Massachusetts Institute of Technology

Organic Chemistry 5.511

September, 2007
Prepared by Julia Robinson

Problem Set 1
Functional Group Transformations Study Guide
SOLUTIONS

Part I - Functional Group Interconversions and Protective Group Chemistry

(1) Tosylate formation

O R O
R-OH
Cl S Me O+ S Me ROTs
O H O
N

Mesylate formation
O O O
R
Cl S CH2 H2C S
HO R H2C S O MsOR
O H NEt3 O
O H

(2) In order to convert a primary alcohol to the corresponding nitrile, the alcohol must first be
converted to a sulfonate or halide. DMSO is superior to ethanol as a solvent for the conversion of
primary sulfonates or halides to the corresponding nitriles because DMSO solvates cations
selectively, resulting in more nucleophilic anions.

O (COCl)2 O
(3) When the pre-formed carboxylate salt is used,
these conditions are essentially neutral.
R OH R Cl

O O O O O O
Cl Cl + Cl
Cl- R O Cl O R Cl O
O R O O

CO2 + CO + Cl-
 O
Cy Cy Cy
(4) N C N N C N- N C NH R OR'
Cy HO
Cy Cy O O +
R R R'
O
H O+ O O
R OH
HN NH
Cy Cy

(5) OH CH N OCH3 Alcohols do not work for this reaction because their pKa
2 2
is too high... they do not protonate the diazomethane as
phenol does in order to make the activated methylating
N species.

H N+ Ph
C- H3C N+ N PhOCH3 + N2
H O
H
Ph O-

(6)
OCH3 OH
BBr3
CH2Cl2

Br-
CH3 CH3 CH3
Ph O Ph O+ Br Ph O+
BBr3
B- Br BBr2
Br

3 H2O
Ph O + H3CBr Ph OH + B(OH)3 + 2 HBr
BBr2

O
Cl CN
(7) Cl CN
O
R O R OH
H2O
OMe
O
Cl CN O
OH
Cl CN
Cl CN R OH
Cl CN H2O
O Cl CN
Cl CN +
OH
OH
H O
OH
R O Ar H Ar
R O Ar R O Ar
Provide conditions for effecting each of the following transformations. In this and related problems
in 5.511, you will be expected to indicate reagents, an appropriate solvent, and in cases where it is
critical to the success of the reaction, the number of equivalents of reagents and the reaction
temperature.

OH MsCl OMs
Et3N
CH2Cl2
0-25 oC

OH DEAD Br
Ph3P
LiBr
THF

OH DEAD OMs
Ph3P
MsOH
THF

1. Ph3P, DEAD, THF

OH OH
p-nitrobenzoic acid

2. NaOH, THF

OH DEAD NHTs
Ph3P
H2NTs
THF

OH DEAD 1) Na NHCO2t-Bu
Ph3P liq. NH3
H2NBoc 2) Boc2O
THF
 (EtCO)2O
OH Me3SiOTf (cat.) O

THF
O

CN HCl CO2H
H2O

1. NH2OH, PhH
CHO 2. POCl3, Et3N CN

1. NaN3, DMSO
2. Ph3P
Ph Ph
Br NH2

1. NaCN
Ph DMSO Ph NH2
Br 2. LiAlH4

Ph CO2H DCC Ph
NH2 + N
DMAP H
THF

CO2H (PhO)2P(O)N3 NHCO2t-Bu

tBuOH, Δ

Provide conditions for the formation of each of the following protected functional groups and
for their deprotection.
Me3Si
O Cl
OH iPr2NEt, CH2Cl2 O O
SiMe3
TBAF, THF
SEM ether
 NaH, NaI, ClCH2SCH3,
OH DME O SMe

HgCl2, H2O, CH3CN MTM ether

OH TBSCl, DMAP, Et3N, CH2Cl2 OSit-BuMe2

TBAF, THF
TBDMS ether

OH BF3.Et2O, CH2Cl2 O
OMe
acetonide
OH pTsOH, MeOH O

MeO OMe , CH2Cl2

BF3.Et2O, 4A sieves
OH O O
CH3
PPTS, tBuOH, Δ
MOM ether

OH BOMCl, iPr2NEt, CH2Cl2 O OCH2Ph

H2, Pd/C, EtOAc BOM ether

OMe

OMe O
OH Cl , iPr2NEt, CH2Cl2

DDQ, CH2Cl2 PMB ether

.
HS OH , BF3 OEt2, CH2Cl2 O
hemithioketal
O
HgCl2, H2O, CH3CN S

NH2 Boc2O, NaOH, H2O NHCO2t-Bu

TFA, CH2Cl2
 Part II - Oxidation Methods

(1) Swern oxidation of a secondary alcohol

O
O NEt3
Cl Me Cl
Cl Cl Me
O S+
O S+ H
S+ O Me Me O+
Me + O- Me Me
S OH
R R'
Me
Cl- R R'

Me Me
H S+ -CH
S+ O O
C O 2 O +
S
H2 R R' Me Me
NEt3 H R'
R R' R

(2) Transition state for epoxidation of an alkene with a peracid

O R

H O
O

(3) Reaction of enol ethers with peracids such a m-CPBA (the “Rubottom Oxidation”) produce α-silyloxy
ketones (usually hydrolyzed in situ or during workup to the α-hydroxy derivatives). However, oxidation with
DMDO often allows isolation of the epoxides. Provide a mechanism for each transformation and explain the
different outcome of the reactions.
Rubottom oxidation:
OTMS
TMSO R' R R'
OTMS SiMe3
O R R' O OH O R'
R
O O+
O R R' R OTMS
H O H H
Ar O
O Ar
O R'
Oxidation with DMDO:
TMSO R' R OH
TMSO R' O
R + Peracid epoxidation results in the formation of a
O R carboxylic acid which protonates the epoxide,
O O Me Me
Me leading to epoxide-opening and 1,4-silyl migration.
Me Epoxidation with DMDO occurs under neutral
conditions, so the epoxide does not open.
 (4) Oxone = 2 KHSO5 . KHSO4 . K2SO4

(5) Ground state oxygen Excited state "singlet" oxygen

O O O O

(6) A photosensitizer is a compound that absorbs light and is promoted to an excited state, then
transfers that excitation to triplet oxygen in order to form singlet oxygen and regenerate the ground-state
photosensitizer. This is the most common method for generation of singlet oxygen.

(7) Selenium dioxide oxidation of alkenes to allylic alcohols

R
ene
reaction R R R
CH2 =
solvolysis
O
Se H O Se HO Se OSeOH
O
O H O
[2,3] sigmatropic
R rearrangement

OH

(8) Ozonolysis of a simple alkene in dichloromethane

O+
O O- O O
O O O O
O

O O
[4+2] cycloaddition [4+2] cycloreversion [4+2] cycloaddition

PPh3
PPh3 PPh3
O O O O O
O

O O O
(9) Org. Syn. 1986, 64, 150

O3, MeOH, CH2Cl2;

then add TsOH;
OMe
then add NaHCO3;
then add Me2S OMe
CHO

O3

MeOH
MeO MeO MeO
O+ - O O O
O OH TsOH OH OH
CHO
H-O-Me OMe
O O+ O+H2
H
MeO MeO MeO Me MeO
O O O OH
OH OH HCO3- OH S
+ DMSO
Me
O+Me OMe OMe OMe
O+Me OMe OMe
H-O-Me
H

CHO

OMe
OMe

O3, MeOH, CH2Cl2;

CO2Me
then add Ac2O, Et3N
CHO

O3
MeOH
Et3N O
MeO O O H
O+ O O
O- OH O
O MeO
CHO CHO CHO
 O3, MeOH, CH2Cl2;
then add TsOH;
then add NaHCO3;
then add Ac2O, Et3N CO2Me

OMe
OMe
see above O3, MeOH, CH2Cl2;
for mech. of then add TsOH;
these steps then add NaHCO3

Et3N O
MeO O O H
O O
OH O
O MeO
OMe OMe
OMe OMe

(10) Migratory aptitude in the Baeyer-Villiger oxidation:

tert-alkyl, sec-alkyl > benzyl, phenyl > cyclopropyl > methyl

Migratory aptitude is based on the ability of a group to accomodate partial positive charge. In the
transition state of the reaction, one of the alkyl groups develops a partial positive charge.
O
δ+ δ-
R1 O O Ar
R2 OH

(11) Dess Martin reagent IBX

AcO OAc -
OAc HO O
I
I+
O
O

O
O

(12) H2O2 works for B-V oxidation in this case (even though it doesn't work for cyclohexanone) because the
ring strain of the cyclobutanone makes it more reactive.
H O H
O
O

H H
Provide detailed conditions for effecting each of the following transformations.

NaOCl2, NaH2PO4
CHO aq. tBuOH CO2H

5 methods:

CH2OH CHO 1. PCC, CH2Cl2

2. (COCl)2, DMSO, CH2Cl2; Et3N
3. CrO3 . pyr2, CH2Cl2
4. Dess-Martin periodinane*, CH2Cl2
5. TEMPO (cat), NaOCl, CH2Cl2
AcO OAc
* OAc
OH PCC I
CH2Cl2 O

O O

cat. PdCl2
O
Ph CuCl2
H2O, O2 Ph
DMF

O O
KHMDS;

O
N OH
Ph SO2Ph
 Part III - Reduction Methods
(1) Crabtree's catalyst is especially useful for hydroxyl-directed hydrogenations because the hydroxyl group
coordinates very strongly to the cationic iridium center.
+ PF -
6

Ir PCy3
N

(2) O Amines are the products of this reaction

LiAlH4 because R2N- is a terrible leaving group
R' R'
R N R N compared to HO-, so the iminium is formed
rather than the aldehyde, and the iminium is
R'' R''
reduced to the amine.

O OH H-
H- R' R' R' R'
R N R N R N+ R N
R'' R'' R'' R''

(3) In reduction of ketones and aldehydes the reactivity order is Zn(BH4)2 > NaBH4 > NaBH3CN because
zinc is a stronger Lewis acid than sodium, and the cyano group of NaBH3CN reduces the nucleophilicity of
the hydrides due to its electron-withdrawing effect.

(4) Diborane reduces carboxylic acids to alcohols but reacts very slowly with carboxylic esters because
diborane reacts with carboxylic acids to give a triacyloxyborane intermediate via protonolyis of the B-H
bonds. In this intermediate the carbonyl exhibits enhanced reactivity towards the reducing agent because
the ester oxygen donates some electron
3 RCO2H + BH3 (RCO2)3B + 3H2 density to the boron, decreasing donation to
the carbonyl, and thus increasing the
O CO2R O CO2R electrophilicity of the carbonyl compared to
an ester carbonyl.
B B
R O CO2R R O CO2R

(5) DIBAL reduction of esters to aldehydes without over-reduction to alcohols

iBu
O
iBu Al+
O- O
OR OR workup
H H

H At low temperatures the hemi-acetal intermediate is stable and does not

Al
collapse to the aldehyde until workup, preventing over-reduction.
(6) Esters react slowly with borane and alane (AlH3) but tertiary amides and lactams are reduced smoothly to
amines because borane and alane form a Lewis acid-base complex with the carbonyl of the amide or lactam
and then deliver the hydride in an intramolecular fashion. The carbonyl oxygen of tertiary amides and lactams
are more Lewis basic than the carbonyl oxygens of esters because nitrogen is more electron-donating than
oxygen, so the Lewis acid-base adduct forms more readily with tertiary amides and lactams.

(7) Suggest several reagents that effect selective 1,2-reduction of conjugated enones to produce allylic
alcohols and explain why these reagents favor 1,2-reduction while the use of NaBH4 and LiAlH4 often leads
to mixtures of 1,2 and 1,4-addition products.
NaBH4 + CeCl2 (Luche reduction), DIBAL, and 9-BBN all give exclusive carbonyl reduction because the
reactivity of the carbonyl group is enhanced by Lewis acid complexation at oxygen, and these reagents
are more Lewis acidic than sodium borohydride and lithium aluminum hydride.
(8) The reduction of propargylic alcohols with Red-Al to (E)-allylic alcohols:

H
NaH2Al(OR)2
OH H2O
trans addition RO Al-
H O
HO

(9)
OH 1. NaH, CS2, MeI
2. nBu3SnH, AIBN, PhH, reflux

OH O- O S-
NaH S
C
S
S H3C I

O SMe O SMe

S S
Sn(nBu)3
Sn(nBu)3

H Sn(nBu)3

Sn(nBu)3

O SMe

S
Sn(nBu)3
(10) Birch reduction of anisole: explain regiochemical course of reaction

OCH3 OCH3

Li, NH3
EtOH

OCH3 OCH3 OCH3 OCH3 OCH3

Li EtOH Li EtOH

protonation kinetic control:

occurs ortho protonation of pentadienyl
to EDG anions occurs at central carbon

Provide conditions for effecting the following transformations.

O Li OSiMe3
liq. NH3, Et2O;

TMSCl

O
Et3SiH
1) NH2NHTs, EtOH OH BF3.OEt2
2) NaBH3CN

O NH2
NH4OAc;

NaBH3CN
LiAlH4
THF OH
OH
OH
1. NaH, CS2, MeI
2. nBu3SNH, AIBN, PhH, reflux