Markovnikov = nucleophile goes to more substituted carbon (because of carbocation intermediate)

Reaction type

Reagent

Attacks at

Preference

Result

Mark / Anti

Syn / Anti

SN2

Nu:

Leaving Group

Aprotic solvent; 1°, 2° carbons

C―Nu (inversion)

   

Hydroxyl activation

SOCl2, PBr3

―OH

 

C―Cl or C―Br (inversion)

   

Hydroxyl activation

OTs―Cl

―OH

 

C―OTs (retention)

   

SN1

Nu:

Carbocation

Protic solvent;

Good LG, bad Nuc; 2° (mostly allylic & benzylic), 3° carbons

C―Nu (racemic), LG-

   

Hydroxyl activation

H+

―OH

 

Carbocation

   

Elimination (E1, E2)

Good base, bad Nuc (e.g. bulky)

H, LG―anti

More substituted double bond

C=C

   

Hydrogenation

H2, Pd

Double bond

Less sterically hindered side

HCCH

N/A

Syn

Elec Add

H―X

(H attacks carbocation) Double bond

 

HCCX

Mark

Anti

Elec Add

H+ (aq)

(H attacks) Double bond

 

HCCOH

Mark

Anti

Elec Add

BH3; H2O2, OH-

Double bond

Less sterically hindered

HCCOH

Anti (b/c B (OH) is elec but OH is nuc)

Syn

Elec Add

O3; Me­2S

Double bond

 

C=O (both sides)

   

Elec Add

O3; H2O2, OH-

Double bond

 

COOH (both sides)

   

Elec Add

OsO4; Me2S

Double bond

 

HOCCOH

N/A

Syn

Elec Add

HOT KMnO4; OH-

Double bond

 

COOH (both sides)

   

Elec Add

COLD KMnO4; OH-

Double bond

 

HOCCOH

N/A

Syn

Elec Add

HBr, peroxides

Double bond

 

HC―CBr

Anti

Anti

Elec Add

Ring-forming

X2

(X- attacks) Double bond

Less sterically hindered side

XCCX

N/A

Anti

Elec Add

Ring-forming

X2; Nu: (e.g. H2O)

(X- attacks) Double bond

Ring―less sterically hindered side

XCCNu

Mark

Anti

Elec Add

Ring-forming

Hg(OAc)2; NaBH4

Double bond

Ring―less sterically hindered side

HCCOH

Mark

Anti

Elec Add

Ring-forming

mCPBA

Double bond

Ring―less sterically hindered side

Epoxide ( )

N/A

Syn

Elec Add

Ring-forming

mCPBA; strong Nuc

Double bond

Ring―less sterically hindered side

HOC―CNu

Anti

Anti

Oxidation

CrO3, H2SO4, propanone, 0°C; or CrO3, pyridine, HCl (PCC) and CH2Cl2, CH3COONa

―OH

 

C=O

   

Oxidation

MnO2, CHCl3

―OH

Must be allylic

C=O

   

Nuc Add
Strong Nuc

(Reduction)

R―Li or ―MgBr

Carbonyl carbon

 

CRO- (or CROH in H3O+)

   

Nuc Add
Weak Nuc
Reversible

ROH (or HOH); for protection: HOEtOH or HSEtSH

Carbonyl carbon

Catalysis: acid protonates O, while base activates Nuc

COROH (hemiacetal); in acid, may be COROR (acetal)

   

Thioacetal hydrolysis

2O, HgCl2, CaCO3, CH3CN

Protection by HSEtSH

 

C=O

   

Desulfurization

Raney Ni, H2

Protection by HSEtSH

 

H―C―H

   

Nuc Add

R―NH2 or R2NH, -H2O

Carbonyl carbon

 

C=N―R (imine)
or C=C―NR2 (enamine)

   

Wolff-Kishner Reduction

NaOH, (EtOH)2O, heat

C=N―NH2

 

H―C―H, N2 (g)

   

Nuc Add

CN-, HCl

Carbonyl carbon

 

HO―C―CN

   

Wittig Reaction

Ph3P=R

Carbonyl carbon

 

C=R

   

Proton Exchange (Elec Add)

D2O, acid/base

α-H to Carbonyl

 

α-D to Carbonyl (all of them)

   

Racemization

Acid/base

α-Stereocenter to Carbonyl

 

Racemic mix at center

   

Elec Add (Halogenation)

X2, acid/base

α-H to Carbonyl

 

α-X to Carbonyl (more than one if in base)

   

Elec Add (Alkylation)

R―X, base (LDA)

α-H to Carbonyl or enamine or ester

 

α-R to Carbonyl (multiple)

   

Elec Add (Aldol Condensation)

Base, (other carbonyl)

Carbonyl carbon

 

HO―C―C―C=O

   

Hydration

H3O+ (aq)

R―CC―R

 

(through enol form) R―C―CO―R (terminalketone)

Mark (if not symmetric or terminal, get mix)

 

Hydroboration

BH3 (or B2H6)

R―CC―R

 

R―C―CO―R

(terminalaldehyde)

Anti

 

Oxidation

KMnO4, cold & mild

C=C

 

C=O, O=C

   

Oxidation

PCC

R―CH2OH (1° or 2° alcohol)

 

R―CHO

   

Oxidation (Tollens Reaction)

Ag+

R―CHO (only aldehyde group)

 

R―COOH

   

Oxidation (Baeyer-Villiger)

R―CO―OOH (esp R = CF3)

R1―CO―R2

R2: 3° > 2° > 1° > CH3

R1―CO―OR2

   

Reduction

ROH, H3O+; dibal (cold)

R―COOH

 

(through ester)
R―CHO

   

Reduction

LiAlH4, H3O+

R―CN

 

R―CH2NH2

   

Reduction

dibal, H3O+

R―CN

 

R―CHO

   

Reduction

R―Li, H3O+ (aq)

R―CN

 

R―CO―R

   
Hydrolysis H3O+, D R―CN   R―COOH    

Nuc Add
Strong Nuc (Reduction)

LiAlH4 in ether or NaBH4 in MeOH

Carbonyl carbon

NaBH4 doesn't react <= esters

C―OH

   

Reduction

H2/Ni, high temp & press

Carbonyl carbon

Will destroy double bonds

Alcohol

   

Reduction (Wolff-Kishner)

H2NNH2, KOH, heat

Carbonyl carbon

 

(through hydrazone) CH2 (regular alkane)

   

Addition-Elimination

SOCl2

Carboxyl carbon

 

COCl

   

Reduction

H2/Pd-C or LiAl(tBu)3H

R―COCl

 

R―CHO

   

Addition-Elimination (Gillman Reagent)

R2CuLi (RLi+CuI); H3O+

R―COCl

Only acyl chlorides

R―CO―R

   

Decarboxylation

D

R―CO―CH2―COOH

 

R―CO―CH2, CO2

   

Addition-Elimitnation

ROH, H+ (only acid)

R―COOH
(―COR)

 

R―COR

   

Addition-Elimitnation

ROH, pyridine

R―COCl

 

R―COR

   

Addition-Elimitnation

ROH, -OH

R―CO―O―CO―R

 

R―COR

   

Addition-Elimitnation

CH2N2

R―COOH

 

R―CO―OCH2

   

Addition-Elimitnation

2 RNH2

R―COCl

 

R―CO―NH―R

   

Nucleophilic Addition

R―MgBr

CO2

 

R―COOH

   

Addition-Elimination (Hydrolysis)

Aqueous acid/base

R―CO―NR2

R―CO―OR

R―CN

R―CO―O―CO―R

 

R―COOH

   

Add-Elim + Elec Add
(Claisen Condensation)
(Dieckmann Cond. intermolecularly)

NaOR

2 R―CO―OR

 

β-keto ester (alpha carbon attached to carbonyl) salt (work up in H3O+)

   

Add-Elim

2 R―MgBr; H3O+

R―CO―OR

 

R―CR2―OH

   

Add-Elim + Elec Add
(Hell-Vollhard-Zelinsky)

P, Br2 (PBr3)

R―COOH

 

RBr―COOH (Br on α-C)

   

Add-Elim (Reduction)

LiAlH4; H3O+

R―CO―OR

 

R―COH

   

Add-Elim (Reduction)

LiAlH4; H3O+

R―CO―NR2

(3° amides only)

R―CH2NR2

   

Add-Elim (Reduction)

dibal; H3O+

R―CO―NR2

(3° amides only)

R―CHO

   

Add-Elim (Reduction)

POCl3

R―CO―NH2

 

R―CN

   

Elec Add + Add-Elim
(Haloform)

I2/Br2, -OH

R―CO―Me

Methyl ketones only

R―COOH, HCI3/HCBr3

   

Reductive Amination

R―CHO; NaBH3CN

R―NH2

 

R―NH―R

   

SN2 azide amine synthesis

NaN3; LiAlH4 or H2+Pd/C

R―Br

 

R―NH2

   

SN2/Hydrolysis (Gabriel) amine synthesis

, -OH; -OH/H2O, D

R―Br

 

R―NH2

   

Nuc Add + Elec Add (Mannich)

R―CO―R, HCHO, H2N―R

   

R―CO―R―NH―R

   

Diels-Alder

H2C=CH―CH=CH2 (diene, s-ciscoid)

H2C=CH2 (dienophile)

Good dienes have EDGs; good dienophiles have EWGs. Addition is endo (EWG underneath diene)

Cyclohexene (Double bond forms (between) where diene used to be)

   

Slipping the double bond into conjugation

-OH/H2O

R=CH―CH2―CO―R (β-γ unsat.)

 

R―CH=CH―CO―R (α-β unsat.)

   

Cuprate nuc addition

R2CuLi

R=CH―CO―R′′

 

R―RCH2―CO―R′′

   

[1,4] (Michael) Addition

NaOMe

R―CO―R, R=CH―CO―R′′

 

R―CO―R―R―CH―CO―R′′ (1,5-diketone)

   

[1,4] Add + Aldol (Robinson Annulation)

-OH, D

R―CO―R, R=CH―CO―R′′

 

2-cyclohexenone (α-β unsat. cyclic ketone)

   

Electrophilic Aromatic Substitution

(Halogenation of Aromatics)

Br2/FeBr3 or Cl2/AlCl3

Ar

EWG are meta-directing

Halogens and EDG are ortho/para-directing

Can’t do on aniline—dihalogenation!

ArX

   

Electrophilic Aromatic Substitution

(Nitration of Aromatics)

HNO3/H2SO4

Ar

EWG are meta-directing

Halogens and EDG are ortho/para-directing

ArNO2

   

Electrophilic Aromatic Substitution

(Sulfonation of Aromatics)

SO3/H2SO4

Ar

EWG are meta-directing

Halogens and EDG are ortho/para-directing

Can’t do on unprotected amines!

ArSO3H

   

Electrophilic Aromatic Substitution

(Friedel-Crafts Alkylation)

R—Cl / AlCl3

Ar

Tends to form multiple alkylation products (alkyl chains are mildly activating)

Ar—R

   

Electrophilic Aromatic Substitution

(Friedel-Crafts Acylation)

R—CO—Cl / AlCl3

Ar

Can’t do on nitrobenzene—too deactivated!

Ar—CO—R

   

Nucleophilic Aromatic Substitution

-OH or -OR

Ar—X

Need EWG o/p to good leaving group

Ar—OH

   

Benzyne formation

KNH2

Ar—X

Must use immediately (e.g. in Diels-Alder or addition)

   

Oxidation of alkyl side chains

KMnO4, H2O

Ar—CH3

Requires benzylic C—H

Ar—COOH

   

Oxidation of alkyl side chains

CrO3, H2SO4, H2O

Ar—CH2—R

 

Ar—CO—R

   

Bromination of alkyl side chains

NBS, peroxides

Ar—CH3

Requires benzylic C—H (radical mechanism)

Ar—CHBr

   

Debromination

HBr, Na2SO3

o/p-NH2,Br—Ar

 

Ar—NH2

   

Reduction of benzylic carbonyls

H2/Pd

Ar—CO—R

 

Ar—CH2—R

   

Reduction of nitro group

H2/Pd; or 1) Zn/Hg, HCl 2) -OH; or 1) Fe, HCl 2) -OH (the last will not reduce ketones)

Ar—NO2

 

Ar—NH2

   

Removal of sulfonate

H3O+, D

Ar—SO3H

 

Ar—H

   

Oxidation of amino group

CF3CO3H

Ar—NH2

 

Ar—NO2

   

Oxidation to benzylic aldehyde

DMSO, Et3N

Ar—CH2Br

 

Ar—CHO

   

Oxidation to benzylic aldehyde (Étard Reaction)

CrO2Cl2

Ar—CH3

Will also oxidize alcohols

Ar—CHO    

Oxidation to benzylic aldehyde

1) DMF 2) H3O+

Ar—Li

 

Ar—CHO

   

Diazonium cation formation

HCl, NaNO2 (0 °C)

Ar—NH2

 

Ar—NºN+ Cl-

   

Sandmayer reaction

CuCl (60 °C)

Ar—N2+ Cl-

 

Ar—Cl

   

Sandmayer reaction

CuBr (60 °C)

Ar—N2+ Br-

 

Ar—Br

   

Sandmayer reaction

CuCN, KCN, D

Ar—N2+ Cl-

 

Ar—CN

   

Reduction of diazonium cation

H3PO2, H2O

Ar—N2+ Cl-

 

Ar—H

   

Add-Elim

H2O, D

Ar—N2+ Cl-

 

Ar—OH

   

Electrophilic Aromatic Substitution

 

Ar—N2+ Cl- + Ar¢

other aromatic needs EDG o/p

Ar—N=N—Ar¢

   

Reduction of Aromatic Ethers

H2/Pd

Ar—CH2—O—R

 

Ar—CH3, ROH

   

Claisen Rearrangement

 

6 p e- in almost ring formation (esp. double bond, 3 single bonds, double bond)

 

Single bond rearrangement

   

Electrophilic Aromatic Substitution

NaNO2, H2SO4/SO3, 300 °C

6-membered aromatic heterocycle (e.g. pyridine): Ar

Reacts at “m”—3 position

Ar—NO2

   

Electrophilic Aromatic Substitution

Br2, H2SO4/SO3, 300 °C

6-membered aromatic heterocycle (e.g. pyridine): Ar

Reacts at “m”—3 position

Ar—Br

   

Electrophilic Aromatic Substitution

(Chichibabin Reaction)

NaNH2, NH3; H+/H2O

6-membered aromatic heterocycle (e.g. pyridine): Ar

Reacts only at 2 position; leaving group is H-

Ar—NH2

   

Electrophilic Aromatic Substitution

R—Li

6-membered aromatic heterocycle (e.g. pyridine): Ar

Reacts only at 2 position; same mechanism as Chichibabin

Ar—R