Typical First Year Organic Reactions Beauchamp 1
Organic Reactions Summary
For Use as a Study Guide
Beauchamp
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Important acid/base reactions used in the examples below. Write out every one of these easy mechanisms.
sodium hydroxide
Na OH thiolates are good nucleophiles, H H2 Na 2 K (RSH) S 2>E2atMe,1o and 2o RX, C H K = a C N eq K (H O) R S a 2 R S and strong bases, E2 > SN2at -8 10 +8 3oRX. Keq = =10 thiolates thiols 10-16
H n-butyl lithium Li n-Bu Li N N LDA is a very strong base that Ka(HNR2) is also very sterically hindered, Keq = it always acts as a base in our Ka(H-C4H9) -37 course. K = 10 =10+13 diisopropylamine eq -50 10 LDA = lithium diisopropylamide
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 3
LDA = lithium diisopropylamide
O Na NR O 2 enolates are good nucleophiles, K (ROCOCH ) S 2 > E2 at Me, 1o and 2o RX, R C H K = a 3 R C N eq K (HNR ) O C a 2 O CR2 Na and strong bases, E2 > SN2 R2 -25 o 10 +12 at 3 RX. esters K = =10 eq 10-37 ester enolates
LDA = lithium diisopropylamide 2 eqs. O Na NR2 O Na enolates are good nucleophiles, K ( O CCH ) S 2 > E2 at Me, 1o and 2o RX, H C H K = a 2 3 C Na N eq K (HNR ) O C a 2 O CHR2 and strong bases, E2 > SN2 R2 -25 o 10 +12 at 3 RX. Keq = =10 acid dianion carboxylic acids 10-37
LDA = lithium diisopropylamide 2 eqs. Na NR2 N N Na enolates are good nucleophiles, K ( O CCH ) S 2 > E2 at Me, 1o and 2o RX, C H K = a 2 3 C N eq K (HNR ) and strong bases, E2 > S 2 C a 2 CR2 N R2 -30 at 3oRX. K = 10 =10+7 nitriles eq 10-37 nitrile enolate
n-butyl lithium
H Li n-Bu R R n-butyl lithium removes proton X Ka(HCR2SPh2) from sulfur salt and makes a C Keq = C Ka(H-C4H9) good nucleophile at ketones and R SPh2 R SPh2 10-33 aldehydes, forming epoxides. K = =10+17 sulfur salt = ylid eq 10-50 betaine
n-butyl lithium removes proton from dithiane and makes a n-butyl lithium good nucleophile at all of our Li n-Bu electrophiles. It can react once or twice in SN2 reactions. K (dithiane) Sulfur acetal forms carbonyl S S K = a S S eq K (H-C H ) C a 4 9 C group after hydrolysis using -33 Li Hg+2. Makes aldehydes and H H K = 10 =10+17 H dithiane eq 10-50 dithiane carbanion ketones.
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 4
Arrow-Pushing schemes for the above reactions
O Na O Na Na H H Na O 2 2 C H O H C C H H C H H H R O R O R O R O H carboxylic acids sodium hydoxide carboxylates alcohols sodium hydride alkoxides
H H Na C Na C 2 H2 Na C H O C Na O H C C NR2 R S R S H H R R sodium hydoxide thiols thiolates terminal alkynes sodium amide terminal acetylides H O O Li Li Na H2 N H C N 2 C C H NR C C CH3 2 H2 R C R CH Na H 2 LDA 2 LDA diisopropylamine n-butyl lithium lithium diisopropylamide ketones / aldehydes ketone enolates 2 eqs. O O O O Na Na Na Na R C H R C H C H C NR2 NR Na O C 2 O CHR O C O CR2 2 R R2 2 LDA esters ester enolates carboxylic acids LDA acid dianion
N Li Na N Na H C H 2 C H2C C C NR2 S S C CH3 S S CR2 H R2 C 2 CH Li nitriles LDA nitrile enolate H H n-butyl lithium H dithiane dithiane carbanion
H H Li Li H R H2 R R 2 R X H C C X H2C C C 2 C C C CH C C CH3 3 H R SPh H2 R SPh R PPh3 2 R PPh3 2 2 Wittig salt = ylid n-butyl lithium betaine sulfur salt = ylid n-butyl lithium betaine
Organometallics used in our course (Mg, Li and Cu)
Br Br Li Br R Li R R R Li Li bromohydrocarbons Li organolithium discard reagents
Br +2 Mg Br Br R Mg Br R R R bromohydrocarbons Mg Mg R (MgBr) Grignard reagents (organomagnesium reagents)
Cu Br reacts with RBr (SN2) Cu R R Cu reacts with acid chlorides R R Li R Li Li reacts with ,-unsaturated C=O dialkyl cuprates
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 5
o SN2 versus E2 choices at 2 RX.
At secondary RX (X= OTs, I, Br, Cl) SN2 and E2 products are in close competition with each other. Anions whose conjugate acids have higher pKa’s (stronger bases have weaker acids) generally produce more E2 relative to SN2. The o examples that we will emphasize at 2 RX centers are carboxlyates (SN2 > E2) vs hydroxide and alkoxides (E2 > SN2), and cyanide (SN2 > E2) vs terminal acetylides (E2 > SN2), azide (SN2 > E2) vs dialkylamides (E2 > SN2) and metal hydrides (SN2 > E2) vs simple hydride (E2 > SN2). Higher basicity and steric hindrance in either RX or the electron pair donor also favors E2 > SN2.
The following examples show similar looking base/nucleophiles (used in our course) that react differently with 2oRX o o o structures. (They all react by SN2 at methyl and 1 RX and they all react by E2 at 3 RX.) It is the reactions at 2 RX centers that are ambiguous.
2o RX structures are the most ambiguous.
More basic, so E2 > SN2. Less basic, so SN2 > E2. More basic, so E2 > SN2. Less basic, so SN2 > E2. O
N C R C C C H O R O R O cyanide terminal acetylides carboxylates hydroxide and alkoxides pKa of conjugate acid = 9 pKa of conjugate acid = 25 pKa of conjugate acid = 5 pKa of conjugate acid = 16-19
More basic, so E2 > SN2. Less basic, so SN2 > E2. More basic, so E2 > SN2. Less basic, so SN2 > E2. H Na H Li H Na N Na H B H N H Al H N H K N R R Na H H hydrides sodium borohydride pK of conjugate acid = 37 azide dialkyl amides lithium aluminum hydride a
pKa of conjugate acid = 5 pKa of conjugate acid = 37 pKa of conjugate acid = ?
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 6
1. Making RBr from alkane and alkene hydrocarbons and alcohols
3 3 a. RBr from alkanes - mechanism using Br2 / h for free radical substitution of alkane sp C-H bonds to form sp C-Br bonds at the weakest C-H bond.
overall reaction Br H2 h C Br Br H Br CH H3C CH3 H3C CH3
1. initiation h Br Br Br Br H = 46 kcal/mole weakest bond ruptures first 2a propagation H BE = +95 kcal/mole H H BE = -88 kcal/mole Br C H Br C H = +7 kcal/mole H3C CH3 H3C CH3 (overall) H = -15
2b propagation both steps H Br BE = +46 kcal/mole H BE = -68 kcal/mole Br Br C Br C H = -22 kcal/mole H C CH H3C CH3 3 3 (overall) 3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations H H Br C Br C H = -68 kcal/mole H3C CH3 H3C CH3
CH3 H H H C CH H = -80 kcal/mole C C 3 CH CH3 H3C CH3 H3C CH3 very minor product CH3
Example reactions
Br2 / h CH4 H C Br 3 achiral
Br2 / h Br achiral
Br Br / h enantiomers 2 (R and S)
Br / h Br 2 achiral
Br Br 2 Br / h can do E2 twice, 2 to make alkynes
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 7
Br
Br2 / h allylic substitution
b. RBr from alkenes (anti-Markovnikov addition of HBr using free radical chemistry): mechanism using HBr / ROOR / h for free radical addition to alkane pi bonds (anti-Markovnikov addition = Br adds to less substituted position to form most stable free radical intermediate, and then H adds to more substituted position)
HBr H2 overall reaction H C Br C R2O2 (cat.) H C C H C h 3 3 CH2 H2
1. initiation (two steps) R O R O H = 40 kcal/mole O R h O R (cat.)
R BE = +88 kcal/mole BE = -111 kcal/mole O H Br R H Br O reagent H = -23 kcal/mole 2a propagation H H C BE = +63 kcal/mole Br BE = -68 kcal/mole H3C CH2 C Br H3C C H = -5 kcal/mole H2
2b propagation H H2 BE = +88 kcal/mole H = -15 C Br BE = -98 kcal/mole C Br H Br Br H3C C both steps H3C C H2 (2a + 2b) H2 H = -10 kcal/mole
3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations
H H Br Br C Br C Br H = -68 kcal/mole H3C C H3C C H2 H2 CH3 H H H2 C CH H = -80 kcal/mole C C Br Br Br CH C C CH Br 3 H3C C H2 H2 H2 CH3 very minor products
Example reactions H-Br / h ROOR (cat.) Br achiral
Br2 / h ROOR (cat.) Br achiral
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 8
Br Br2 / h ROOR (cat.) R/S enantiomers
Br Br2 / h ROOR (cat.) cis and trans
c. RBr from alkenes (anti-Markovnikov addition of HBr using borane chemistry): mechanism using 1. BH3 2. -- Br2 / CH3O for anti-Markovnikov addition of H-Br to alkane pi bonds (concerted, syn addition of H-BH2 to alkene pi bond, followed by complex with Br2 and migration of R group to Br)
H2 overall reaction H 1. (BH ) C Br C 3 2 2. Br , CH O H C C H C 2 3 3 3 CH2 H2
step 1 R CH 3 H H3C H B R B R C C H C CH H C C H 2 R 2 syn addition, with H2C CH2 H at more substituted H2C CH2 C position and B at less C H2 substituted position. H2
step 2 R R R H H3C H3C H H C H 3 B R B R B R C C Br C H C C H Br Br H C C Br Br 2 2 H2C C H H H C CH H C CH 2 2 2 2 H2C CH2 Br C C C H 2 H2 H2
H3C O
R R H C H 3 H C H B R 3 B R C CH3 CH3 Br O C O H C C Br 2 H C C H 2 H C CH H 2 2 H C CH C 2 2 H2 C H2
Example reactions 1. (BH ) 3 2 Br achiral 2. Br2, CH3O
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 9
1. (BH3)2 Br 2. Br2, CH3O achiral
Br 1. (BH3)2 2. Br2, CH3O R/S enantiomers
Br 1. (BH3)2 2. Br2, CH3O
() or (dl) enantiomers
d. RBr from alcohols:
o o o i. mechanism using HBr SN2 at methyl and 1 ROH; SN1 at 2 and 3 ROH, with possibility of rearrangements
acid H H 2 base H2 H C S 2 2 H O H C O N C Br H C C Br 3 H Br H3C C H H C C O H2 H 3 2 H2 H H H O H H H top O H Br Br H H acid SN1 H C base H3C Br H C C H3C C 3 H3C C CH CH3 C CH CH CH3 3 CH CH3 sp2 = flat CH3 CH bottom S (top) CH3 3 CH3 rearrangement H Br
H2 H2 C H C C H3C Br H C C 3 3 CH CH C CH3 C CH3 3 Br R (bottom) achiral CH CH3 CH 3 3
Example reactions
HI OH I SN2
OH Cl SN2 HCl R/S enantiomers
S 1 HBr N achiral OH Br
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 10
R OH S 1 HBr N Br achiral S rearrangement
OH Cl HCl SN2 or SN1 achiral Br HO H Br H2 H3C C H C CH C CH 3 C 3 CH CH3 H3C CH CH HBr 3 CH3 major CH3 minor achiral R/S CH3 rearrangement enantiomers
CH3
CH3 HBr Br Br OH CH achiral (cis and trans) 3
o o o ii. mechanism using PBr3 : SN2 at methyl and 1 ROH; SN1 at 2 and 3 ROH, with possibility of rearrangements
H H Br 2 H2 H C 2 H O C O SN2 C Br H3C C H P Br H3C C PBr2 H C C O H2 H 3 Br Br 2 H2 PBr2 PBr 2 H H H H H Br H O Br O SN1 H H C C C C C 3 H3C H3C P H3C C CH 3 CH CH3 CH CH3 Br Br CH CH3 R
CH3 CH CH adds to CH3 3 3 Br both faces rearrangement H Br
H2 H H C C C 2 3 H3C Br H C C CH CH3 C CH 3 S 3 C CH3 Br CH achiral 3 CH3 CH 3
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 11
Example reactions
P/I2 = PI3 OH I SN2
OH Cl SN2
PCl3 R/S enantiomers
SN1 PBr3 achiral OH Br R OH S 1 PBr3 N
Br achiral S rearrangement
OH Cl PCl3 SN2 or SN1 achiral
Br HO H Br H2 C H3C H3C CH C CH3 CH CH3 H3C C CH CH PBr3 3 CH3 major CH3 minor achiral SN1 R/S CH3 rearrangement enantiomers
CH3 CH 3 Br Br PBr3 OH CH SN1 achiral (cis and trans) 3
o o o iii. mechanism using SOBr2 SN2 at methyl and 1 ROH; SN1 at 2 and 3 ROH, with possibility of rearrangements
O O Br O H2 S C S O H2 Br H2 Br H3C C H S C O C O H2 Br H C C Br H C C 3 H 3 H H2 H2
Br SN2 O O O S H S H S 2 Br C Br O Br Br O O H3C C H H2 H
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 12
O O Br H S S H H Br Br O H O H H C O H O H H3C C CH C S 3 H3C C H C C H3C CH CH3 Br Br 3 SN1 CH CH3 CH CH3 CH3 Br CH adds to 3 CH CH3 3 both faces
rearrangement Br H
O O C O H2 H3C H H C C CH R CH3 S 2 3 S S H C C Br C CH Br 3 3 C CH CH O O O 3 3 Br H H CH3 achiral Br H CH3 H Br Br C H3C CH CH S 3
CH 3
Example reactions
SOCl OH 2 Cl SN2
OH Cl SN2
SOCl2 R/S enantiomers
SN1 SOBr2 achiral OH Br R OH S 1 SOBr2 N
Br achiral S rearrangement
OH Br SOBr2 SN2 or SN1 achiral Br HO H Br H2 H3C C H C CH C CH 3 C 3 CH CH3 H3C SOBr2 CH CH 3 CH3 major CH S 1 3 minor N achiral R/S CH3 rearrangement enantiomers
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 13
CH3
CH3 SOBr2 Br Br OH S 1 CH N achiral (cis and trans) 3
o o iv mechanism using 1. TsCl/pyridine 2. NaBr SN2 at methyl, 1 and 2 ROH, avoids rearrangements
O O Ar N Ar H S O H O N S Cl H O H O H O H O H3C C Cl S CH CH3 C H3C H3C C O CH CH3 CH CH CH3 3 avoids rearrangement o CH3 at 2 centers CH3
O Ar O H Br Ar S N H C NaBr S H3C O H O Cl CH CH3 O O C H3C CH3 CH CH3
CH3 Br
Example reactions
1. TsCl / py. OH 2. NaBr Br 1. acyl substitution 2. SN2 OH Br 1. TsCl / py. 1. acyl substitution 2. NaBr 2. SN2 R S
1. TsCl / py. 2. NaBr SN1 achiral OH Br
R OH S I 1. TsCl / py. chiral 2. NaI 1. acyl substitution S S 2. SN2
Br OH 1. TsCl / py. achiral 2. NaBr 1. acyl substitution 2. SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 14
HO H H Br
C C H3C 1. TsCl / pyridine H3C CH S CH3 2. NaBr CH R CH3
SN1 enantiomer CH3 CH3
R S OH I 1. TsCl / pyridine R 2. NaI R enantiomer SN1
2. SN2 reactions using RBr compounds:
o o o a. mechanisms using NaOH, SN2 at methyl and 1 RBr; E2 > SN2 at 2 and only E2 at 3 RBr,
H H H SN2 O C Br O C Br H H H H H
D H D S 2 N S O C Br O C Br H H R S H CH2 H2C CH H3C 3
H H H O C Br H R H C S O C Br H2 E2 > SN2 CH CH3 3 C H C Ha E2 (-CH2-H) E2 (-CHa-H) 2 E2 (-CHb-H) CH SN2 3 Hb
Example reactions
SN2 NaOH OH inversion of Br configuration
E2 > SN2 Br OH NaOH
R S
E2 NaOH Br
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 15
R Br E2 > S 2 NaOH N
S S
OH Br achiral NaOH SN2
o o o b. mechanisms using NaOCH3, SN2 at methyl and 1 RBr; E2 > SN2 at 2 and only E2 at 3 RBr,
H H H3C SN2 O C Br O C Br H3C H H H H
D D H3C S 2 N S O C Br O C Br H3C H R S H CH2 H2C CH H3C 3
H H O C Br H3C H C 3 H C S O C R Br H2 E2 > SN2 CH CH3 3 C H C Ha E2 (-CH2-H) E2 (-CHa-H) 2 E2 (-CHb-H) CH SN2 3 Hb
Example reactions S 2 CH3 N NaOCH3 O inversion of Br configuration
E2 > SN2 CH3 Br O
NaOCH3
R S
E2 NaOCH3 Br
R Br
E2 > SN2 NaOCH3
S S
CH3 O Br achiral NaOCH3 SN2 y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 16
o o o c. mechanisms using NaO2CCH3, sodium carboxylates, SN2 at methyl 1 and 2 RBr; and only E2 at 3 RBr Ester synthesis (can hydrolyze with NaOH (base) to ROH and RCO2H, providing an alternate approach to secondary alcohols). CH3
H O C H S 2 H3C O H C O N O 3 C Br O C Br C H H C H H O O H H
O
D H C C D H D S 2 3 H C O N S 3 C Br O C S NaOH O C C H R H H CH H C 2 Br H2C 2 O CH H3C CH3 3
H O H C O C Br H H H 3 H3C C C H C S SN2 > E2 NaOH R R H2 O C O C CH 3 CH3 O Ha C CH3 H2C H2C Br CH3 Hb CH3
Example reactions
O O Na H C Br SN2 3 C C CH3 R O R O
O O Br Na C R C S 2 > E2 R O O N achiral
O
C R OH O NaOH / H2O acyl 2o alcohol substitution
O Br Na C E2 R O
O O SN2 Na C Br C O R R O allylic and benzylic, very fast SN2 reactions
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 17
O Na C Br no reaction R O
o o o d. mechanism using potassium t-butoxide, KOC(CH3)3, SN2 at methyl and E2 at 1 , 2 and 3 RBr,
H C H S 2 H C H 3 O N 3 C C Br O C H C Br 3 H H CH3 H H D H H E2 D C Br C C D H C 3 O H R Z E C CH3 H C C Br Ha C b H3C H3C CH 3 Ha CH3 Hb
H H C 3 O C Br C H C S E2 (-CH2-H) H3C H2 E2 Br CH CH3 3 Ha C E2 (-CHb-H)
Hb E2 (-CHa-H)
Example reactions
E2 > SN2 KOC(CH3)3 anti Br elimination
Br
KOC(CH3)3 E2 R
E2 KOC(CH3)3 Br
R Br
KOC(CH3)3 E2
S S
H3C CH3 Br C S 2 KOC(CH3)3 O CH3 N no other option
o o o e. mechanism using NaSH, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 18
H H H SN2 S C Br S C Br H H H H H
D H D SN2 S C Br S C Br H H R S H CH2 H2C CH H3C 3
H H H S C Br H H C S SN2 S C Br H2 R CH H 3 H C Ha C 2 CH3 Hb
Example reactions
SN2 NaSH SH inversion of Br configuration
Br SH
NaSH SN2 R S
NaSH E2
Br
R Br S SH NaSH SN2 S S
SH Br achiral NaSH
SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 19
o o o f. mechanism using NaSCH3, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
H H H3C SN2 S C Br S C Br H3C H H H H
D D H3C SN2 S C Br S C Br H3C H R S H CH2 H2C CH H3C 3
H H C H S C Br 3 H3C H C S SN2 S C Br H2 R CH H 3 H C Ha C 2 CH3 Hb
Example reactions
SN2 CH3 NaSCH3 S inversion of Br configuration
CH3 Br S
NaSCH3 SN2 R S
NaSCH3 E2
Br
R Br S S CH3 NaSCH3 SN2 S S CH3 Br S achiral NaSCH3
SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 20
o o o g. mechanism using NaCN, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
H H SN2 C C Br N C C Br N H H H H
D D SN2 C C Br N C C Br H R N S H CH 2 H2C H3C CH3
H H C C Br N H C S SN2 N C C Br H2 R CH CH3 3 H C Ha C 2 CH3 Hb
Example reactions
SN2 inversion of Br NaCN C N configuration N
Br C NaCN SN2 R S
NaCN E2 Br
N R Br S C
NaCN SN2 S S
Br C achiral NaCN N
SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 21
o o o h. mechanism using NaCC-R, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
H H SN2 C C Br R C C C Br C H R H H H
D D SN2 C C Br R C C C S Br R C H H R CH2 H2C H3C CH3
H Br D C C Br S R C H C R C C C R H2 E2 > SN2 CH3 CH3 Ha C E2 (-CH -H) E2 (-CHa-H) H2C 2 E2 (-CHb-H) S 2 N CH3 Hb
Example reactions
SN2 NaCC-R inversion of Br R configuration
Br NaCC-R
R E2 > SN2
NaCC-R E2
Br
R Br
NaCC-R E2 > SN2
S S
achiral Br C NaCC-R C R SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 22
o o o i. mechanism using 1. NaN3, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr 2. LiAlH4 3. Workup, o makes 1 amines (RNH2) H H N H H H Al H N C Br SN2 N N N H H2N C N C Wk N N H H H Br H H H SN2
D N H D C Br S 2 D N N N S N N H R S H Al H H N C N C 2 N N CH2 H H H Wk H3C Br H2C H2C CH3 CH3 SN2
H
H C Br N N H H N N H C S N H Al H R H N N 2 SN2 CH N C H2N C 3 R H Wk Ha C CH CH Br 3 3 H C H2C 2 SN2 Hb CH3 CH3
Example reactions
1. NaN3 2. LiAlH SN2 4 NH Br 3. workup 2 twice
Br NH2 1. NaN3 2. LiAlH4 3. workup SN2 R S
1. NaN3 2. LiAlH4 E2 3. workup Br
R Br S NH2 1. NaN3 2. LiAlH 4 SN2 3. workup S S NH Br 1. NaN3 2 achiral 2. LiAlH4 3. workup SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 23
+ o o o j. mechanism using 1. Na imidate, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr 2. NaOH
O O 2 O
Br Na 1 N N H acid/base N OH rxn Na SN2 rxns imidate imide O alkyl imide O -8 O Ka1 10 resonance stabilized makes K = +8 eq = = 10 imidate less basic and a better Ka2 10-16 behaved nucleophile OH 3 acyl substitution #1 Na O H reaction leads to O OH O O a primary amine O
acid/base N N N N H H O O H O O OH acyl substitution #2 O -5 O 10 +10 O Keq = = 10 10-15 H O O
H N N O H O acid/base H 10-5 rxn primary amine K = +32 throw away eq = 10 also made by 10-37 O 1. NaN3 O 2. LiAlH O 4 Look at similarities with ester hydrolysis, just above. O 3. workup
Example reactions O 1. NaOH 2. N H 1. SN2 Br 2. acyl substitution NH2 O 3. NaOH (2 times)
O 1. NaOH NH 2. Br 2 N H R SN2 O 3. NaOH S
O 1. NaOH 2.
N H E2 Br O 3. NaOH 1. NaOH O 2. R Br S NH2 N H S SN2 O 3. NaOH S y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 24
o o o k. mechanism using ketone enolates, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr (See acid/base reactions at the beginning for synthesis of LDA.)
O O O H N Li H3C C H S 2 C H R R C C Br N H2C C H C C LDA H3C CH2 H 3 H H2 H -78oC H
O O O N Li D S 2 H C C D C H R R N 3 C C Br S H C C LDA 3 H3C CH2 H R H2C C H2 o -78 C CH2 H H2C H3C CH3
H O O O N Li H H R R H C C C C C Br S 2 3 C LDA N H3C H C CH H C S C H2 3 2 H2C o H2 R -78 C CH CH3 3 H C Ha C 2 CH3 Hb
Example reactions
O O S 2 1. LDA, -78oC N inversion of 2. Br configuration
O o O 1. LDA, -78 C 2. Br S 2 R N S o O 1. LDA, -78 C 2. E2
Br
O S O R Br
SN2 S S 1. LDA, -78oC O O 2. Br achiral
SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 25
o o o l. mechanism using ester enolates, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
O O O H N Li RO C H S 2 C H R R C C Br N H2C C RO C LDA RO CH2 H H H2 H -78oC H
O O O N Li D S 2 RO C D C H R R N C C Br S RO C LDA RO CH2 H R H2C C H2 o -78 C CH2 H H2C H3C CH3
H O O O N Li R R RO C H C H C C Br S 2 RO C LDA N RO CH2 H C S C H2 H2C o H2 R -78 C CH CH3 3 H C Ha C 2 CH3 Hb
Example reactions
O O S 2 1. LDA, -78oC N R R inversion of O 2. Br O configuration O O 1. LDA, -78oC 2. Br R O SN2 R S O 1. LDA, -78oC 2. R E2 O Br O 1. LDA, -78oC O 2. R Br S R O R O SN2 S S O O 1. LDA, -78oC 2. R O achiral R Br O SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 26
o o o m. mechanism using acid dianion enolates, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
O O O N Li H HO C H S 2 C H R R C C Br N H2C C O C LDA O CH2 H H 3. Wk H 2 H -78oC H
O O O N Li D D R R SN2 HO C C H C C Br O C LDA S O CH2 H R H2C C H2 3. Wk o -78 C CH2 H H2C H3C CH3
H O O O N Li H H R R HO C C C C Br S 2 O C LDA N O CH2 H C S C H2 H2C o H2 R -78 C CH 3. Wk CH3 3 H C Ha C 2 CH3 Hb
Example reactions
O O 1. 2 eqs. LDA 2. H Br H SN2 O 3. workup O
O 1. 2 eqs. LDA O 2. Br OH H S 2 O R N 3. workup S 1. 2 eqs. LDA O 2.
H E2 O Br 3. workup
1. 2 eqs. LDA O 2. O R Br S H O H O S S 2 3. workup N S 1. 2 eqs. LDA O O 2. Br achiral H OH O SN2 3. workup
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 27
o o o n. mechanism using nitrile enolates, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
N
N N H C H N Li R R C SN2 C H C Br H C C C LDA CH2 H 2 H H2 Li H -78oC H
N N Li D N N D R R SN2 C C H LDA C C Br S C CH2 H R H2C C H2 o -78 C Li CH2 H H2C H3C CH3
H N N Li N N R H C H R C Br C LDA C SN2 C CH H C S C H 2 H2C 2 o H2 R -78 C Li CH CH3 3 H C Ha C 2 CH3 Hb
Example reactions
N 1. 2 eqs. LDA N SN2 C 2. inversion of Br C configuration CH3 3. workup 1. 2 eqs. LDA N N 2. Br C C
CH3 R SN2 3. workup S 1. 2 eqs. LDA 2. N C E2 CH3 Br 3. workup
1. 2 eqs. LDA 2. N R Br S C C N CH3 SN2 S S 3. workup
1. 2 eqs. LDA 2. Br N N C achiral C CH S 2 3 3. workup N
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 28
o o o o. mechanism using dithiane anions, SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
H S S Li S H H H S 2 H2C C Br N C CH C C H H H S S H S H
D S S S 2 S D H H N H2C C Br C S C H R CH C H CH H S S 2 S H2C H3C Li CH3
H S H S S H H2C H C Br C SN2 C H C S CH C H H2 R S CH CH3 S 3 S H C Ha C 2 CH3 Li Hb
Example reactions
S S
1. n-BuLi SN2 2. inversion of Br configuration S S
S 1. n-BuLi S 2. Br S SN2 S R S 1. n-BuLi S 2. E2 S Br
1. n-BuLi 2. S R Br S S
S SN2 S S S
S 1. n-BuLi 2. S achiral Br S SN2 S
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 29
Hydrolysis of thioacetals (one as aldehyde and one as ketone)
Li Li Br Hg+ S S H C Br Hg+2 2 S S S S C S S C C C H H H H H 2. workup 1,3-dithiane Li (also continued below to a ketone)
S S S + Hg Hg+ Hg Hg+ S O S S S S C H H C C C O H H H O O O H H H H H H H
H H H S C resonance C C Hg O O H H O O S aldehyde H H
Li Li Br
S S H C Br Hg+ 2 Hg+2 S S C S S S S C C C H 2. workup (from above) Li
S S S + Hg+ Hg Hg+ S S Hg S O S C S C H H C O C O H O H H O H H H
S C resonance C C Hg O O H H O O S ketone H H
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 30
o o o p. mechanism using LiAlH4 or NaBH4 (and deuterides), SN2 at methyl, 1 and 2 RBr and only E2 at 3 RBr,
D H Li H S 2 D Al D C Br N D C H H D H H
D H D Na SN2 C Br H C H B H H R H CH 2 H2C H H3C becomes CH3 achiral
H
D H Li C Br SN2 D Al D H C S D C H2 R CH3 CH3 D H2C Ha C CH3
Hb
Example reactions
SN2 inversion of LiAlD4 D Br configuration
Br D
NaBD4 SN2 R S
LiAlD4 E2 Br
R Br S D NaBD4
SN2 S S
Br D achiral LiAlD4
SN2
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 31
o o q. mechanism using diphenylsulfide to make diphenylsulfonium salt, SN2 at methyl, 1 and 2 RBr and only E2 at 3o RBr, used to make a diphenylsulfonium ylids, which are used to make epoxides with aldehydes and ketones.
Ph Ph H Ph Br O S C S H CH 1. n-BuLi 2 S Ph Ph C 2. H2C=O C H H Ph CH2 H H H H Li Br Ph = phenyl ylid salt similar Ph Ph
mechanisms CH2 H2 S S C H2C Ph O Ph C O H2
H Br CH H Ph 3 O Ph Ph CH2 C Br H2C SN2 1. n-BuLi S H R S C 2. H C=O S C Li 2 CH2 H Ph C H H H Ph Ph H C H3C 2 CH3 ylid salt
Ph Ph H H2 2 C CH S C S 2 H C HC Ph CH O Ph 3 O CH2 H3C
H Ph Br CH Ph 3 O Ph H C Br CH2 S 1. n-BuLi H2C H C S S 2 S H N S C 2. H C=O C Ph 2 R Li 2 CH Ph C CH3 H H CH3 Ph 3 Ha C H2C CH3 ylid salt Hb Ph Ph H H2 2 C CH S C S 2 H C C Ph C O Ph 3 H C O 3 H3C CH2 H3C
Example reactions 1. Br O SN2 S 2. n-BuLi Ph Ph inversion of 3. H2C=O configuration
1. Br R O S Ph Ph 2. n-BuLi SN2 3. H2C=O S
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 32
1.
S Br E2 Ph Ph 2. n-BuLi 3. H2C=O
1. R Br O S Ph Ph S 2. n-BuLi SN2 3. H2C=O S 1. Br O S achiral Ph Ph 2. n-BuLi SN2 3. H2C=O
o o r. mechanism using triphenylphosphine to make triphenylphosphonium salt, SN2 at methyl, 1 and 2 RBr and only E2 at 3o RBr, used to make a triphenylphosphonium ylid to make Z and E alkenes with aldehydes and ketones.
Br Ph H H Ph O Br S 2 Ph N CH Ph Ph P C 2 1. n-BuLi CH3 Ph P C P 2. H2C=O C Ph H CH Ph C 3 CH3 Li H CH3 Ph H H betaine Ph = phenyl ylid salt
H Ph O Ph O Ph Ph Ph C H H H CH P C P C Ph P O C 3 Ph C CH3 Ph C CH3 Ph Z alkenes CH H H 3 CH3 CH3 oxaphosphatane
Br Ph H3C O H H Ph Br S 2 Ph Ph P N CH Ph C 2 1. n-BuLi CH2 C Ph P C P 2. H2C=O Ph C H CH3 Ph H3C CH2 CH2 Li Ph CH CH3 3 H C CH betaine Ph = phenyl 3 ylid salt 3
H Ph O Ph O Ph Ph Ph C H H H C CH P C P C Ph P O 3 C 3 Ph C CH3 Ph C CH3 Ph Z alkenes CH H3C H C 2 CH2 3 CH2 H3C H3C oxaphosphatane H3C
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 33
Schlosser Modification of the Wittig reaction to make E alkenes
H OH2 H H H H O C O C Ph3P O C acid/base Ph3P O C Ph3P Ph3P R at -78oC neutralize R C H R R C H C C R R The stereochemistry R R H betaine H C of the alkene is 2 flat sp2 carbon determined in this step. Li can react from extra equivalent of n-BuLi either side
H H O O C Ph3P C R Ph3P R C R phosphine C R oxide H H E alkene
Example reactions 1. Br P 2. n-BuLi Ph Ph 3. CH3CH=O Normal Wittig Ph Z alkene preferred
1. Br P R Ph Ph 2. n-BuLi Ph 3. CH CH=O Normal Wittig 3 Z alkene preferred
1.
P Br Ph Ph 2. n-BuLi Ph 3. CH3CH=O E2
1. R Br
P S Ph Ph 2. n-BuLi Ph 3. CH CH=O Normal Wittig 3 Z alkene preferred S 1. Br P Ph Ph Ph 2. n-BuLi Normal Wittig 3. CH3CH=O Z alkene preferred
1. Br 2. n-BuLi P 3. CH3CH=O o Schlosser modification Ph Ph 4. -78 C, n-BuLi 5. HCl, warm of the Wittig Ph E alkenes preferred
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 34
3. SN1 reactions using RBr compounds:
a. RX compounds with water. SN1 conditions form carbocations with possible rearrangements. Alcohol synthesis is the major product with E1 as minor product (unless reaction is run at high temperature). H H OH2 O H Br O O
SN1 H H top = bottom
H H H2O H2O H top H O H Br H O H H O H H H C C H3C C H3C H3C H3C C C CH3 CH CH3 CH CH3 CH CH3 SN1 sp2 = flat S (top) R (bottom) CH3 bottom CH3 CH3 CH3 rearrangement
H2O H H2 2 H2O C H C C H3C O H 3 H2 H H O H C CH H C CH3 3 H3C C O O C CH C 3 H3C C CH H3C CH3 3 CH CH3 H CH CH3 H achiral CH3 S (top) CH3 CH3 R (bottom)
Example reactions
H2O H3C Br no reaction
SN1 > E1 H2O OH Br diastereomers top & bottom achiral
Br H2O OH SN1 > E1 top = bottom
S 1 H2O Br N Br resonance stabilization of R+
no reaction, vinyl H2O Br carbocation is too unstable
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 35 b. RX compounds with alcohols. SN1 conditions form carbocations with possible rearrangements. Ether synthesis is the major product with E1 as minor product (unless reaction is run at high temperature).
H H OH2 O CH3 Br O O
SN1 CH CH top = bottom 3 3
H H R H top O O Br H H H O H R R H O H C R H O R H3C H C C CH CH 3 3 C CH3 C H3C C SN1 H3C sp2 = flat CH CH3 CH CH CH3 3 CH3 bottom S (top) R (bottom) CH3 H CH3 R O rearrangement H O H H2 2 C H C C H3C R O H 3 H2 R H O R C CH H C CH3 3 H3C C O O C CH C 3 H3C C CH H3C CH3 3 CH CH3 R CH CH3 R achiral CH3 S (top) CH3 CH3 R (bottom)
Example reactions
H3C Br OH no reaction
diastereomers SN1 > E1 top & bottom Br OH achiral O
Br O SN1 > E1 OH top = bottom
OH SN1 Br O
no reaction Br OH
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 36 c. RX compounds with liquid carboxylic acids. SN1 conditions form carbocations with possible rearrangements. Ester synthesis is the major product with E1 as minor product.
OH
HO H O O O O Br O O SN1 top = bottom
HO HO O H O O HO H O Br H H top O H O H C H O H3C H C C CH CH 3 3 C CH3 H C C 3 H C C SN1 3 sp2 = flat CH CH3 CH CH CH3 3 CH3 bottom S (top) R (bottom) CH3 CH3 HO rearrangement O O H H2 2 C H C C H3C O H 3 H2 H O C CH C CH3 3 H3C C O O C CH C O 3 H3C C CH H3C CH3 3 CH CH3 CH CH3 achiral H CH3 O OH S (top) O CH3 CH3 R (bottom) O
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 37
d. Oxidation of ROH with: CrO3 / pyridine (PCC). Synthesis of aldehydes or ketones.
O O N H O N O Cr H O H Cr O O O O O
Cr H3C C H3C C O O H3C C C H C H C H H2 H H2 H H2 H E2 primary alcohols N
PCC = pyridinium chlorochromate oxidation O of primary alcohol to an aldehyde (no water to O hydrate the carbonyl group) N H O H3C C C H Cr O H2 aldehydes H CrO3 / pyridine OH (PCC) oxidation O OH O CrO3 / pyridine (PCC) oxidation
CrO3 / pyridine (PCC) no reaction OH
OH CrO3 / pyridine O (PCC) oxidation
O
OH CrO3 / pyridine (PCC) H
oxidation
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 38
e. Oxidation of ROH with: CrO3 / acid / water (Jones). Synthesis of carboxylic acids or ketones.
H O O O O O H H Cr O O Cr O O O H H Cr H H O O O O H C C H C C 3 3 H3C C C H C H C H H H 2 H 2 H H2 H primary alcohols Jones = CrO3 / H2O / acid H primary alcohols oxidize to carboxylic acids (water hydrates the carbonyl group, O which oxidizes a second time ) H H O H H O O O O O Cr H H resonance H C C O H3C C H3C C 3 C H C H hydration of C H H H 2 H2 the aldehyde 2 aldehydes (cont. in water)
O H H H O H H O O H H O Cr O H O H H O O H O O H H Cr H C C O H C C 3 H C C O O O 3 C 3 C O H H H C H2 2 H H H H 2 H second oxidation of the carbonyl hydrate
H O O O O O Cr H H Cr H O O O O
O H3C C H H3C C H H C O C O H2 H2 H carboxylic acids H O H H
OH CrO3 / acid / H2O OH (Jones) oxidation O OH O CrO3 / acid / H2O (Jones) oxidation
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 39
CrO3 / acid / H2O (Jones) no reaction OH
OH CrO3 / acid / H2O O (Jones) oxidation
O
OH CrO3 / acid / H2O (Jones) OH
oxidation
d. Oxidation of ROH with: DMSO / ClOCCOCl / Et3N (Swern, many variations). Synthesis of aldehydes or ketones. O O O O O Et3N COCl C Cl C C C Cl O C Cl O S Cl H C CH 3 3 S S O H C CH DMSO H3C CH3 3 3 Cl oxalyl chloride
CH3 Et N 3 H H S O O O O CH3 C H C C H C CH C H C C 3 3 3 3 C H S O C H H2 H2 H H Cl Cl primary alcohols CH3 NEt S H 3 CH3 O C O H2 S CH3 H C C O CH 3 2 H C C C H 3 S H2 C H H H3C C H2 CH3 C H H2 H aldehydes
H DMSO / oxalyl chloride (Swern) OH oxidation O OH O DMSO / oxalyl chloride (Swern) oxidation
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 40
DMSO / oxalyl chloride no reaction (Swern) OH
OH DMSO / oxalyl chloride O (Swern) oxidation
O
OH DMSO / oxalyl chloride (Swern) H
oxidation
e. RCO2H with thionyl chloride. Synthesis of esters. Amides, thioesters and anhydrides (Need to make RCOCl with SOCl2 + acid.) There are a variety of approaches you could propose for this transformation. O Cl O Cl O Cl O O S S S Cl Cl Cl O O O C H S resonance resonance R O Cl Cl C H C H C H Base R O R O R O O Cl O S O Cl O Cl S Cl S O Cl O C R O C R C O R C O R O C acylium ion R O Cl H Base resonance
ester synthesis from acid chloride and alcohols O O Cl O Cl H O R O O Cl R O R R H H H O R There are many variations of ROH and H O RCO2H joined together by oxygen. O R H
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 41
amide synthesis from acid chloride and amines O Cl O Cl O R R R H N N N Cl R H H H H H N H 2
O
There are many variations of RNH2 or R2NH R and RCO2H joined together by nitrogen. R N H3N H
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 42 f. ROH with acid chlorides. Synthesis of esters. (Need to make RCOCl with SOCl2 + acid.) O O acyl substitution OH R Cl R O O acyl OH O substitution
R Cl R O
O acyl O substitution
R Cl OH R O O O acyl OH substitution
R Cl R O
O O acyl OH substitution
R Cl R O
g. RNH2 with acid chlorides. Synthesis of amides. (Need to make RCOCl with SOCl2 + acid.) O O acyl substitution NH R Cl R N 2 H
O O acyl NH2 substitution
R Cl R N H
O O acyl substitution R Cl R N NH2 H O O acyl NH2 substitution
R Cl R N H
O O acyl NH2 substitution R N R Cl H
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 43 h. RSH with acid chlorides. Synthesis of thioesters. (Need to make RCOCl with SOCl2 + acid.)
O O acyl substitution R Cl R S SH
O O acyl SH substitution
R Cl R S
O O acyl SH substitution R S R Cl
i. RCO2H with acid chlorides. Synthesis of anhydrides. (Need to make RCOCl with SOCl2 + acid.)
O O O O acyl substitution R O H H OH R Cl There is no 1C acid chloride, so the anhydride works as a substitute.
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 44 j. ROH with sodium hydride, NaH. Synthesis of sodium alkoxides.
OH O Na Na H acid/base
OH O Na Na H acid/base
k. ROH with sulfuric acid / heat. Synthesis of alkenes (our only useful E1 reaction. Rearrangement is possible).
H H H O SO3H OSO3H H O H O H
H (heat) H O O E1 H H O SO3H H slow step H OSO3H pK = -10 water is a good a H o secondary alcohol leaving group bp = +83 C bp = +161oC alcohol alkene distills out o Tbp = 78 C
H H H H O CH (heat) H H H 3 O CH3 O H H H O SO3H H3C C H3C C C C C C H rearrangement H slow step H pKa = -5 CH3 CH3 H o o alcohol 2 carbocation 3 carbocation
H3C H H3C C HO3S O H O H C CH3 alkene (E1 mechanism) CH3
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 45
OH H2SO4 / probably E2
OH H SO / 2 4 E1
H SO / 2 4 E1 OH
OH H2SO4 / E1
OH E1 H2SO4 /
l. Double elimination from dibromoalkanes to form alkynes and terminal acetylides used in many additional reactions (SN2 with RBr, C=O addition to aldehyses and ketones, and reaction with epoxides)
Br Br Br H 2 eqs. Br2 Na h H Na
N N H R R N R R H rd R R 3 equivalent H most stable a anion in mixture O H a H H Na 2. workup b 2. H2 C H2 Na C b X R R H S 2 O c N O H c CH H2OH 2. b R CH C Na R O R
b d d HO 2. H OH O 2 O Na
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 46
The zipper reaction moves a triple bond in an unbranched linear chain to the end and allows all of the above reactions. H2 C CH CH2 Na 2 C H N C C C R R C C R R R
H N R R R R H N H H Na H C C C C C C R R C H C C C R R C C H H H Na N H H H N R R R R R R N H C 2. workup C R H H C O C C H H H H R C H2
j. Formation of conjugate base + addition of epoxide electrophile forms an alkynyl alcohol via SN2 reaction.
1. NaNR2 2. O R
R OH
1. NaNR2 OH 2. O
1. NaNR2 OH 2. O
1. NaNR2 2. O
R OH R
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 47
Epoxide chemistry a. Epoxides with aqueous hydroxide (followed by workup = neutralization).
NaOH O HO H2O OH achiral 2. WK
O NaOH HO R H O OH 2 chiral R 2. WK
O NaOH OH H2O OH achiral 2. WK
S OH R NaOH R OH O H2O 2. WK S S OH S S S diastereomers R OH
b. Epoxides with alcoholic alkoxide (followed by workup = neutralization).
O RO / ROH HO OR achiral 2. WK
O HO R RO / ROH OR chiral R 2. WK
O RO / ROH OH OR achiral 2. WK
S OR R R OH O RO / ROH 2. WK S S OH S S S diastereomers R OR
c. Epoxides with aqueous acid. H SO / H O O 2 4 2 HO (H O+) 3 OH achiral 2. WK
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 48
O H2SO4 / H2O S + (H3O ) OH chiral R (inversion) 2. WK OH
O H2SO4 / H2O OH + (H3O ) OH achiral 2. WK
S OH R R OH H2SO4 / H2O O + (H3O ) S S OH S S 2. WK S diastereomers R OH
d. Epoxides with alcoholic sulfuric acid. H2SO4 / ROH O + HO (ROH2 ) OR achiral 2. WK
O H2SO4 / ROH S + OH (ROH2 ) chiral R (inversion) 2. WK OR
O H2SO4 / ROH + OH (ROH2 ) achiral OR 2. WK
S OR R H2SO4 / ROH R OH + O (ROH2 ) S S OH S S 2. WK S diastereomers R OR
e. Epoxides with cyanide (followed by workup = neutralization).
O NaCN HO DMSO C achiral 2. WK N
O HO R NaCN C DMSO chiral R N 2. WK
O NaCN OH N DMSO C achiral 2. WK
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 49
N R S C NaCN O DMSO and SRR S S 2. WK S S OH diastereomers
f. Epoxides with terminal acetylides (followed by workup = neutralization).
Na HO O R achiral 2. WK R
Na O HO R R chiral R 2. WK R
R O Na OH R achiral 2. WK R R Na S O R and SRR S S 2. WK S diastereomers S OH g. Epoxides with LiAlH4 (LAH) (followed by workup = neutralization).
1. LiAlH4 O 2. WK HO achiral
HO O chiral 1. LiAlH4 No inversion, 2. WK R S but priorities have changed.
O 1. LiAlH4 OH 2. WK achiral
No inversion, OH R but priorities 1. LiAlH4 have changed. O achiral 2. WK S S S not stereoismers R OH
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 50 h. Epoxides with NaBH4 (followed by workup = neutralization).
1. NaBH4 O 2. WK HO achiral
HO O chiral 1. NaBH4 No inversion, 2. WK R S but priorities have changed.
O 1. NaBH4 OH 2. WK achiral
No inversion, OH R but priorities have changed. 1. NaBH O 4 achiral 2. WK S S S not stereoismers R OH i. Epoxides with cuprates (followed by workup = neutralization).
O 1. (CH3)2Cu Li cuprate reagent HO achiral 2. WK CH3 HO O 1. (CH3)2Cu Li cuprate reagent achiral R 2. WK CH3
O 1. (CH3)2Cu Li OH cuprate reagent achiral 2. WK CH3
not stereoismers R OH R
1. (CH3)2Cu Li S CH3 O cuprate reagent 2. WK S R CH S S 3 S S OH
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 51 j. Epoxides with lithium diisopropyl amide (LDA, followed by workup = neutralization).
1. Li R OH R N R R O lithium diisopropylamide (LDA) 2. WK S S enantiomers 1. Li O N R R achiral lithium diisopropylamide (LDA) OH R 2. WK
1. Li O N OH R R lithium diisopropylamide (LDA) achiral 2. WK
not stereoismers R OH R 1. Li N O R R lithium diisopropylamide (LDA) S S S 2. WK S OH S k. Epoxides with Grignard reagents (followed by workup = neutralization).
1. H2 C O H3C H2C (MgBr) Grignard reagent HO achiral 2. WK
1. H2 HO O C H3C H2C (MgBr) chiral Grignard reagent R R 2. WK 1. H2 O C OH H3C H2C (MgBr) Grignard reagent achiral 2. WK S R 1. H2 C OH O H3C H2C (MgBr) S S OH R Grignard reagent S S 2. WK not stereoismers S R
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 52 l. Epoxides with organolithium reagents (followed by workup = neutralization).
1. H3C organolithium reagent HO O HC Li achiral
H3C 2. WK
1. H C organolithium reagent HO O 3 HC Li R chiral R H3C 2. WK
1. H3C organolithium reagent O OH HC Li achiral
H3C 2. WK
R organolithium reagent R 1. H3C R OH O HC Li S S S OH S S S H3C 2. WK not stereoismers
m. Epoxides with conjugate base of phthalimide (followed by hydrolysis and workup = neutralization).
O 1. NaOH N H HO O NH 2. epoxide O 2 achiral 3. NaOH 4. WK O 1. NaOH N H HO O chiral 2. epoxide O R R 3. NaOH NH 4. WK 2
O 1. NaOH N H O OH 2. epoxide O achiral 3. NaOH NH2 4. WK
O R 1. R NaOH NH2 R OH O N H
2. epoxide OH S S O S S S S NH2 3. NaOH not stereoismers 4. WK
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 53 a. Aldehydes and ketones in aqueous acid form carbonyl hydrates.
O H2SO4 / H2O HO OH + (H3O ) H carbonyl hydrate H
O H2SO4 / H2O + HO OH (H3O ) carbonyl hydrate
O OH H2SO4 / H2O + OH (H3O ) carbonyl hydrate
O OH H2SO4 / H2O + (H3O ) OH carbonyl hydrate
b. Aldehydes and ketones in aqueous base form carbonyl hydrates.
O NaOH HO OH H2O
H carbonyl hydrate H
O NaOH HO OH H2O
carbonyl hydrate
O OH NaOH OH H2O
carbonyl hydrate
O OH NaOH OH H2O
carbonyl hydrate
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 54 c. Aldehydes and ketones with Jones reagent. Converts aldehydes to carboxylic acids.
O CrO3 O acid / water Jones H OH
O CrO3 acid / water Jones No reaction with ketones.
d. Aldehydes and ketones with Zn/HCl (Clemmenson reduction).
O Zn / HCl
H Clemmenson reduction
O Zn / HCl
Clemmenson reduction
O Zn / HCl
Clemmenson reduction
O Zn / HCl
Clemmenson reduction
e. Aldehydes and ketones with hydrazine and base (Wolff-Kishner reduction).
O H2NNH2 / RO / D
H Wolff-Kishner reduction
O H2NNH2 / RO / D
Wolff-Kishner reduction O
H2NNH2 / RO / D
Wolff-Kishner reduction
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 55
O H2NNH2 / RO / D
Wolff-Kishner reduction
f. Aldehydes and ketones with LiAlH4 (LAH).
1. LiAlH4 O 2. WK achiral H OH
O OH 1. LiAlH4 2. WK enantiomers (R and S)
O OH OH
1. LiAlH4 2. WK
achiral diastereomers OH OH O 1. LiAlH4 R S 2. WK chiral enantiomers
g. Aldehydes and ketones with NaBH4.
O 1. NaBH4 2. WK achiral H OH
O OH 1. NaBH4 2. WK enantiomers (R and S)
O OH OH
1. NaBH4 2. WK
achiral diastereomers OH OH O R 1. NaBH4 S 2. WK chiral enantiomers
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 56 h. Aldehydes and ketones with cyanide, cyanohydrin synthesis or conjugate addition to alpha-beta unsaturated C=O.
OH O cyanohydrins 1. NaCN 2. acid addition C H enantiomers (R and S) N cyanohydrins O HO N C 1. NaCN 2. acid addition enantiomers (R and S)
cyanohydrins OH N O C
1. NaCN 2. acid addition achiral diastereomers
O O conjugate addition, R and S enantiomers 1. NaCN 2. acid addition
C N i. Aldehydes and ketones with terminal acetylides.
OH O Na 1. R 2. WK H enantiomers (R and S) R O Na enantiomers (R and S) R 1. R HO 2. WK
OH O Na R 1. R 2. WK achiral diastereomers
O OH Na 1. R R 2. WK
enantiomers (R and S)
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 57 j. Aldehydes and ketones with LDA makes enolates (carbanion nucleophiles).
O O enolate N Li R R lithium diisopropylamide (LDA) H H
O enolate O N Li R R lithium diisopropylamide (LDA)
O enolate O N Li R R lithium diisopropylamide (LDA)
O N Li O R R enolate lithium diisopropylamide (LDA)
k. Aldehydes and ketones with Grignard (Mg) reagents.
1. H2 OH O C H3C H2C (MgBr) Grignard reagent H 2. WK enantiomers (R & S)
O OH 1. H2 C H3C H2C (MgBr) Grignard reagent 2. WK enantiomers (R & S)
O OH 1. H2 C H3C H2C (MgBr) Grignard reagent 2. WK diastereomers (cis & trans) O OH 1. H2 C H3C H2C (MgBr) Grignard reagent 2. WK enantiomers (R & S)
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 58 l. Aldehydes and ketones with organolithium reagents.
OH 1. H3C O HC Li organolithium reagent H C H 3 2. WK enantiomers (R & S) OH O 1. H3C HC Li organolithium reagent
H3C 2. WK enantiomers (R & S)
O 1. H3C OH HC Li organolithium reagent
H3C 2. WK diastereomers (cis & trans)
O H C 1. 3 OH HC Li organolithium reagent
H3C 2. WK enantiomers (R & S)
m. Aldehydes and ketones with cuprates.
1. (CH ) Cu Li O 3 2 cuprate Cuprates react slowly with reagent ketones, esters and aldehydes. 2. WK H
O 1. (CH3)2Cu Li cuprate Cuprates react slowly with reagent ketones, esters and aldehydes. 2. WK
O 1. (CH3)2Cu Li cuprate Cuprates react slowly with reagent ketones, esters and aldehydes. 2. WK
O O 1. (CH3)2Cu Li cuprate reagent 2. WK conjugate addition to a,b-unsaturated CH carbonyl compounds 3
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 59 n. Aldehydes and ketones with secondary amines (enamine synthesis, alkylation, hydrolysis).
H
TsOH (-H2O) O N N E & Z possible 2o amines H H H O TsOH (-H2O) N N E & Z possible 2o amines
H O TsOH (-H2O) N N
2o amines achiral S R also possible H O TsOH (-H2O) N N
2o amines
o. Aldehydes and ketones with primary amines (imine synthesis).
O N NH2 TsOH (-H2O) H H E & Z possible
O N NH2 TsOH (-H2O) E & Z possible
O N
NH2 TsOH (-H2O) E & Z possible
O N
NH2 TsOH (-H2O)
E & Z possible
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 60 p. Aldehydes and ketones with ammonia + NaBH3CN = primary amine synthesis.
O 1. NH3 NH2 2. NaH3BCN 3. WK H
O 1. NH3 NH2 2. NaH3BCN 3. WK
q. Aldehydes and ketones primary amine + NaBH3CN = secondary amine synthesis.
1. O NH2 HN
2. NaH3BCN H 3. WK
O 1. NH2 HN
2. NaH3BCN 3. WK
r. Aldehydes and ketones secondary amine + NaBH3CN = tertiary amine synthesis.
1. O N NH 2. NaH3BCN H 3. WK
O 1. N NH 2. NaH3BCN 3. WK
s. Aldehydes and ketones ethylene glycol, acid, dehydration: ketal and acetal synthesis = protection).
O OH O HO O acetal = TsOH (-H2O) protected aldehyde H H
O OH O ketal = HO O protected ketone
TsOH (-H2O)
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 61
O O OH HO O TsOH (-H2O) ketal = protected ketone
O O OH HO
TsOH (-H2O) O ketal = protected ketone
t. Aldehydes and ketones with 1. LDA 2. RX = alkylation of C=O.
O
O 1. N Li R R H lithium diisopropylamide (LDA) H 2. RX (R = Me, 1o, 2o) R achiral
O 1. N Li O R R lithium diisopropylamide (LDA) R o o 2. RX (R = Me, 1 , 2 ) achiral enantiomers and diastereomers (RR, SS, RS, SR) O 1. N Li O R R lithium diisopropylamide (LDA) 2. RX (R = Me, 1o, 2o) R
R O 1. N Li R R O lithium diisopropylamide (LDA) 2. RX (R = Me, 1o, 2o) enantiomers (R and S)
u. Aldehydes and ketones with 1. LDA 2. epoxide = alkylation of C=O.
O
1. N Li O R R H lithium diisopropylamide (LDA) O OH 2. epoxide H S S
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 62
O 1. N Li O R R H lithium diisopropylamide (LDA) O 2. epoxide OH S
1. N Li O R R O lithium diisopropylamide (LDA) OH O 2. epoxide
S
v. Aldehydes and ketones with 1. LDA 2. another C=O = addition to C=O. Forms a beta hydroxyl carbonyl, which can be dehydrated in acid or base (with heat) to an ,-unsaturated carbonyl compound.
O 1. Li O N O R R lithium diisopropylamide (LDA) H O H acid H 2. carbonyl (-H2O) OH
Li O 1. O N O R R lithium diisopropylamide (LDA) O acid 2. carbonyl (-H2O) OH
1. Li N O O O R R acid lithium diisopropylamide (LDA) (-H O) O 2 2. carbonyl OH
w. Aldehydes and ketones with mCPBA (Baeyer-Villigar oxidation) to form esters (cyclic = lactones).
O O H O aldehyde forms O O carboxylic acid H meta chloroperbenzoic acid (mCPBA) OH
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 63
O O O H
O O meta chloroperbenzoic acid O (mCPBA) The better R+ group migrates better.
O O O H
O O O Cyclic esters meta chloroperbenzoic acid are called (mCPBA) lactones.
Show the products of the following miscellaneous reactions.
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc Typical First Year Organic Reactions Beauchamp 64 other possible reactions cuprates Sulfur ylids Phosphorous ylids (4 variations) Ketals / acetals Imines amines amides
y:\files\classes\Organic Chemistry Tool Chest\Reactions Lists\Org rxns summary, SN-E, C=O, epoxides chem, with mechs.doc