents closer
together
1.2. unactivated carbonyl reacts with good nucleophiles
1.2.1. RS-, CN-, RLi, RMgBr, RO-, RNH2
1.2.2. Acids activate carbonyl but deactivate basic nucleophile
1.3. Lewis acid required for weak nucleophiles
1.3.1. ROH, RSH, arene, PhNH2
O
H
O
AlCl3
H OR
H3C
H3C
CH3
O 
Cl
H3C
HOR
CH3
1.3.2. hydrogen bonding in protic solvent weakly activates
1.4. Carbonyl is activated by electron withdrawing groups
>
>
H3C
H
>
OH
H3C
C
H2
H3C
O
O
O
O
O
CH3
>
H3C
Ph
H3C
1.5. deactivated by electron donating groups, bulky groups, resonance
1.6. alkyl groups stabilize, and sterically inhibit attack, sp2 to sp3 (see hydration)
2. Hydration – water addition
2.1. readily occurs for formaldehyde (reactive carbonyl) but not acetone
2.2. steric and electronic effect
NH2
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 2
2.3. hydration unfavorable for most ketones
2.4. hydration is reversible, 18O slow at pH 7, fast with trace acid or base
2.5. occurs in acid or base condition.
2.6. RDS is water addition.
2.7. GA, GB, SA and SB catalysis.
2.8.
What is mechanism with base-catalyzed water addition?
H3O+
O
O
H
O
H
O
H
+ H3O
H3C
H3C
CH3
H2O
CH3
H3C
H3C
CH3
OH2
CH3
OH
H2O
3. Alcohol addition is reversible as well: acetal and ketal formation
3.1. acetals from aldehydes, ketals from ketones
3.2. formation of hemiacetal fast when acid or base catalyzed even if not favorable
3.2.1. hemiacetal is half alcohol, half ether from aldehyde, addition half done
3.2.2. mechanism just like hydration
3.3. protonation of OH leads to dehydration and to acetal
3.4. geminal oxygen assists loss of water by concerted bond making with bond breaking
H+
O
O
H
O
H
H
O
+ H2OR
H3C
H3C
H
H3C
H
OR
H
OR
H3C
H
H
OR
HOR
HO
H
H
+
RO
H3C
RO
H
OR
H3C
H
HO
H
OR
H3C
H
+
H3C
HOR
HO
H
OR
H3C
H
O
R
H
H
OR
3.5. OH is poor leaving group, WHY? protonate first
3.6. note interchange between 3 sp2 and 4 sp3 orbitals, preserves octet
3.7. acid or base conditions forms hemiacetal, only acid forms the acetal. Why?
HOR
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 3
3.8. drive reaction to completion with water or alcohol
3.9. acetal is base stable, requires proton for loss of OR group
3.9.1. ketals normally only form with diols
O
O
O
H+
+ HOCH2CH2OH
H2 C
CH2
O
O
H
+ H2O
H
3.10. acetal and ketal formation good for protecting carbonyl from nucleophiles and strong
bases
3.11. thioacetals and thioketals also form, not as readily reversible
O
+ 2RSH
H3C
R
H+
S
R
S
H3C
CH3
+ H2O
CH3
4. cyanohydrin
4.1. quantitative for aldehydes and ketones but not aromatic ketones:
4.2. HCN plus catalytic amount of base. show mechanism?
4.3. CN attack rate determining, rate = k[R2CO][CN-]
5. HCl addition
5.1. equilibrium poor in water because Cl- is good leaving group
5.2. addition works in alcohol where ether is stable, why?
O
+ HCl
H
H
CH3OH H3CO
H
Cl
+ H2O
H
6. metal hydrides
6.1. aldehydes and ketone have single H- addition
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
R
R
R
O
R
H
R
H
R
O
R
AlH3
page 4
R
O
AlH3
2016January17
H
R
O
AlH3
R
Al
H+
OH
R
H
H
4
O
R
6.2. esters have two H- addition, loss of OR has assistance from geminal oxygen and AlX3?
6.3. LiAlH4 reacts with aldehydes, ketones, esters, carboxylic acids and amides
6.4. Cannot use protic solvent?
6.5. NaBH4, reacts with aldehyde and ketones
6.6. selectively reduce ketone in presence of amide? Amide in presence of ketone?
7. Meerwein-Pondorf – carbon to carbon H transfer
O
i
Pr O
OPri
Me
Me
Al
OPri
R
R
O
OPri
O
Al
H
O
R
Me
Me
OPri
R
O
+
R
H
HO
H
Al
H
O
R
OPri R
OPri
R
7.1. metal alkoxide transfer  H
7.2. 6-member cyclic transition state
7.3. Al is important in bringing together alkoxide and carbonyl
7.4. equilibrium determined by reactivity of carbonyl
7.5. driven by removal of propanone by distillation
8. Cannizzaro Reaction
8.1. disproportionation, two aldehydes, one oxidized, the other reduced
R
R
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
Na
Ph
H
O
O
Ph
H Ph
Ph
H
OH Ph
Na
O
O
H
Ph
O
OH
Ph
H
OH
OH
page 5
Na
O
O
2016January17
H
H
8.2. Rate = k[PhCHO]2[HO-]
8.3. Hydride transfer assisted by geminal oxygen
8.4. does not work with ketones, alkyl does not migrate
9. amino group addition
9.1. acid catalyzed, but not too much, Why?
O
-
O
+ RNH2
+
N H2R
B
HO
+
NHR
BH
+
H2 O
NHR
two steps
+
H2O +
N HR
B
NR
NHR
+
9.2. low pH (RDS changes with pH)
9.2.1. water elimination is fast (why?)
9.2.2. amino group is protonated and amino addition is rate limiting
9.3. high pH
9.3.1. water elimination is slow (why?) and rate limiting
9.3.2. amine addition is faster
9.4. imine is more stable than enamine but tends to polymerize
9.5. secondary amines can only form enamines (why?)
9.6. enamine is formed like an enol
9.7. powerful nucleophiles when R = OH, H, alkyl, NH2, NHCONH2, NHPh
9.7.1. i.e. H2NOH, NH3, H2NNH2, etc.
10. Grignard addition
Br
R'
Mg
R'
R
R
Br
O
Mg Br
R'
Mg
Mg
R'
R'
R
R
Br
O
Mg Br
R'
O
R
Mg Br
R R
C
CH2
R H
Mg Br
R
O
R
10.1. chelation by Mg important, impedes acid base reaction
10.2. acid base reactions compete for carbonyl with -H
10.3. reaction with esters?
R R
C
CH2
H
R
Mg Br
R
O
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
R
R2C
R'
O
page 6
H
H
R2C
2016January17
Mg Br
R'
R
O
Mg Br
10.4. RLi
10.4.1. tend not to undergo acid base reaction, or hydride transfer
10.4.2. prefer 1,2 over 1,4 addition
10.5. R2Cd react with ketones/aldehydes but not esters
11. acetylide addition
Na
HC CH
NaNH2
O
O
HC C
Ph
HC C
H
Na
neutralize
H
Ph
12. aldol condensation
12.1. base catalyzed – enolate formation
O
H
O
NaOH
CH3
H
H2O
O
Na
CH2
O
H
CH3
H
Na
NaOH
O
C
H2
H2O
CH3
H
H
O
OH
C
H2
CH3
H
12.1.1. carbonyl activates -CH, stabilized anion
12.1.2. equilibrium favorable for aldehydes
12.1.3. not favorable for ketones
12.2. acid catalyzed – enol formation add proton
12.2.1. favorable for aldehydes and ketones
12.2.2. tertiary alcohol products dehydrate, easy formation of tertiary carbocation
12.3. crossed aldol
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 7
12.3.1. mixed aldehydes gives four possible products if both aldehydes have -H
12.3.2. synthetically useful if one does not have -H
O
Ph
H3C
H
CH3
O
OH
H+
O
+
Ph
H
C
H2
H+
CH3
Ph
O
H
C
C
H
CH3
13. Claisen Condensation add a lone pair
HOEt
O
EtO
NaOEt
CH3
O
EtO
Na
O
O
CH2 EtO
CH3
EtO
Na
O
C
H2
O
CH3
O
C
H2
EtO
OEt
O
EtO
13.1. unfavorable leaving group assisted by geminal oxygen
13.2. pKa of -keto ester?
13.3. equilibrium favors -keto enolate
13.4. neutralize to obtain product
14. Dieckmann - intramolecular Claisen condensation (in class)
15. Benzoin condensation
15.1. Aromatic aldehydes used to avoid aldol condensation
15.2. start with cyanohydrin formation
15.3. Rate = k[ArCHO]2[CN-], rate determining step? nucleophilic catalysis
16. Benzylic acid rearrangement
CH3
NaOEt
O
C
H
CH3
HOEt
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 8
16.1. migration of Ph to electron deficient atom (carbon)
16.2. similar to rearrangement of carbon cation
16.3. in PhCOCHO, H instead of Ph migrates
17. Wittig reaction
PPh3
+
CH2Br
PPh3
H2C
HC
-
Br
Ph
Ph
BuLi
Ph3
P
PPh3
+
Ph
Ph
O
HC
O
Ph3P
O
CH
Ph
17.1. Phosphorus like amine, good nucleophile, not as good base (poor overlap)
17.2. Phosphorus is polarizable, lone pair deformed by electrophile
17.3. formation of strong P=O bond drives reaction
17.4. does not react with esters or unconjugated C=C
18. Addition/elimination of acid derivatives: X = direct heteroatom attached: halogen, S, O, N
O
O
O
X
X
R
R
X
Y
Y
R
Y
18.1. trigonal-tetrahedral interchange, oxygen lone-pair assisted dissociation
18.2. concerted SN2 never observed
19. AKA acyl transfer reactions (for example, from X to Y)
O
O
>
R
Cl R
O
O
O
R
>
R
O
>
OR' R
NH2
19.1. base “catalyzed” hydrolysis of esters follows this mechanism
O
O
O
O
+
H3C
18
H3C
OR'
18
OR'
OH
H3C
18
OH
+
OR'
H3C
H18OR'
O
OH
19.2. no attack on R’, no label in carboxylate: Carbonyl 18O shows up in water. How?
19.3. H* = 112 kJ mol-1, S* = -109 J K-1 mol-1
19.4. OH-, OR-, RNH2 attack ester carbonyl without acid catalysis
20. acid catalyzed hydrolysis:
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
H3O
O
H3C
18
O
+
H3C
OR'
H
O
H2O
18
OR'
H3C
O
18
H3C
OR'
H3C
OH
18O
H3O+
H3C
OH
+ H3O+
OR'
OH
O
+ H18OR'
page 9
H
18
H2O
OH
+ H18OR'
20.1.
H
OH2
O
2016January17
H
+ H2O
H3C
H2O
18
OR'
OH H
in carbonyl, 30 min recover all starting material, missing some 18O, is in the water?
20.2. H* = 75 kJ mol-1, S* = -105 J K-1 mol-1
20.3. normally O-acyl not O-ether cleavage
20.4. If R’ makes good carbon cation (tert-butyl or benzyl) carboyxlate leaves and ether
oxygen cleaves
O
H3C
H3O
18
O
CH2Ph
H3C
OH
OH
18
O
CH2Ph
-H
+ CH2Ph
H3C
18
O
H2OCH2Ph
H2O
20.5. For t-butyl ester: H* = 112 kJ mol-1, S* = 55 J K-1 mol-1
20.6. if acyl group is bulky, acylium is formed (strongly ionizing solvent required?)
O
O
18
OEt
18
OEt
O
OH2
H
H
20.7. acid esterification, same mechanism and restrictions
20.8. acid hydrolysis activation parameters indicate two different mechanisms
HOCH2Ph
Chem 43-6311, ch8-physical-organic-sykes-co-addition.docx
2016January17
page 10