JEE Chemistry Organic Chemistry Some Basic Principles and Techniques Notes Set 25

Bond Breaking and Types of Attacking Species

In homolytic fission the shared pair is split equally, one electron to each atom, giving free radicals. In heterolytic fission both electrons go to one atom, giving a cation and an anion.
Reagents attack in one of three ways: as electrophiles (electron-deficient, accept a pair of electrons), as nucleophiles (electron-rich, donate a pair, always Lewis bases) or as radicals (species with an unpaired electron).
Electrophiles: positively charged ions such as H+, NO2+ and carbocations, and neutral species with an empty orbital such as BF3, AlCl3, SO3, PCl5 and carbenes.
Nucleophiles: CN-, OH-, halide ions, NH3, H2O, ROH, alkenes and arenes (pi electrons).
Radicals: CH3·, C2H5·, halogen atoms, alkoxy and acyloxy radicals.

Nucleophilicity versus Basicity

Nucleophilicity is the tendency to donate an electron pair to an electron-deficient carbon; basicity is the tendency to donate it to a proton. Both rise with electron density on the donor atom, but nucleophilicity also rises with polarisability and falls with steric crowding.
Along a period (same size of donor atom) the two orders agree and both fall left to right: CH3- > NH2- > OH- > F-.
Down a group basicity falls but nucleophilicity in a polar protic solvent rises: F- < Cl- < Br- < I- for nucleophilicity, while basicity runs F- > Cl- > Br- > I-. The large anions are polarisable and less tightly held by hydrogen bonding. In the same way RS- and HS- are better nucleophiles but weaker bases than RO- and HO-.
In a polar aprotic solvent (acetone, DMSO, DMF) the anions are not hydrogen bonded, so nucleophilicity follows basicity and the halide order reverses: F- > Cl- > Br- > I-.
When the donor atom is the same, nucleophilicity and basicity again agree: RO- > HO- > PhO- > RCOO-; HO- > H2O; NH2- > NH3. The more the negative charge is spread by resonance, the weaker the nucleophile.
Steric effect: a bulky base such as tert-butoxide is a strong base but a poor nucleophile because it cannot approach the carbon easily.
Ambident nucleophiles have two reactive sites, for example CN- (C or N), NO2- (N or O) and enolate ions (C or O).

Leaving Group Ability

A good leaving group is a weak base, because it is stable as an anion. A stable leaving group lowers the energy of the transition state and so speeds up the reaction.
Order for halides: I- > Br- > Cl- > F-. Across a period it runs the other way to basicity: F- > HO- > H2N- > H3C-. Other orders: RCOO- > PhO- > HO- > RO-; HS- > HO-.
Excellent leaving groups are the conjugate bases of strong acids: sulphonate ions (tosylate, mesylate), alkyl sulphate ions and the triflate ion CF3SO3-, which is a super leaving group. Water is a good leaving group (from protonated alcohols) while OH- is not.
Strong bases such as OH-, OR-, NH2- and carbanions are poor leaving groups, which is why alcohols need acid activation before substitution and why alkanes do not undergo substitution by loss of CH3-.
Two further points: the bond from carbon to the leaving atom should be weak, and the negative charge left behind should be stabilised by dispersal or delocalisation.

Types of Solvents

Polar protic solvents are polar and contain an O-H or N-H group that can donate a hydrogen bond: water, methanol, ethanol, formic acid, acetic acid, ammonia. They solvate anions strongly, which lowers the reactivity of small anions, and they stabilise carbocations and leaving groups, so they favour SN1 and E1.
Polar aprotic solvents are polar but have no acidic hydrogen: acetone, dimethyl sulphoxide (DMSO), dimethylformamide (DMF) and dimethylacetamide. They solvate cations but leave anions bare and very reactive, so they favour SN2.
Non-polar solvents: benzene, cyclohexane, pentane and other hydrocarbons.

Reactions of Acidic Hydrogen

Compounds with an acidic hydrogen (RCOOH, ArOH, ROH, H2O, terminal alkynes, amines in some cases) take part in acid-base reactions.
Carboxylic acids react with sodium, with alkalies, with sodium bicarbonate (evolving CO2) and with NaH (evolving H2): \( \ce{CH3COOH + NaHCO3 -> CH3COONa + CO2 + H2O} \).
A Grignard reagent behaves as a very strong base towards any Z-H group: \( \ce{RMgBr + Z-H -> R-H + Mg(Br)Z} \), where Z-H can be H-OH, H-OR, H-NR'2, a terminal alkyne C-H or the O-H of an acid. Because of this, Grignard reagents must be prepared and used in dry, hydroxyl-free conditions, and the alkane formed carries the R group of the reagent.

Nucleophilic Addition to Carbonyl Compounds

The carbon of C=O is electrophilic because oxygen is more electronegative, and it is sp2 hybridised and planar, so a nucleophile can attack from either face. The characteristic reaction of aldehydes and ketones is nucleophilic addition: a nucleophile adds to carbon and an electrophile (usually H+) adds to oxygen.
Base-catalysed path: the nucleophile attacks first to give an alkoxide, which then picks up a proton. Acid-catalysed path: the carbonyl oxygen is protonated first, which makes the carbon far more electrophilic, and then the nucleophile adds. Acid-catalysed addition is generally faster for weak nucleophiles.
Reactivity: HCHO > other aldehydes > ketones. Two reasons: the +I effect of alkyl groups reduces the positive charge on carbon, and bulky groups hinder the approach (steric effect). Aromatic aldehydes are less reactive than aliphatic ones because of resonance.

Addition of HCN. A little base generates CN-, the real nucleophile. The product is a cyanohydrin. Hydrolysis with acid gives an alpha-hydroxy acid; treatment with NH3 then hydrolysis gives an alpha-amino acid. With ketones the equilibrium is less favourable because of steric hindrance.
\( \ce{CH3CHO + HCN -> CH3CH(OH)CN} \)
Addition of Grignard reagent. The R group of RMgBr acts as a carbanion nucleophile; acid hydrolysis of the alkoxide gives an alcohol.
HCHO gives a primary alcohol (HCHO + CH3MgBr gives ethanol); any other aldehyde gives a secondary alcohol (CH3CHO + CH3MgBr gives propan-2-ol); a ketone gives a tertiary alcohol (butanone + C2H5MgBr gives 3-methylpentan-3-ol).

Nucleophilic Acyl Substitution

Carboxylic acids and their derivatives (acid chloride, anhydride, ester, amide) show nucleophilic acyl substitution, SN2Th, by an addition-elimination path. The nucleophile adds to the carbonyl carbon to form a tetrahedral intermediate; the C=O is then restored by expelling the better leaving group (the weaker base).
Conditions for substitution: the leaving group L must be a weaker base than the incoming nucleophile Nu; Nu must be nucleophilic enough to attack; the carbonyl carbon must be electrophilic enough. If Nu and L have similar basicity, a mixture of starting material and product results.
Reactivity order: acid chloride > anhydride > ester > amide, which is the order of decreasing leaving group ability (Cl- > RCOO- > RO- > NH2-) and also of decreasing electrophilicity of the carbonyl carbon.

Reactions of carboxylic acids.
Acid chlorides: \( \ce{RCOOH + SOCl2 -> RCOCl + SO2 + HCl} \) (PCl5 and PCl3 also work).
Fischer esterification: \( \ce{RCOOH + R'OH <=> RCOOR' + H2O} \) under acid catalysis. The mechanism is protonation of C=O, attack by the alcohol, proton transfer and loss of water. The reverse of the same steps is acid-catalysed ester hydrolysis. To make the ester use excess alcohol and remove water; to hydrolyse it use a large excess of dilute aqueous acid and reflux.
Amides: a carboxylic acid and an amine just form an ammonium salt; the salt must be heated strongly to lose water. For example benzoic acid with NH3 gives the ammonium salt and then, on strong heating, benzamide. Amides are therefore usually made from acid chlorides or anhydrides instead.