Download Study Guide for Exam 2-‐ Aldehydes and Ketones

Study Guide for Exam 2-­‐ Aldehydes and Ketones Oxidation of Alcohols to Carbonyl Compounds The oxidation of alcohols to carbonyl compounds is the reverse of nucleophilic addition (below). Most oxidants accept the alcohol oxygen as a nucleophile followed by loss of the acidic hydrogen. The process is completed by an E2-­‐like elimination of hydrogen from the proto-­‐carbonyl carbon in concert with formation of the C=O π-­‐bond and reductive loss of the leaving group. General Mechanism B
H
H
O
H
O Ox
H
Ox
B H
H
-H +
Ox
O
Ox
O
Swern B
H
O
H
Me
Cl
S
H
Me
H
Me
-HCl
O S
H Me
Chromic Acid Me
O S
Me
B H
Me
S
Me O
B
O
Cr O
O
H
O
H
H
O
O Cr O
H O
H+
xfer
H
OH
O Cr O
O
B H
OH
Cr O
O
O
Scope and Limitations 1. As a hydrogen atom is needed for the elimination step, 3o alcohols do not oxidize to carbonyl compounds. 2. Normally 1o alcohols are converted to aldehydes and 2o alcohols to ketones. 3. However, in the presence of water, aldehydes form hydrates that undergo more rapid oxidation than the starting 1o alcohols. Thus with CrO3/H2SO4, Na2CrO7, K2CrO7, H2CrO4, 1o alcohols are converted to carboxylic acids. B
R
H
O
H 2O
H
R
HO
O
H
O
Cr O
O
H
R
HO
O
O Cr O
H O
H+
xfer
B H
H
R
HO
OH
O Cr O
O
R
O
HO
OH
Cr O
O
4. This over-­‐oxidation is avoided with the Swern oxidation or the use of PCC. Nucleophilic Addition Most of the reactions of aldehydes and ketones in these chapters are nucleophilic addition reactions. The oxygen in C=O polarizes the bond. Therefore, while electrophilic addition (electrophile first, followed by nucleophile) was favored for the comparatively non-­‐polar, electron-­‐rich alkene, carbonyls undergo nucleophilic addition (nucleophile first, followed by electrophile). Note how all the mechanisms begin exactly the same way: General Mechanism E+
O
O
O E
Nu
Nu
Hydride Nu
tetrahderal
intermediate
O
H 3B O
H OR
O H
+ H 3BOR
LiAlH4 is similar H
H B
H
H
H
H
O
BrMg O
Carbanion Grignard/Alkyllithium/Acetylide 1)
R
Br Mg
Ylide H
H O H
2)
O H
+ BrMgOH2
R
R
O
O
Wittig Reaction Ph 3P
O
O
PPh 3
CH2
+
Ph 3P CH2
Ph 3P CH2
CH2
The Wittig is unique in that the alkoxide oxygen in the tetrahedral intermediate attacks the phosphonium center forming an oxaphosphetane intermediate. Thus, the electrophile is not H+ as in the previous examples but the phosphonium center. The intermediate undergoes a reverse 2+2 process to form triphenylphosphine oxide and an alkene product to complete the process. If the nucleophile is a weaker base than the alkoxide in the tetrahedral intermediate, an alternative mechanism is proposed. Here, the electrophile (usually H+) is added first to enhance the polarity of the C=O bond, and reduce the energy of the tetrahedral intermediate (transition state resembles this intermediate; stabilizing it will increase the rate). The reverse reaction rates are also enhanced, so the mechanisms feature equillibria. Alcohol as Nucleophile – Acetal/Ketal Formation O
H 3O+
H O
R O H
H O
R O H
H+
xfer
H O H -H O
2
R O
H O R
H O R
-H3O+
R O
R O
O R
R O
1o Amine as Nucleophile – Imine Formation O
H O
H 3O+
H+
xfer
H O
H O H -H O
2
R N
R N
H
R N H
H
R N H
H
2o Amine as Nucleophile – Enamine Formation O
H O
H 3O+
H+
xfer
H O
H O H -H O
2
O H
H
R N
R
R N
R
R N H
R
R N H
R
H
H O H
H
R N
R
Cyanide as Nucleophile – Cyanohydrin Formation O
H O
HCN
H O
N C
N C
Peracid as Nucleophile – Baeyer-­‐Villager Oxidation B:
O
H O
H 3O+
H O
B H
H O
O
R
R
O
O
O
O
O
O
O H
O H
O
H+
xfer
O
O
R
HO
H
R
Developmental P roblems 1. Complete the following ‘reactivity tree’ for a ketone: H 3O+, H 2O
ROH, H 3O+
HO
H 3O+
PPh 3
O
Ph
HCN, KCN
OH,
1) RMgBr
2) dil. H 3O+
RNH 2,
pH 5.5
R 2NH,
pH 5.5
NH 2OH,
pH 5.5
1) LiAlH 4
2) dil H 3O+
2. Predict the products: a. O
1) LiAlH 4
2) dil. H 3O+
b. O
1) PhMgBr
2) dil. H 3O+
c. O
H 2C PPh 3
d. e. f. g. h. i. j. OH
HO
Na 2Cr2O7
H 2SO 4/H2O
3. Predict the products – Part II: a. O
mCPBA
CH2Cl2
b. O
PPh 3
c. O
Ag2O, KOH
H
d. 1) DIBAH, -78 oC
2) H 3O+
O
O
e. O
1) KCN, HCl
2) HCl, H 2O
f. 1) DIBAH, -78 oC
2) H 3O+
O
O
g. OH
1) (COCl) 2, DMSO
2) Et 3N
h. OH
PCC
CH2Cl2
i. Br
1) Mg, ether
2) O
3) H 3O+
j. O
NaBH 4
O
O
EtOH
4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C7H6O2. Identify it! O
OH
H
H
H 3O+
OH
cathecol
5. How would you synthesize the following from cyclopentanone?
a.
b.
c.
HO
O
C OH
6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved.
Propose a mechanism for the following transformation:
O
O
H
HO
H 3O+
O
OH
H
7. Hydrolyze the following derivatives back to the original aldehydes and ketones:
a.
b.
c.
d.
e.
N
N
O
O
O
O
OCH3
O
8. Difficult to start; however easy once you finish! Propose a synthesis for the following transformations:
O
O
O O
a.
O
O
b.
O
O
9. Identify A, B, C and D: A
1) O3
2) Me 2S
1)
D
MgBr
2) H 3O+
C
N
H
B
AlCl3
N
pH 5.5
10. Identify A-­‐E: 1) O
Br 2
Mg
A
H
H
2)
H 3O+
B
FeBr 3
C
PCC
D
CH2Cl2
HO
OH H 2SO 4
E
11. Provide an efficient synthesis for the following:
a. b. MeO
OMe
Br
Br
c. O
O
d. e. f. g. O
O h. Br
i. OH
CN
j. Br
H
O
E X A M P R E P A R A T I O N Nomenclature: Aldehydes and Ketones Syntheses: This is the first exam with targeted syntheses that you need to work out prior to the exam. You are free to work with your classmates as much as you want (except during the exam of course!). I will not post a key, nor provide you finished syntheses. If you want questions answered you must have made a reaonable attempt (in writing) at solving the synthesis on your own. During review sessions, any student that asks about the syntheses will be asked to go to the board to present what they have worked out so far. I will guide the class towards through any difficulties. Enovid®: This common contraceptive
contains the compound norethynodrel.
Convert the precursor to this component
using any reagents you require. (Hint: at
some point you will need to use a
protecting group!)
OH
O
OH
C CH
O
Precursor
Tamoxifen®: This is a drug used in the
treatment of breast cancer. Propose a
synthesis of tamoxifen from the following 3’hydroxybenzophenone, benzene and any
carbon containing compounds of three
carbons or less with any reagents you
require.
Norethynodrel
O
OH
O
N
Tamoxifen
Ibuprofen (Motrin®, Advil® Nuprin ®) Synthesize this common NSAID (non-steroidal
anti-inflammatory drug) from benzene and any other reagents you wish.
O
C
OH
Disparlure: This molecule is a sex attractant of the Porthetria dispar gypsy moth. Propose a synthesis of disparlure
starting with any two aldehydes and/or ketones you wish as your sole sources of carbon atoms. Assume any Wittig
reaction (hint) would give you exclusively the Z-isomer alkene as a product:
K E Y 1. Complete the following ‘reactivity tree’ for a ketone: HO
OH
H 3O+, H 2O
RO OR
Ph
ROH, H 3O+
HO
H 3O+
O
PPh 3
O
Ph
Ph
Ph
HCN, KCN
OH,
1) RMgBr
2) dil. H 3O+
RNH 2,
pH 5.5
O
Ph
NR
R 2NH,
pH 5.5
Ph
N OH
OH
O
HO
Ph
1) PhMgBr
2) dil. H 3O+
c. O
H 2C PPh 3
OH
Ph
R
1) LiAlH 4
b. CN
Ph
Ph
O
2) dil. H 3O+
Ph
OH
NR 2
Ph
2. Predict the products: a. 1) LiAlH 4
2) dil H 3O+
NH 2OH,
pH 5.5
OH
d. e. f. g. h. i. j. O
OH
Na 2Cr2O7
OH
H 2SO 4/H2O
HO
O
3. Predict the products – Part II: a. O
O
mCPBA
CH2Cl2
O
b. O
PPh 3
c. O
O
Ag2O, KOH
H
HO
d. 1) DIBAH, -78 oC
2) H 3O+
O
O
e. H
O
O
1) KCN, HCl
2) HCl, H 2O
HO
O
C
OH
f. 1) DIBAH, -78 oC
2) H 3O+
O
O
H
O
OH
g. OH
1) (COCl) 2, DMSO
2) Et 3N
O
h. H
OH
PCC
CH2Cl2
i. Br
O
1) Mg, ether
2) O
OH
3)
H 3O+
j. OH
O
NaBH 4
O
EtOH
O
O
O
4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C 7H6O2. Identify it! O
OH
OH
O
H
H
H 3O+
O
5. How would you synthesize the following from cyclopentanone? O
a)
1) MeMgBr
2) H 3O+
OH
H 2SO 4
O
Ph 3P
b)
CH2
HO CN
O
c)
KCN/HCl
HO
H 3O+, H 2O
O
C OH
6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved.
Propose a mechanism for the following transformation:
O
O
H
O H
H 3O+
H
H
O
H
H 3O+
H
O
H
H
HO
H
H 3O+
H
-H+
H
O
H
O H
O
H
H
O H
H
O H
H 3O+
H
O
H
O H
O
H
O
OH
H
HO
-H+
O
OH
O H
7. Hydrolyze the following derivatives back to the original aldehydes and ketones:
8. Difficult to start; however easy once you finish! Propose a synthesis for the following transformations:
O
HO
O
OH
O
a.
1) O3
2) Me 2S
O
O
H 3O+
O
O
O
H
O
1) LiAlH 4
2) H 3O+
1) LiAlH 4
2) H 3O+
O
OH
OH
O
O
H 3O+
OH
H
OH
H 3O+
OH
O O
OH
O
b.
O
O
HO
OH
OH
O
1) LiAlH 4
2) H 3O+
H 3O+
OH
H 3O+
O
O
O
O
O
OH
OH
H 3O+
O
O
O
9. Identify A, B, C and D: HO
1) O3
2) Me 2S
1)
MgBr
O
2) H 3O+
O
N
H
Cl
AlCl3
N
pH 5.5
10. Identify A-­‐E: Br
Br 2
MgBr
Mg
FeBr 3
OH
1) O
H
H
2)
H 3O+
H
O
PCC
CH2Cl2
HO
OH H 2SO 4
O
O
11. Provide an efficient synthesis for the following:
a. H 2O
H 3O+
OH
PCC
CH2Cl2
O
PPh 3
b. O
Br
NaNH 2, Δ
MeO
CH 3OH
H 2O
H 3O+
H 2SO 4
Br
c. H
1) O3
2) Me 2S
O
O
O
OH
NaBH 4
OMe
CH 3OH
OH
O
O
H 2SO 4
H
d. e. f. g. O
OH
KMnO 4
NaOH
h. Br
1) Mg, ether
2) H
O
OH
OH
O O
H 2C PPh 3
PCC
3) H 3O+
CH2Cl2
i. H 2O
H 3O+
j. O
H
H
H 2SO 4
OH
O
PCC
CH2Cl2
OH
KCN
CN
HCl
Br
KO tBu
1) BH 3. THF
2) H 2O2, KOH
PCC
OH
CH2Cl2
H
O