Subject Chemistry

Paper No and Title 5, Organic Chemistry-II, Reaction mechanism-1

Module No and Title 19, Ambident nucleophile and regioselectivity.

Module Tag CHE_P5_M19

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction 3. Hard and soft acid and base concept and factors influencing ambident reactivity 3.1 Polarizability of the nucleophile 3.2 Nature of solvent 4. Reaction mechanisms involving ambident nucleophiles 5. Regioselectivity 5.1 Alkylation of Ketones 5.2 Hydroboration 5.3 Diels Alder Reaction 5.4 Ring opening of epoxides 5. Summary

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

1. Learning Outcomes

After studying this module, you shall be able to

 Know what are ambident nucleophile  Learn mechanism of ambident nucleophilic substitution  Identify factors that decide point of attack by ambident nucleophile  Evaluate various types of functional groups as ambident nucleophile  Analyze regioselectivity because of ambident nucleophiles

2. Introduction

A nucleophile is a chemical entity that donates an electron pair to an electrophile centre to form a chemical bond. The terms nucleophile was derived from nucleus and Greek word philos (meaning love) and was coined by Christopher Kelk Ingold in 1929. All molecules or ions that can donate a free pair of electrons or have at least one π bond can act as nucleophiles. A nucleophile can have more than one atoms carrying a pair of electrons or the electrons may be shared by two or more atoms, so that canonical forms can be drawn in which two atoms bear an unshared pair of electrons. If such is the case, the nucleophile may attack in two or more different ways to give different products. Such nucleophiles are called ambident nucleophiles (ambi is Latin for “both”; dent is Latin for “teeth”).

According to the IUPAC, ambident nucleophiles consist of two (or more) alternative and strongly interacting distinguishable reactive centers which all can undergo the reaction. However, when the reaction occurs at either site, it generally stops or greatly retards a subsequent attack at the other sites.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

A common example of ambident nucleophile is enolate ion with oxygen and carbon as two nucleophilic centers,

A nucleophile with two potentially attacking sites can exhibit dual reactivity by attacking with either of the electron rich centre. There are various factors that decide which atom of an ambident nucleophile will attack a given substrate under a given set of conditions i.e., if the kinetically controlled product will predominate or the thermodynamic control will take place preferentially. Therefore, depending on reaction conditions ambident nucleophiles lead to regioselective reactions (reactions where formation of two or more constitutional isomers (e.g., ROCN or RNCO), can take place but actually only one product is formed).

Structure of some of the important ambident nucleophiles can be shown to be a resonance hybrid as follows;

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

S C N S C N

CH3 CH3 H2C H2C S S

N CH3 N CH3 H3C H3C

O O

CH2 CH2 CH2

O O O

O O O

CH2 CH2 CH2

O N O N O N

O O O

O O O O O O

R R R

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

3. Hard and Soft Acid and Base Concept and Factors Influencing Ambident Reactivity

Which end of an ambident nucleophile should react predominantly under a particular set of conditions? To answer this question two most important factors are:

a) Polarizability of the nucleophile and b) Nature of solvent

3.1. Polarizability of the Nucleophile

To explain the ambident character and polarizability of the ligands the principle of hard and soft acids and bases (HSAB) was used. According to the principle hard acids prefer hard bases and soft acids prefer soft bases (based on experimental calculation of enthalpy). For an ambident nucleophile the more electronegative atom is a harder base than the less electronegative atom. Thus in enolate anion, the more electronegative oxygen atom with negative charge is harder base than carbon atom. The following table classifies common organic ligands as hard and soft acids and base.

Table1: Classification of ligands as hard and soft acids and bases.

Hard base Soft base Borderline base - - - (Donor atom has high electro- (Donor atom has low electro- For e.g. ArNH2, N3 , Br , NO2 negativity and low negativity and high

polarizability). For e.g. H2O, polarizability). For e.g. R2S,

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

- - - 2- - OH , F , AcO , SO4 , RO , RSH, I-, CN-, RCN, C2H4,

RNH2, NH3, ROH C6H6

Hard acid Soft acid Borderline acid (Possess small acceptor atoms (Possess large acceptor atoms For e.g. Fe2+, Co2+, Cu2+, Zn2+,

3+ + + + and have high positive charge, and have low positive charge, Bi , R3C , NO , C6H5 without an unshared pair of and contain unshared pair of electrons). For e.g. H+, Li+, electrons). For e.g. Cu2+, Ag+,

+ + 2+ 2+ 2+ 2+ 2+ Na , K , Mg , Ca , BF3, Pd , Pt , Hg , BH3, I2, Br2

+ AlCl3, AlH3, SO3, RCO

For SN1 mechanism a carbocation intermediate is a hard acid that would prefer attack by a hard

base i.e. attack by oxygen of enolate. On the other hand for SN2 mechanism the carbon at reaction centre is softer acid and would be preferably attacked by carbon atom of enolate ion. This was

generalized as, as the character of a given reaction changes from SN1 to SN2 like, an ambident nucleophile would more likely attack with its less electronegative end.

3.2 Nature of Solvent

The nature of solvent has been shown to guide the position of attack in a number of reactions for ambident nucleophiles. In protic solvents, through hydrogen bonding the more electronegative atom is better solvated than the less electronegative atom. Thus less electro negative atom is more prone to attack. In contrast, polar aprotic solvents offer no stabilization to either end of the nucleophile however, they stabilize the substrate cation by solvation. As a result of this the more electronegative end of the nucleophile is freer so the extent of attack by the more electronegative atom increases.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

As an e.g. for the following reaction under different solvent conditions (Table 1) the ratio of N- alkylation to C-alkylation changed dramatically as shown by the proportion of products formed in the reaction.

Br +

N N N K H (A) (B)

Solvent %A %B Tetra hydro furan 81 19 Dioxane 71 29 Di isopropyl ether 21 79 Benzene 15 85 Toluene 14 86 n-heptane 14 86

The leaving group and counter positive ion of the nucleophile also influences mechanism of reaction and therefore influences the major product formed. For the alkylation of 2-hydroxyl

+ pyridine (enolate ion) when the reaction was carried out with K as the counter ion, a SN2 mechanism was favored and the soft reaction centre N atom participated in the reaction (73% product).

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

CH3CH2I S 2 K+ N N N O O N O

CH2CH3

CH CH I 3 2 SN1 Ag+ N O N O N OCH2CH3

On the other hand, if instead of K+ the counter ion is Ag+ then due to the ability of Ag+ to

coordinate with the leaving group iodide ion, the reaction was found to favor SN1 mechanism and therefore O-acylation product (80%) was obtained as the major product.

Steric hindrance at the nucleophilic centre may become predominating factor to decide point of attachment where applicable. For e.g. the alkylation of phenol with RI gives O-alkylated product.

R R O O OH O O

RI RI +

Phenoxide ion 2,6-Dimethyl (Major) phenoxide ion R

However, when the reaction centre is crowded as in 2,6-dimethyl phenol then, the para alkyl substitution leading to C-alkylation is favored over O-alkylation.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

4. Reaction Mechanism Involving Ambident Nucleophiles

Nef Reaction involves conversion of a nitro compound to carbonyl compound through a nitronate anion. The nitronate anion is an ambident nucleophile which can either attack from the carbon end acting as a soft base or from oxygen end acting as a strong base. The reaction goes by attack from the carbon end predominantly as follows:

However, in the reaction O-alkylation is possible if a hard alkylating agent such as MeOSO2F is used. Thus the reaction would proceed like:

O O

MeOSO2F R N R N O O Me

Kolbe nitrile Synthesis: The reaction of primary aliphatic halides with alkali metal cyanides gives nitriles in good yield.

+ R Cl KCN DMSO R CN Mechanism:

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

K N: C + -KX R Cl R CN

However, since cyanide is an ambident nucleophile, in the reaction, attack from nitrogen end of the nucleophile results in isocyanide product as follows:

M -KX C :N + R Cl R N C

The nature of cation here plays an important role as isocyanides are formed with Ag+ and Cu+ metal cations.

Compounds with active methylene group such as acetyl acetone can be alkylated at either the carbon (C-alkylation) or at the oxygen (O-alkylation) atom through an enolate anion. It was reported that the value of the O/C-alkylation ratio depends on the polar effect of the substituent, the steric effect of the alkyl groups and the nature of the leaving groups.

O O O O O OCH3 CH X 3 +

CH3 where X= OTs 97% 3% X= I 3% 97%

When the leaving group is a soft base (iodide, bromide, chloride) the steric effect predominates and the O/C-ratio decreases in the order of

CH3CH2CH2CH2> (CH3)2CH > CH3CH2 > CH3 CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

The alkyl group sequence opposite to the order given above operates for the hard leaving groups. The reaction between nucleophiles and poly nitro aromatics has been a focus of a lot of mechanistic studies. This is because of the possibility of isolation of an intermediate or transition state and the diverse number of products formed such as π-complexes, radical anions, radicals, and anionic σ-complex.

The phenoxide ion is an ambident nucleophile. When reacted with 2,4,6-tri nitro benzene both O

- and C alkylation products are possible. The attack by C6H5O through oxygen end was found to be reversible and kinetically preferred; as the formation of the C adduct would not lead to disruption of aromaticity of the ring.

However, the C-bonded adduct once formed rapidly aromatized by proton loss to give the final product; therefore this pathway was found to be effectively irreversible. The C-bonded adduct was therefore obtained as the product of thermodynamic control

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

5. Regioselectivity

Many reactions have a strong preference for forming one regoisomer over the possible other isomer. This property is known as “regioselectivity”. The subject has been partly covered earlier in the module dealing with ambident nueleophile. In this module we will now illustrate regioselectivity with more examples.

5.1 Alkylation of Ketones Unsymmetrical ketones of the type

can be alkylated at either α- position or at position depending on the experiments conditions. The methodology consists of steps shown in the following reactions:

The first reaction is deprotonation on α or α’ position (acid – base reaction) and the

second reaction is a SN2 reaction (carbanion is the nucleophile and CH3 is the electrophilic agent). In point of fact, the two new products are not formed in equal CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

amounts. If A is the major C-alkylated compound we say the reaction is regioslective alkylation. Alkylation of ketones via carbanion or its equivalent enolate is a very important topic of very wide scope.

The concept of regioselectivity can best be illustrated with selected examples 1. Bromination of acetanilide

4- Bromo acetanilide is the chief product, (o- or m- isomers negligible). This is regioselective bromination.

2. Hydroboration

The addition of BH3 to a double bond or a triple bond to give an organoborane is known as hydroboration

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

The mechanism involves a concerted 4-membered transition state .The boron always combines with the carbon of the double bond that is less substituted

Hydroboration of a alkane is a regioselective addition reaction.

3. Diels –Alder reaction Regioselectively in cycloaddtion reactions such as Diels Alder reaction can be observed.

4. Hydrogen halide addition to an alkene

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

HBr addition to methyl cyclohexene is a regioselective addition to give 1- bromo- 1-methyl cyclohexane.

5. Ring opening of epoxides. Epoxides are very useful intermediates in synthetic organic chemistry. Epoxides are readily prepared by treatment of an alkene with peracids (epoxidation). This reaction and its subsequent transformations are been extensively studied and documented. Epoxides contain strained three membered ring. It is subjected to ring opening by two ways. (i) Acid catalysed ring opening (ii) Base catalysed ring opening.

The first process starts with attack by acid (H+ or lewis acid) at oxygen and in the + 2 second process, base (a nucleophile, H or a base) attacks one of the carbon (SN ). The topic of regioselectivity in epoxide ring opening is, therefore, important.

In general, nucleophiles attack at the less highly substituted carbon atom of the

epoxide ring in neutral or basic media as expected for a SN2 process. In acidic media the proportion of attack at the more highly substituted carbon is increased and may become the predominant reaction.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

Study the examples below carefully. You will get answers to what do the above statements mean (ignore the stereo chemistry for convenience)

Acid catalysed methanolysis of epoxide.

Epoxide ring opening under SN2 and acidic conditions.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity

6. Summary

 An ambident nucleophile is a nucleophile that can react at more than one site.  Ambident nucleophiles generally carry hetero atoms with lone pair of electrons or π- electrons and exist as resonance stabilized structures.  Reactions of substrate with ambident nucleophiles lead to regioselective reactions where one constitutional isomer is favored based on the reaction conditions.  In a reaction the polarizability of nucleophile (HSAB principle) and nature of solvent decide which end of an ambident nucleophile will give rise to the major product.  According to HSAB principle hard acid prefer to combine with hard bases and soft acids prefer to combine with soft bases.

 As the character of a given reaction changes from SN1 to SN2 like, an ambident nucleophile would more likely attack with its less electronegative end.  The prediction of regioselectivity in a reaction depends upon the substrate , reagent and the experimental conditions.

CHEMISTRY PAPER: 5, Organic Chemistry-II, Reaction mechanism 1 MODULE:19, Ambident nucleophile and regioselectivity