Chem 5011

organic chemistry

Huckle's rule

Planar, fully conjugated, monocyclic systems (one ring of p orbitals) with (4n + 2) pi electrons have a closed shell of electrons all in bonding orbitals and are exceptionally stable. Such systems are said to be aromatic.

Analogous systems with 4n pi electrons are described as anti-aromatic

General Electrophilic aromatic substitution (SEAr) of benzene

Bromination/chlorination of benzene reaction scheme

Bromination/chlorination of benzene generation of electrophile

Bromination/chlorination of benzene mechanism

Nitration of benzene reaction scheme

Nitration of benzene generation of electrophile

Nitration of benzene mechanism

Sulfonation of benzene: reaction mechanism

Sulfonation of benzene: generation of electrophile

Sulfonation of benzene: mechanism

Desulfonation: reaction scheme

Desulfonation: mechanism

Friedel-crafts alkylation: reaction scheme

Friedel-crafts alkylation: generation of electrophile

Friedel-crafts alkylation: mechanism

Friedel-crafts acylation: reaction scheme

Friedel-crafts alkylation: alternatives to RCl/AlCl3

Friedel-crafts acylation: generation of electrophile

Friedel-crafts acylation: mechanism

Friedel-Crafts acylation to access to primary alkyl groups: Clemmensen reduction -> reaction scheme

Friedel-Crafts acylation to access to primary alkyl groups: Wolff-Kishner reduction -> reaction scheme

Friedel-Crafts acylation to access to primary alkyl groups: Wolff-Kishner reduction -> mechanism

Effects of substituents on rate of SEAr reaction: Electron donating groups

• Donate electron density to the benzene ring

• Activating groups (double bond more nucleophilic)

• EDG-substituted benzene more reactive than benzene

• Examples of EDG: NR2 , OR, SR, alkyl, aryl

Effects of substituents on rate of SEAr reaction: Electron withdrawing groups

• Withdraw electron density from the benzene ring

• Deactivating groups (double bond less nucleophilic)

• EWG-substituted benzene less reactive than benzene

• Examples of EWG: NO2, SO3H, CO2R, C=O, CN, CF, halides

How to identify EWG

Double bonds from benzene ring can be delocalised onto electronegative atom of

substituent, revealing a positive charge in the benzene ring

Other EWG: perfluoro alkyl groups by negative inductive effect (also called negative

hyperconjugation)

How to identify EDG

Lone pair on EDG can be delocalised revealing a negative charge in benzene ring:

lone pair donation

Other EDG: alkyl groups by pi-donation also called positive inductive effect or

hyperconjugation

Activating ortho/para (o/p) directing groups (R = EDG)

• Positive mesomeric effect (lone pair or π-bond donation): +M

• Examples: OH, OR, NR2

, SR, Ph

• Positive inductive effect (σ bond donation): +I

• Example: Alkyl groups

Deactivating meta (m) directing groups (R = EWG)

• Negative mesomeric effects (delocalisation of benzene double

bonds onto R group): −M

• Examples: NO2, SO3H, CO2R, C=O, CN

• Negative inductive effects (through σ bond): −I

• Examples: CF3 (and fluoroalkyls)

Deactivating ortho/para (o/p) directing groups (R = halogen)

+M (lone pair donation) and −I (electronegativity of halogen)

Dose mesomeric or inductive effects have a greater effect on directing effect?

generally M > I

Reactivity of multisubstituted benzenes: Rules to predict outcome

Consider the directing effects of each group in turn. You never get substitution

at a position that is occupied with a group

• +M more directing than +I more directing than −M more directing than −I

(+M > +I > −M > −I)

• “Never” get substitution between two meta substituents.

• Sterics can also have an impact

Nucleophilic aromatic substitution (SNAr) general reaction scheme

Three different classes of reaction (different mechanisms) of S_NAr

• Diazonium (S_N1) → Diazonium chemistry Only N₂ is a good enough leaving group (LG)

• Addition/elimination → No SN2 on sp2 carbon Analogous to nucleophilic substitution reaction with carbonyls

• Benzyne → Strained triple bond, Very reactive

SNAr: SN1 pathway (synthesis of diazonium ions) → Reaction scheme

SNAr: SN1 pathway (synthesis of diazonium ions) → formation of nitrosium ion

SNAr: SN1 pathway (synthesis of diazonium ions) → formation of diazonium ion

SNAr: SN1 pathway (reaction of diazonium ions) → general reaction scheme

SNAr: SN1 pathway (reaction of diazonium ions) → phenol synthesis

SNAr: SN1 pathway (reaction of diazonium ions) → Substitution with H using phosphinic acid

Diazonium chemistry: Sandmeyer reaction → reaction scheme

Diazonium chemistry: Sandmeyer reaction → mechanism

SNAr: Addition/elimination pathway → general reaction scheme

SNAr: Addition/elimination pathway → important to remember

• SN2 not possible on sp2 carbon

• Nu: H2O, NR2, ROH, CN-

• EWG = NO2, CF3, SO3R, CO2R

• LG (generally): Cl-, F-

• LG ability is unimportant (not involved in RDS)

SNAr: Addition/elimination pathway → mechanism

What if the EWG is Meta to the LG?

SNAr addition/elimination: influence of leaving group (LG)

• Leaving group (LG) ability DOES NOT matter: LG does not depart in rate determining step (RDS)

• But: nature of LG still influences the reaction

• Electronegative LG (- I effects) make C attached to LG electrophilic (δ+):

• favours Nu attack on C in RDS: increased reaction rate

• If LG = halide, reactivity goes as follows: F > Cl > Br > I

• LG- must be a better leaving group than Nu-

What is benzyne?

• Strained triple bond

• Benzyne π-bond (in the plane of the benzene ring) not conjugated with aromatic system (perpendicular to it)

• Very reactive

• Cannot be isolated (formed in situ)

• Electrophilic: reacts with poor nucleophiles

• Can react in concerted reactions (alkene-like)

Formation of benzyne

S_NAr benzyne pathway: the benzyne reaction → Example: Synthesis of aniline → reaction scheme

SNAr benzyne pathway: the benzyne reaction → Example: Synthesis of aniline → mechanism

The nucleophile can attack at either end of the triple bond.

SNAr benzyne pathway: evidence for a benzyne intermediate

Pyridine

• Fully conjugated, monocyclic ring of p orbitals, 6 π electrons (& flat): aromatic

• Lone pair (in sp2 orbital) is not in π system

• Reactive in SEAr and SNAr

Not (very) reactive in SEAr (unless activated with electron donating groups)

• N atom is more electronegative than C:

• lower electron density in ring

• lower energy π orbitals (compared to benzene), so more stable (less reactive)

• double bond less nucleophilic

• Nitrogen lone pair interacts with chemicals necessary for SEAr

• N-directing effects: directs substitution at 3-/5-positions (Wheland intermediate less

stabilised if substitution at 2-/4-/6-positions)

Very reactive towards SNAr

• SNAr occurs with LG in 2- or 4-position

• Even with moderate nucleophiles (H2O)

Activated Pyridines: Electrophilic Aromatic Substitution (EArS) → reaction scheme

Activated Pyridines: Electrophilic Aromatic Substitution (EArS) → genration of electrophile

Activated Pyridines: Electrophilic Aromatic Substitution (EArS) → mechanism

Pyridines: nucleophilic aromatic substitutions (NArS) → reaction scheme

Pyridines: nucleophilic aromatic substitutions (NArS) → mechanism

Pyridine N-oxides

• Aromatic (3 double bonds = 6 π electrons, flat

monocyclic ring of p orbitals, fully conjugated)

• Stable compound

• Increased electron density

• Reactive in SEAr and SNAr

SEAr

• N-oxide:

• Activating group

• 2- (ortho) and 4- (para) directing

• 4-position preferred

SNAr

• N-oxide

• Stabilises intermediate of SNAr (addition elimination mechanism when LG at 2-and 4-positions only

• Alternative SNAr possible when LG = H (giving a pyridine product)

Pyridine N-oxides: SEAr → Reaction scheme

Pyridine N-oxides: SEAr → mechanism: pyridine N - oxide synthesis

Pyridine N-oxides: SEAr → mechanism: generation of electrophile

Pyridine N-oxides: SEAr → mechanism: SEAr and removal of N-oxide group

Pyridine N-oxides: example of a different SNAr → reaction scheme

Pyridine N-oxides: example of a different SNAr → mechanism

Pyrrole

SEAr of pyrrole: regioselectivity

SEAr of pyrrole: Mannich reaction → Reaction scheme

SEAr of pyrrole: Mannich reaction → generation of electrophile

SEAr of pyrrole: Mannich reaction → mechanism

SEAr of pyrrole: Vilsmeier reaction → recation scheme

SEAr of pyrrole: Vilsmeier reaction → generation of electrophile

SEAr of pyrrole: Vilsmeier reaction → mechanism

Indole

Furan

Alkene as a nucleophile reacting with bromine → mechanism

Epoxidation of alkenes → mechanism

Stereochemistry of epoxidation of alkenes

How to achive different carbonyl oxidation sates via ozonolysis

Hydroboration → reaction scheme

Hydroboration of unsymmetrical alkenes

• boron adds to the less substituted carbon

• Two contributing factors to the selectivity:

1. Electronics: the reaction is governed by donation of the p-electrons into the empty p-orbital. The resultant positive charge is stabilised at the other end of the alkene.

2. Sterics: BR2 is larger than H, and therefore to minimize steric repulsion, the larger group is directed away from the substituent.

Hydroboration → addition pf borane mechanism

Hydroboration → addition of hydroxyl group → mechanism

Radical reactions → addition of HBr

• switches selectivity → bromine adds to less substituted carbon

Allylic radical bromination → reaction scheme

Allylic bromination (radical) → mechanism

Radical reactions → C-C bond formation

E1 and E2 elimination mechanisms

anit- vs syn- periplanar Newman projections

stereospecificity of E2 elimination

dehydration of alcohols →E1

Stereospecificity of E1

Wittig reaction → reaction scheme

Wittig reaction → mechanism

Wittig reaction → changing stereoselectivity

Wittig reaction → Z selective reasoning

Wittig reaction → E selective reasoning

Julia olefination → reaction scheme

Julia olefination → starting material production

Julia olefination → formation of alkene