Terms and Terminologies in Mechanistic Organic Chemistry

Key words: Acids, bases, nucleophiles, electrophiles, Hardness-Softness (HSAB) concepts Introduction

In this module, some very basic terms and terminologies are described. Historical perspectives and origin of some of the concepts are presented. Concepts such as electrophiles, nucleophiles, hardness and softness etc., are discussed.

These concepts are of high significance to the following modules under reaction Mechanisms. The term acid • It comes from the Latin root ac, was first used in the seventeenth meaning sharp, as in acetum i.e. century. vinegar.

• a characteristic sour taste Acids have long been recognized • ability to change the color of as a distinctive class of litmus from blue to red compounds whose aqueous • react with certain metals to solutions exhibit produce gaseous H2 the following properties. • react with bases to form a salt and water.

First definition • According to his definition, acids of acid was are substances containing common given by element which gives that Antoine compound the acidic nature. Lavoisier, in • And he postulated that element to 1787. be oxygen. In 1811, • By 1830, dozens of oxygen free Humphrey Davy acids had been discovered. showed that muriatic acid • But it was only after 1840, the (HCl) does not hydrogen theory of acid became contain oxygen. generally accepted.

In 1890, the • According to his theory, acid is a Swedish chemist substance containing hydrogen Svante Arrhenius atom, that can dissociate or ionize, formulated the when dissolved in water, first important producing hydrated hydrogen ion theory of acids. and an anion.

However, there are substances • Hence, definition of acid was which do not contain H, but modified to “a substance that still yield H+ yields an excess of hydrogen ions ions when when dissolved in water.” dissolved in water. • HCl is a strong acid, it dissociates completely in water.

H O 2 + - HCl H3O + Cl

• H2SO4 is a polyprotic acid, it dissociates completely in water in two stages.

H2O + - HCl H2SO4 H3O + HSO4

H2O - + 2- HSO4 H3O + SO4

• Acetic acid is a weak acid, it does not dissociate completely in water.

H O 2 + - CH3COOH H3O + CH3COO ‘Base’ , as • The word alkali is synonymous defined by Arrhenius, is with base. It is of Arabic origin, but substance that the root word comes from the same yields excess of Latin kalium i.e., potash OH- ions when dissolved in • Alkali more specifically used for water. those containing OH- ions.

• a bitter taste The name base • a soapy feeling when applied to the has long been associated with a skin class of • ability to restore the original blue compounds color of litmus that has been turned whose aqueous solutions are red by acids characterized by • ability to react with acids to form salts.

H2O NaOH, KOH, + - oxides of certain NaOH Na + OH metal and hydrogen H2O compound of CaO Ca2+ + 2OH- certain nonmetals are classified as H O 2 + - Arrhenius bases. NH3 NH4 + OH Although Arrhenius gave useful definition of acid and base, • acidic nature of FeCl3 he could not • basic nature of NH , Na S justify nature of 3 2 certain substances.

In 1923, a • Danish chemist J.N. Bronsted theory that is and English Chemist T.M.Lowry, both simple and put forward, independently, the more general was proposed by proton donor-acceptor concept. two chemists.

According to this concept, acid is a proton • Definition makes no reference to donor whereas the environment in which proton base is a proton transfer takes place, so that it acceptor. applies to all kinds of reaction. Reaction • If the acid is denoted by AH and between acid and base is thus the base by B, then we can write a a proton generalized acid-base reaction as exchange reaction. AH + B A- + BH+

• It gives rise to a very important concept of conjugate acid-base In this reaction, pair. the protonated base formed is • Conjugate pair differ by one capable of proton. losing H+ ions in • Conjugate acid and base are in the solvent. equilibrium in solution.

acid1 + base2 base1 + acid2

Some common conjugate acid-base pairs Substance Acid Conjugate Thus, the base protonated base Hydrochloric acid HCl Cl- - is another Acetic acid CH3COOH CH3COO potential acid Nitric acid HNO - and anion of 3 NO3 Ammonium + NH first acid is NH4 3 another potential chloride - base. Water H2O OH + Hydronium ion H3O H2O The stronger an acid is, the • Table showing examples of weaker its strong and week conjugate acid conjugate base will be and vice base pairs. versa.

Many • For example water is a Bronsted- substances can Lowry base in its reaction with Proton act as an acid in Acid one reaction and HCl and an acid in its reaction as a base in with NH . another are 3 Base + - called HCl + H2O -----> H3O + Cl amphoteric. + - H2O + NH3 -----> NH4 + OH

Another • In fact the amino acids usually important group of amphoteric species exist in zwitterion form, where the is the amino acids. proton has transferred from Each amino acid molecule contains the carboxyl to the amino group.

an acidic carboxyl NH2 group and a basic NH3 R CH COOH amino group. R CH COO The Bronsted- • But still it fails to explain Lowry theory is reactions between substances that more general show similar features but no than any that protons are transferred in the preceded it. reaction.

This deficiency was overcome by more general • According to this concept, acid is concept proposed by an electron pair acceptor while American base is an electron pair donor. chemist, G N Lewis in 1923.

The acid-base • If acid is denoted by A and base reaction is by B:, then acid-base reaction sharing of between them is formation of electrons between the adduct A-B. two. A + B: A B The principal advantage of the • Therefore the number of acid- Lewis theory is the way it base reactions are also in majority expands the in relation to this theory. number of acids.

Various molecules, ions, • A classical example is formation etc., can be of adduct between molecules BH3 grouped as acid and NH3. according to this theory. BH3 + :NH3 H3B-NH3

Like BH3, acidic • Al3+, thus exhibits acidic properties of various other properties as it can accept lone pair molecules and of electrons from water molecule ions can be in the hydration reaction. explained using 3+ 3+ Lewis theory. Al + 6H2O: [Al(H2O)6] The Lewis acid- base theory can • In the course of the reaction, also be used to water molecule acts as a base explain why nonmetal oxides donating a pair of electrons to such as CO2 carbon in CO2 molecule. dissolve in water to form acids. CO2(g) + H2O H2CO3(aq)

+ The proton (H+) • Ignoring the fact that H is is one of the solvated, acid-base reactions of H+ strongest but can be viewed as formation of also one of the adduct. most + - complicated H + OH H2O Lewis acids. + + H + NH3 NH4

Nearly all compounds of • Many Lewis bases are transition metals multidentate, i.e., they can form can be viewed several bonds to the Lewis acid. as a collections These multidentate Lewis bases of the Lewis bases. are called chelating agents. • Reactions like, The acid-base - - nomenclature FeCl3 + Cl ------> FeCl4 can create are a little confusing viewed as the confusion with acid (FeCl3) being a species Bronsted lacking an octet, (Fe3+) is a neutral nomenclature. species.

Molecular orbital The reactions can be viewed as • a filled atomic or molecular interpretation involving the orbital on the base interaction of molecular orbitals • an empty atomic or molecular on the base and the acid. orbital on the acid.

The filled orbital • Then we refer to the reaction would be the highest energy occupied simply as a filled-empty molecular orbital, the HOMO, and the interaction or a HOMO-LUMO empty orbital will be interaction. the lowest energy H unoccupied molecular orbital, H H B the LUMO. H HOMO 1s LUMO 2p Oxalic acid acid, PTSA Benzenesulfonic Acetic acid, HNO H HClO HClO, HClO Halogen: oxyacids HCl,HBr, HI Hydrogen halides : 2 SO 3 4 3 , H , HSO , HClO , ARRHENIUS THEORY ACID 3 PO H is actually AH H BOH solutionin (H Substanceyields that Substanceyields that . ACID Cl + Na + Cl + 3 2 4 3 F 4 , + OH + O ------> + ------> B ) in solutionin ) - OH -----> Al(OH) Mg(OH) Ba(OH) NaOH, NaOH, H is a BASE a is + + A + + 3 KOH, BASE 2 H 2 , - Ca(OH) OH 2 is an an is O LiOH H OH - . + 2 , -

BRONSTED-LOWRY THEORY pairs 1. acceptor BASE Base ACID conjugate acid called are These NH HCl Acid 2. Acid Base 3 -----> 1 1 + H . + + proton donor proton a is proton proton a is 1 2 Acid Base . ----> H + H + -----> H + + 2 2 -----> + -----> - base + Cl NH + - Base 4 Acid + . 1 2

LEWIS THEORY BF octet Acid: I A donor BASE acceptor ACID Cl electrons unsharedof pair an with species Base: 2 + - + , etc. 3 I + : BH - B: . species species -----> I F electron pair pair electron an is electron pair pair electron an is - . -----> A : H -----> BF 3 , CH 2 O, NH O, 3 lacking an - 3 + - , etc. B 4 - 3 , H - , In 1965, Ralph Pearson • He introduced the hard and soft attempted to explain the acid-base (HSAB) principle. differential affinity of Lewis • He classified Lewis acids and bases towards bases as hard, borderline or soft. Lewis acids.

According to him, hard acids • This statement is neither an prefer to explanation or a theory. It is coordinate to simply a guideline that helps one hard bases and to qualitatively predict the relative soft acids to soft stability of acid-base adducts. bases.

• The adjectives hard and soft doesn't mean strong and weak. Ralph G • Classification in the original Pearson, JACS, work was mostly based on 85, 3533(1963) equilibrium constants for reaction of two Lewis bases competing for a Lewis acid. In 1968, G. Klopman • Hard acids bind to hard bases to quantified give charge controlled ionic Pearson's HSAB principle using complexes. frontier • Soft acids bind to soft bases to molecular orbital theory. give FMO controlled covalent complexes.

In 1983, the qualitative • A less polarizable atom or ion is definition of HSAB was hard. converted to a quantitative one • A more easily polarized atom or by using the idea ion is soft. of polarizability.

• High positive charge With these • Small size modifications, • Not easily polarizable hard acid is • High energy LUMO supposed to be associated with • No electron pairs in their valence properties such shells as • Low electron affinity • Strongly solvated • Low or partial positive charge • Large size On the other • Easily oxidized hand soft acids • Highly polarizable have properties • Low energy LUMO and large such as LUMO coefficients • Electron pairs in their valence shells

• Low polarizability Hard bases have • High electronegativity properties such • Not easily oxidized as • Low energy HOMO • Highly solvated

• High polarizability • Diffuse donor orbital Soft bases have • Low electronegativity properties as • Easily oxidized • High energy HOMO and large HOMO coefficients Characteristic Properties of Hard and Soft acids and bases

Properties Hard Acids Soft Acids Soft Bases Hard Bases

Electronegativity 0.7 – 1.6 1.9 – 2.5 2.1 – 3.0 3.4 – 4.0

Ionic radius (pm) < 90 > 90 > 170 ~ 120

Ionic charges ≥ +3 ≤ +2

Borderline species have intermediate properties. It is not necessary for species to possess all properties. HARD SOFT BORDERLINE + + + + H , Na , K , Li Cu+, Ag+, Au+, Tl+, Hg+, Cs+, Bi2+, Mg2+, Ca2+, Mn2+, Sr2+ + Fe2+, Co2+, Ni2+, Sn2+, Co 3+ 3+ 3+ 3+ 3+ Al , Se , Ga , Gd , In , Ru2+, Rh3+, Cu2+, Zn2+, Pd2+, Cd2+, Pt2+, Hg2+ 3+ La 2+ + Pb , B(CH3)3, SO2, CH3Hg 3+ 3+ 3+ 3+ 3+ Cr , Co , Fe , As , Ir NO+, C H + 3+ 6 5 Tl , Ti(CH3)3, RH3, InCl3 4+ 4+ 4+ 4+ 4+ Si , Ti , Zr , Tb , Pu , RS+, RSe+, RTe+, BH VO2+ 3 I+, Br+, HO+, RO+ UO 2+, (CH ) Sn2+ 2 3 2 I , Br , INC, etc. BeMe , BF , BCl , B(OR) 2 2 2 3 3 3 Trinitrochlorobenzene, etc. Al(CH ) , Ga(CH ) , 3 3 3 3 Chloranil, Quinones, etc. In(CH3)3 + + Tetracyanoethylene RPO2 , ROPO2 + + Carbenes RSO2 , ROSO2 , SO3 0 I7+, I5+, Cl7+ M (Metal atoms) + + + Bulk Metals R3C , RCO , CO2, NC ACID HX (Hydrogen bonding molecules) BORDERLINE

- Aniline, Pyridine, N3 , HARD - - 2- SOFT Br NO2 , SO3 , N2

- - - H2O, HO , F R2S, RSH, RS - 3- 2- - - 2- CH3CO2 , PO4 , SO4 I , SCN , S2O3 - 2- - - Cl , CO3 , ClO4 , NO3 R3P, R 3As, (RO)3P - - ROH, RO , R2O CN , RNC, CO

NH3, RNH2, N2H4 Ethylene, Benzene H-, R-

BASE The HSAB Principle for Organic and Main Group Chemists

For our purposes main group and organic reaction chemistry the Pearson approach is very successful when comparing pairs of species:

 Sodium ion, Na+, is harder than the silver ion Ag+

 Copper(II) ion is harder than copper(I) ion

 Alkoxide ions, RO–, are harder than thioanions, RS–

 The nitrogen anion end of the ambidentate cyanide ion, CN–, is harder than the carbon anion end, NC-

 The ambidentate enolate ion, has a hard oxyanion centre while the carbanion centre is softer and more nucleophilic

This type of analysis can be very useful in explaining reaction selectivity.

For example, in ring opening reaction of β-propiolactone by nucleophilic Lewis bases, attack can occur at two positions and nucleophiles exhibit regioselectivity. O

O - Nu O Nu(soft) (soft)

O (hard)Nu O

- O Nu(hard)

O O Harder nucleophiles like alkoxide – - ion (RO ) attack the carbonyl carbon. - O OR RO O

O - O Softer nucleophiles like a cyanide NC – – ion (NC ) or a thiolate (RS ), - O NC O attack the β-alkyl carbon.

O - O RS

- O RS O In a nucleophilic substitution reaction in which one Lewis base replaces another, for example, if the acid site is hard, then soft nucleophile will not provide a high rate of reaction. If the acid is soft, then a soft nucleophile will react more quickly. [Pearson R. G. and Songstad J, JACS, 1967, 89, 1827.]

Although, it certainly does not say that soft acids do not ever complex with hard bases, or that hard acids do not form stable complexes with any soft bases. ELECTROPHILES AND NUCLEOPHILES  History  Terminology  Examples  Types  Key Facts • The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1929, replacing the terms cationoid and anionoid proposed earlier by A. J. Lapworth in HISTROY 1925. • The word nucleophile is derived from nucleus and the Greek word phile for affinity, while electrophile is derived from electros meaning electron.

• Electron loving • electron deficient molecules Electrophile • attracted to negative charge i.e. high electron density (E / E+) • bear partial or full positive charge or an open octet • accepts pair of electrons • similar to Lewis acid

• deficiency in valence electron shell Examples O

H N Positively charged ions C

O H Polar molecules Oδ- O δ+ δ valence saturated but contain an atom Cδ+ H Cl - δ+ O O from which bonding electron pair can δ− C be removed as leaving group Br H H

Polarizable molecules # easily polarizable bond • Br Br Cl Cl I I # generates electrophilic end

Neutral molecules with incomplete • Carbenes AlCl3 BF3 octet

• for same electrophilic atom, greater degree of positive charge Key Facts gives stronger electrophile + δ+ δ─ e.g. H3C > H3C -Br • Nucleus loving • abundance of electrons i.e. electron rich molecules Nucleophile • attracted to positive charge i.e. low electron density (Nu: / Nuc) • bear partial or full negative charge or pi bond or lone pair of electrons • donates pair of electrons • similar to Lewis base

• easily available non-bonding electron pair

Examples Br OH C N Anions Cl OR HC C I SR

H

H H H C H pi bonds C C H C C H C C H H H C H

H Molecules with lone pairs H O bonding electron pair that can be O N H H donated from bond involved H H

δ- δ+ Polar molecules H3C MgBr

• Carbon nucleophiles: alkyl metal halides such as Grignard reagent, organolithium, organozinc reagents, and anions of a terminal alkyne. Enolates are also carbon nucleophiles. Enolates are commonly used in Types of nucleophiles condensation reactions such as Claisen condensation, Aldol condensation reactions, etc. ─ • Nitrogen nucleophile: NH3, RNH2, RCN, H2N , etc.

─ ─ ─ • Oxygen nucleophiles: H2O, HO , ROH, RO , H2O2, COO , etc. • Sulfur nucleophiles: hydrogen sulfide and its salts (HS), thiols (RSH), Types of nucleophiles thiolate anion (RS─), thiocarboxylic acids (RCOSH), dithiocarbonates ─ ─ (ROCSS ), dithiocarbamates (R2NCSS ), etc. In general, sulfur is very nucleophilic. Due to its large size, it is polarizable and its lone pair of electrons are easily accessible. • all nucleophiles are bases but not all bases can act as nucleophiles e.g. lithium diisopropylamide is a very strong base but a very poor nucleophile Key Facts • stronger base is stronger nucleophile (same nucleophilic atom) ─ e.g. HO is better nucleophile than H2O ─ ─ ─ RO > HO > phenoxide > carboxylate >> alcohol, H2O >>> RSO3

• nucleophile with negative charge is more powerful than its conjugate acid ─ ─ e.g. H2N >NH3, HO >H2O Key Facts • nucleophilicity decreases with increasing electronegativity of the attacking atom (within same period) ─ ─ ─ ─ e.g. R3C > R2N > RO > F ─ ─ ─ ─ ─ ─ H2N > RO > R2HN > ArO > NH3 > Py > F > H2O > ClO4

• going down in a group nucleophilicity increases e.g. I─ >Br─ > Cl─ >> F─ RS─ > RO─ Key Facts • more free nucleophile, more nucleophilicity e.g. NaOHDMSO >NaOHwater In water Na+ and HO ─ both are solvated while in DMSO Na+ is solvated preferably than HO ─, leaving HO ─ as free nucleophile. • Steric effect is also important in deciding strength of nucleophile. Less basic but sterically unhindered nucleophiles have higher nucleophilicity. ─ ─ ─ e.g. RCH2O > R2CHO > R3CO Key Facts • Nucleophilicity is increased by attached heteroatom that possess free electron pair (α-effect). ─ ─ e.g. HO-O > H-O , H2N-NH2 > H-NH2

• Sometimes not whole molecule, but small region on large molecules can function as nucleophile or electrophile. • Some molecules have both electrophilic and nucleophilic regions Key Facts within them. They often go hand-by-hand. • More electronegative atom functions as nucleophilic region. It may be partially negatively charged.

• Similarly, less electronegative atom functions as electrophilic region. It may be partially positively charged. e.g. C=O bond Key Facts • Flow of electrons, in a reaction, is always from nucleophile to electrophile. Nu E+ Electrophilic moiety Nucleophilic moiety H Cl H Br H I

H OSO3H

H OH2 Cl Cl Br Br Cl OH Br OH RS Cl

Hg (OAc)2

R2B H