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 E2like elimination of hydrogen from the protocarbonyl carbon in concert with formation of the C=O πbond and reductive loss of the leaving group. General Mechanism Swern Chromic Acid Scope and Limitations 1. As a hydrogen atom is needed for the elimination step, 3 o alcohols do not oxidize to carbonyl compounds. 2. Normally 1 o alcohols are converted to aldehydes and 2 o alcohols to ketones. 3. However, in the presence of water, aldehydes form hydrates that undergo more rapid oxidation than the starting 1 o alcohols. Thus with CrO3/H2SO4, Na2CrO7,K2CrO7,H2CrO4,1 o alcohols are converted to carboxylic acids. 4. This overoxidation is avoided with the Swern oxidation or the use of PCC. H O H Ox H O H Ox -H + H O Ox B O Ox B H H O H H O H -HCl H O S B O B H Me S Me Cl S Me Me Me Me S Me Me H O H H O H B O B H O Cr O O O Cr O O H + xfer H O Cr O OH O Cr O OH O HO R H O H HO R H O H B H R O B H O Cr O O O Cr O O H + xfer HO R H O Cr O OH O Cr O OH O H 2 O HO R O
Transcript
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
Swern
Chromic Acid
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.
4. This over-‐oxidation is avoided with the Swern oxidation or the use of PCC.
HOH
OxH
OHOx -H+ H
O Ox
B
O Ox
B H
HOH
HOH
-HClH
O S
B
O
B H
Me S Me
ClSMe
Me
Me
MeSMe
Me
HOH
HOH
B
O
B H
OCr OO
OCr OO H+
xferH
O Cr OOH
OCr OOH
O
HORH
OH HO
RH
OH
B
HR O
B H
OCr OO
OCr OO H+
xferHORH
O Cr OOH
O
Cr OOH
O
H2O
HO
RO
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
Hydride
LiAlH4 is similar
Carbanion
Grignard/Alkyllithium/Acetylide
Ylide
Wittig Reaction
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
Nu
O
Nu
O
Nu
E+ E
tetrahderal intermediate
O O
H
O
H
H
B HHH
H
H ORH3B+ H3BOR
O O
R
O
R
HH OBrMg+ BrMgOH2
Mg RBr
1)2)
HH
O O
Ph3P CH2 Ph3P CH2
O
Ph3P CH2
O
PPh3 CH2+
OO H
R O H
OH
R O H
OH
R O
HH+
xferOH
R O
RH3O+
OH
R O
R-H2O O
R O
R-H3O+
1o Amine as Nucleophile – Imine Formation
2o Amine as Nucleophile – Enamine Formation
Cyanide as Nucleophile – Cyanohydrin Formation
Peracid as Nucleophile – Baeyer-‐Villager Oxidation
Developmental Problems
1. Complete the following ‘reactivity tree’ for a ketone:
OO H
R N H
OH
R N H
OH
R N
HH+
xfer
R N
H3O+ -H2O
H H H
OO H
R N H
OH
R N H
OH
R N
HH+
xfer
R N
H3O+ -H2O
R R R R
H
HO H
R NR
HO HH
OO H
N C
OHHCN
N C
OO H
OO H
OH H+
xferH3O+
OR
OO H
OR
OH
OO
OR
H
O
O
O
HOR
B:B H
Ph
OH3O+, H2O
ROH, H3O+
HO OH,
H3O+
RNH2, pH 5.5
R2NH, pH 5.5
NH2OH,pH 5.5
1) LiAlH42) dil H3O+
1) RMgBr 2) dil. H3O+
HCN, KCN
PPh3
2. Predict the products: a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
2) dil. H3O+
O
1) LiAlH4
O
2) dil. H3O+
1) PhMgBr
O PPh3H2C
H2SO4/H2OOH
HO
Na2Cr2O7
3. Predict the products – Part II: a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
OmCPBACH2Cl2
OPPh3
H
OAg2O, KOH
O
O
1) DIBAH, -78 oC2) H3O+
1) KCN, HCl2) HCl, H2O
O
1) DIBAH, -78 oC2) H3O+
OO
1) (COCl)2, DMSO2) Et3N
OH
OH PCCCH2Cl2
Br
1) Mg, ether2)
3) H3O+
O
O
O
ONaBH4EtOH
4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C7H6O2. Identify it!
5. How would you synthesize the following from cyclopentanone?
a.
b.
c.
6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved. Propose a mechanism for the following transformation:
7. Hydrolyze the following derivatives back to the original aldehydes and ketones: a.
b.
c.
d.
e.
8. Difficult to start; however easy once you finish! Propose a synthesis for the following transformations:
9. Identify A, B, C and D:
OH
OH
H H
O
H3O+
cathecol
CHOO
OH
H H
O OH3O+ OHO OH
N NOO
OO
OOCH3
O
O Oa. b. O
O
O
OO
1) O32) Me2S
AlCl3
MgBr1)
2) H3O+
NH
pH 5.5N
A
B
C
D
10. Identify A-‐E:
11. Provide an efficient synthesis for the following:
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
CH2Cl2PCC
2) H3O+
Br2
FeBr3
Mg H
O
H
1)
HO OH H2SO4
A B C D
E
Br
Br
MeO OMe
O
O
O
O
Br
OH
CN
Br
O
H
EXAM PREPARAT ION
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!)
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.
Ibuprofen (Motrin®, Advil® Nuprin ®) Synthesize this common NSAID (non-steroidal anti-inflammatory drug) from benzene and any other reagents you wish.
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:
O
OH
O
OHC CH
NorethynodrelPrecursor
OH
O
ON
Tamoxifen
CO
OH
KEY
1. Complete the following ‘reactivity tree’ for a ketone:
2. Predict the products: a.
b.
c.
d.
e.
f.
Ph
OH3O+, H2O
ROH, H3O+
HO OH,
H3O+
RNH2, pH 5.5
R2NH, pH 5.5
NH2OH,pH 5.5
1) LiAlH42) dil H3O+
1) RMgBr 2) dil. H3O+
HCN, KCN
PPh3Ph
HO
Ph
OR
Ph
Ph
NR
Ph
NR2
Ph
N Ph
OH
Ph
OH
Ph
OH
Ph
OH
RO
OO
OH
R
CN
2) dil. H3O+
O
1) LiAlH4
OH
O
2) dil. H3O+
1) PhMgBrHO Ph
O PPh3H2C
g.
h.
i.
j.
3. Predict the products – Part II:
a.
b.
c.
d.
e.
f.
H2SO4/H2OOH
HO
Na2Cr2O7OH
O
O
OmCPBACH2Cl2 O
O
OPPh3
H
OAg2O, KOH
HO
O
O
O
1) DIBAH, -78 oC2) H3O+
H
O
1) KCN, HCl2) HCl, H2O
O HOCO
OH
1) DIBAH, -78 oC2) H3O+
OO OHO
H
g.
h.
i.
j.
4. Treatment of cathecol with formaldehyde in the presence of dilute acid leads to a product with formula C7H6O2. Identify it!
5. How would you synthesize the following from cyclopentanone?
1) (COCl)2, DMSO2) Et3N
OH O
OH PCCCH2Cl2
O
H
Br
1) Mg, ether2)
3) H3O+
OOH
O
O
ONaBH4EtOH O
OH
O
OH
OH H3O+H H
OO
O
CHOO
OH
O
a)
1) MeMgBr2) H3O+
OHH2SO4
O
b)Ph3P CH2
O
c)
CNHOH3O+, H2OKCN/HCl
6. Glutaraldehyde is a germicidal agent used to sanitize surgical equipment that cannot be autoclaved. Propose a mechanism for the following transformation:
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:
H H
O OH3O+
H H
O O-H+
H
O H
H
H H
O OH3O+H
O H
H
H H
O OH
O H
H3O+
H H
O OH
O H
HH3O+ OHO
HOHHH
-H+ OHO OH
O
a.HO OH
H3O+
OO 1) O32) Me2S
OO
OO
HH
1) LiAlH42) H3O+
OO
OHOH
1) LiAlH42) H3O+
OO
OHOH
H3O+
OHOH
O
H3O+ O O
9. Identify A, B, C and D:
10. Identify A-‐E:
11. Provide an efficient synthesis for the following:
