Reaction type

Reagent

Attacks at

Preference

Result

Mark / Anti

Syn / Anti

S_N2

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)

S_N1

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

HC―CH

N/A

Syn

Elec Add

H―X

(H attacks→ carbocation) Double bond

HC―CX

Mark

Anti

Elec Add

H⁺ (aq)

(H attacks) Double bond

HC―COH

Mark

Anti

Elec Add

BH₃; H₂O₂, OH^-

Double bond

Less sterically hindered

HC―COH

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

HOC―COH

N/A

Syn

Elec Add

HOT KMnO₄; OH^-

Double bond

COOH (both sides)

Elec Add

COLD KMnO₄; OH^-

Double bond

HOC―COH

N/A

Syn

Elec Add

HBr, peroxides

Double bond

HC―CBr

Anti

Anti

Elec Add

X₂

(X^- attacks) Double bond

Less sterically hindered side

XC―CX

N/A

Anti

Elec Add

X₂; Nu: (e.g. H₂O)

(X^- attacks) Double bond

Ring―less sterically hindered side

XC―CNu

Mark

Anti

Elec Add

Hg(OAc)₂; NaBH₄

Double bond

Ring―less sterically hindered side

HC―COH

Mark

Anti

Elec Add

mCPBA

Double bond

Ring―less sterically hindered side

Epoxide ( )

N/A

Syn

Elec Add

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

H­₂O, 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―C≡C―R

(through enol form) R―C―CO―R (terminal→ketone)

Mark (if not symmetric or terminal, get mix)

Hydroboration

BH₃ (or B₂H₆)

R―C≡C―R

R―C―CO―R

(terminal→aldehyde)

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

R′OH, H₃O⁺; dibal (cold)

R―COOH

(through ester)
R―CHO

Reduction

LiAlH₄, H₃O⁺

R―C≡N

R―CH₂―NH₂

Reduction

dibal, H₃O⁺

R―C≡N

R―CHO

Reduction

R′―Li, H₃O⁺ (aq)

R―C≡N

R―CO―R′

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)

H₂N―NH₂, 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)

R′₂CuLi (RLi+CuI); H₃O⁺

R―COCl

Only acyl chlorides

R―CO―R′

Decarboxylation

D

R―CO―CH₂―COOH

R―CO―CH₂, CO₂

Addition-Elimitnation

R′OH, H⁺ (only acid)

R―COOH
(―COR)

R―COR′

Addition-Elimitnation

R′OH, pyridine

R―COCl

R―COR′

Addition-Elimitnation

R′OH, ^-OH

R―CO―O―CO―R

R―COR′

Addition-Elimitnation

CH₂N₂

R―COOH

R―CO―OCH₂

Addition-Elimitnation

2 R′NH₂

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―CR′₂―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―CH₂―NR₂

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′

S_N2 azide amine synthesis

NaN₃; LiAlH₄ or H₂+Pd/C

R―Br

R―NH₂

S_N2/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―R′―CH₂―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—CH_2­Br

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

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