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 R-OH S O O Cl Me (1) S O O O + Me H R N ROTs Tosylate formation Mesylate formation S O O Cl CH 2 H NEt 3 H 2 C S O O HO R H 2 C S O O O R H MsOR (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. (3) R OH O R Cl O (COCl) 2 O O O Cl O R Cl - When the pre-formed carboxylate salt is used, these conditions are essentially neutral. O O O Cl O Cl R O O O Cl R Cl O + CO 2 + CO + Cl -
Transcript
Massachusetts Institute of TechnologyOrganic Chemistry 5.511
September, 2007Prepared by Julia Robinson
Problem Set 1Functional Group Transformations Study Guide
SOLUTIONS
Part I - Functional Group Interconversions and Protective Group Chemistry
R-OHSO
OCl Me
(1)
SO
OO+ Me
H
R
N
ROTs
Tosylate formation
Mesylate formation
SO
OCl CH2
H NEt3
H2C SO
O HO R H2C SO
OO
R
HMsOR
(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.
(3)R OH
O
R Cl
O(COCl)2
O
OO
ClO
RCl-
When the pre-formed carboxylate salt is used, these conditions are essentially neutral.
O
OO
ClO
ClR
O
OO
ClR Cl
O+
CO2 + CO + Cl-
(4) C NNCy
Cy
R
O
OH
C N-NCy
Cy
O R
O+H
C NHNCy
Cy
O R
O
HOR'
O
R OR'
O
HN NHCyCy
+
(5) OH CH2N2 OCH3 Alcohols do not work for this reaction because their pKa is too high... they do not protonate the diazomethane as phenol does in order to make the activated methylating species.
C-
H
H N+N
H OPh
H3C N+ N
O-Ph
PhOCH3 + N2
(6) OCH3 OHBBr3CH2Cl2
Ph OCH3
BBr3Ph O+
CH3
B-
BrBr
Br Ph O+CH3
BBr2
Br-
Ph OBBr2
+ H3CBr3 H2O
Ph OH + B(OH)3 + 2 HBr
(7)R O
OMe
R OH
O
O
CN
CN
Cl
Cl
O
O
CN
CN
Cl
Cl
R O Ar
H
O
OH
CN
CN
Cl
Cl
R O Ar
OH
OH
CN
CN
Cl
Cl
R O Ar
OH
R OH
H
O
Ar
+
H2O
H2O
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 OMsMsClEt3NCH2Cl20-25 oC
OH BrDEADPh3P
OH OMsDEADPh3P
OH OH1. Ph3P, DEAD, THFp-nitrobenzoic acid
2. NaOH, THF
OH NHTsDEADPh3P
OH NHCO2t-BuDEADPh3P
LiBrTHF
MsOHTHF
H2NTsTHF
H2NBocTHF
1) Na liq. NH3
2) Boc2O
OH O
O
CN CO2HHClH2O
CHO CN
PhBr
PhNH2
PhBr
Ph NH2
PhNH2
CO2H+ NH
Ph
O
CO2H NHCO2t-Bu
DCCDMAPTHF
Provide conditions for the formation of each of the following protected functional groups and for their deprotection.
O OSiMe3
OHO ClMe3Si
iPr2NEt, CH2Cl2
TBAF, THFSEM ether
2. LiAlH4
(EtCO)2OMe3SiOTf (cat.)THF
1. NH2OH, PhH2. POCl3, Et3N
1. NaN3, DMSO2. Ph3P
1. NaCN DMSO
(PhO)2P(O)N3
tBuOH, Δ
O SMeOHNaH, NaI, ClCH2SCH3,DME
HgCl2, H2O, CH3CN MTM ether
OSit-BuMe2OH TBSCl, DMAP, Et3N, CH2Cl2
TBAF, THF
O
O
OH
OH
TBDMS ether
acetonideBF3
.Et2O, CH2Cl2 OMe
pTsOH, MeOH
O OCH3
OH
MOM ether
MeO OMe , CH2Cl2BF3
.Et2O, 4A sieves
PPTS, tBuOH, Δ
O OCH2PhOH
BOM ether
BOMCl, iPr2NEt, CH2Cl2
H2, Pd/C, EtOAc
O
OMe
OH , iPr2NEt, CH2Cl2
DDQ, CH2Cl2
ClOMe
PMB ether
S
OO
HS OH , BF3.OEt2, CH2Cl2
HgCl2, H2O, CH3CN
hemithioketal
NHCO2t-BuNH2 Boc2O, NaOH, H2O
TFA, CH2Cl2
Part II - Oxidation Methods
(1) Swern oxidation of a secondary alcohol
(2) Transition state for epoxidation of an alkene with a peracid
(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.
OOH
RO
Cl
OCl
O
S+
Me
Me O-
O
O
ClOS+
Me Me
Cl-
S+
Me
Me Cl
R R'
OH R R'
O+S+Me
MeH
NEt3
R R'
OS+
Me
CH2
H
NEt3 R R'
OS+
Me-CH2
H R R'
O
MeS
Me
O+
R
TMSO R'Rubottom oxidation:
OO
H
ArO
O
ROTMS
R'
O
OArH
O+
ROTMS
R'
H R
O OH
R'
SiMe3O
R OTMS
R'
O
R OH
R'Oxidation with DMDO:
R
TMSO R'
OOMe
Me
TMSO R'
OR Me
O
Me+ Peracid epoxidation results in the formation of a
carboxylic acid which protonates the epoxide, leading to epoxide-opening and 1,4-silyl migration. 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
(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
(8) Ozonolysis of a simple alkene in dichloromethane
(10) Migratory aptitude in the Baeyer-Villiger oxidation:
(11) Dess Martin reagent IBX
OI+
O
HO O-
OH
H
H
H
OO
(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.
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.
O3, MeOH, CH2Cl2;then add TsOH;then add NaHCO3
see abovefor mech. ofthese steps
OOH
MeO
O
O OO
OH
O
MeO
Et3N
OMeOMe
OMeOMe
CO2Me
OMeOMe
R2 OH
OR1 O
O
Arδ+ δ-
O
I
O
AcO OAcOAc
Provide detailed conditions for effecting each of the following transformations.
. pyr2, CH2Cl24. Dess-Martin periodinane*, CH2Cl25. TEMPO (cat), NaOCl, CH2Cl2
OH
O
PhPh
Ocat. PdCl2CuCl2
O O
OH
H2O, O2DMF
PCCCH2Cl2
KHMDS;
NO
Ph SO2Ph
NaOCl2, NaH2PO4aq. tBuOH
*
OI
O
AcO OAcOAc
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.
Ir PCy3
N
+ PF6-
(2)
R
O
N
R''
R'LiAlH4
R N
R''
R'
R
O
N
R''
R'H-
R
OH
N
R''
R'R N+
R''
R'
H-
R N
R''
R'
Amines are the products of this reaction because R2N- is a terrible leaving group compared to HO-, so the iminium is formed rather than the aldehyde, and the iminium is reduced to the amine.
(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
(5) DIBAL reduction of esters to aldehydes without over-reduction to alcohols
O
OR
AlH
O-
H
OR workup
Al+iBu
iBu
O
H
At low temperatures the hemi-acetal intermediate is stable and does not collapse to the aldehyde until workup, preventing over-reduction.
3 RCO2H + BH3 (RCO2)3B + 3H2
R O
O
BCO2R
CO2R
R O
O
BCO2R
CO2R
the ester oxygen donates some electron density to the boron, decreasing donation to the carbonyl, and thus increasing the electrophilicity of the carbonyl compared to an ester carbonyl.
(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:
(9)OH 1. NaH, CS2, MeI
2. nBu3SnH, AIBN, PhH, reflux
OHNaH
O-
CS
S
O
S
S-
H3C I
O
S
SMe O
S
SMe
Sn(nBu)3
SMe
S
O
Sn(nBu)3
H Sn(nBu)3
Sn(nBu)3
Sn(nBu)3
OH NaH2Al(OR)2
Al-
H
OH
ROH2O
HO
trans addition
(10) Birch reduction of anisole: explain regiochemical course of reaction
Provide conditions for effecting the following transformations.
O OSiMe3
OOH
O NH2
OH
OHOH
OCH3OCH3
Li, NH3
EtOH
OCH3
Li
OCH3
kinetic control:protonation of pentadienylanions occurs at central carbon
