Ozonolysis of Alkenes (review of Chapter 6)

Reaction type: Electrophilic Addition

MECHANISM FOR REACTION OF ALKYNES WITH O3

Step 1: The electrons act as the nucleophile,attacking the ozone at the electrophilic terminal O. A second C-O is formedby the nucleophilic O attacking the other end of the C=C

Step 2: The cyclic species called the ozonide rearranges to the malozonide.

Step 3: On work-up (usually Zn / acetic acid) the malozonide decomposes togive two carbonyl groups.

MECHANISM FOR REACTION OF ALKYNES WITH H3O+ Step 1:

An acid / base reaction. Protonation of the alkyne to generate the more stable

carbocation. The electrons act pairs as a Lewis base. Step 2: Attack of the nucleophilic water molecule on the electrophilic carbocation creates an oxonium ion. Step 3: An acid / base reaction. Deprotonation by a base generates the alcohol and regenerates the acid catalyst forming an unstable enol.

Step 4: An acid / base reaction. Reprotonation by the acid catalyst occurson the carbon. The oxygen atom electrons help facilitate this process generating an oxonium ion. Step 5: Another acid / base reaction. Deprotonation of the oxonium ion createsthe ketone. Steps 4 and 5 show the acid catalysed tautomerisation of the enol to the ketone.

Oxidation of Primary and Secondary Alcohols (review of Chapter 15)

Reaction type: Oxidation-Reduction

1o alcohol aldehyde

Secondary alcohols can be oxidised to ketones, no further:

2o alcohol ketone

Tertiary alcohols cannot be oxidised (no carbinol C-H)

3o alcohol

Cr OXIDATION OF ALCOHOLS

The mechanism is not trivial, so attention here is focussed on the actual oxidation step. Prior to this, the alcohol reacts to form a chromate ester (shown). A base (here a water molecule) abstracts a proton from the chromate ester, the C=O forms and a Cr species leaves. This demonstrates the importance of the carbinol H to this mechanism.

Chapter 17: Aldehydes and Ketones. Nucleophilic Additionto C=O

Friedel-Crafts Acylation of Benzene (review of Chapter 12)

Reaction type: Electrophilic Aromatic Substitution

MECHANISM FOR THE FRIEDEL-CRAFTS ACYLATION OF BENZENE

Step 1: The acyl halide reacts with the Lewis acid to form a a more electrophilicC, an acylium ion

Step 2: The electrons of the aromatic C=Cact as a nucleophile, attacking the electrophilic C+. This step destroysthe aromaticity giving the cyclohexadienyl cation intermediate.

Step 3: Removal of the proton from the sp3 C bearing the acyl- groupreforms the C=C and the aromatic system, generating HCl and regeneratingthe active catalyst.

Chapter 17: Aldehydes and Ketones. Nucleophilic Addition to C=O

Nucleophilic Addition

Nucleophilic addition reactions are an important class of reactions that allow the interconversion of C=O into a range of important functional groups.

What does the term "nucleophilic addition" imply ?

A nucleophile, Nu-, is an electron rich species that will react with an electron poor species (here the C=O) An addition implies that two systems combine to a single entity. There are three fundamental events in a nucleophilic addition reaction:

1. formation of the new s bond between the nucleophile, Nu, to the electrophilic C of the C=O group 2. breaking of the p bond to the O resulting in the formation of an intermediate alkoxide 3. protonation of the intermediate alkoxide to give an alcohol derivative

Depending on the reactivity of the nucleophile, there are two possible general scenarios:

Strong nucleophiles (anionic) add directly to the C=O to form the intermediate alkoxide. The alkoxideis then protonated on work-up with dilute acid.

Examples of such nucleophilic systems are : RMgX, RLi, RCCM, LiAlH4, NaBH4

Weaker nucleophiles (neutral) require that the C=O be activated prior to attack of the Nu.

This can be done using a acid catalyst which protonates on the Lewis basic O and makes the system more electrophilic.

Examples of such nucleophilic systems are : H2O, ROH, R-NH2

The protonation of a carbonyl gives a structure that can be redrawn in another resonance form that reveals the electrophilic character of the C since it is a carbocation.

The reactions on the following pages are catalogued based on the nature of the nucleophilic atom involved. In most cases it is useful to indentify the mechanism in each case in terms of the two general schemes presented above.

Reactivity Overall a simple nucleophilic addition can be represented with curly arrows as follows:

The reactivity of aldehydes and ketones can be easily rationalised by considering the important resonance contributor which has charge separation with a +ve C and -ve O.

Hydride Reductions of Aldehydes and Ketones

(review of Chapter 15)

Reactions usually in Et2O or THF followed by H3O+ work-ups

Reaction type: Nucleophilic Addition

NUCLEOPHILIC ADDITION OF LiAlH4 TO AN ALDEHYDE

Step 1: The nucleophilic H in the hydride reagent adds to the electrophilic C in the polar carbonyl group in the aldehyde, electrons from the C=O move to the O creating an intermediate metal alkoxide complex. (note that in principle all 4 of the H atoms can react)

Step 2: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex.

Cyanohydrin Formation

Reaction type: Nucleophilic Addition Summary

Cyanide adds to aldehydes and ketones to give a cyanohydrin.

The reaction is usually carried out using NaCN or KCN with HCl.

HCN is a fairly weak acid, but very toxic.

The reaction is useful since the cyano group can be converted into other useful functional groups (-CO2H or -CH2NH2)

NUCLEOPHILIC ADDITION OF CYANIDE TO AN ALDEHYDE

Step 1: The nucleophilic C in the cyanide adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating an intermediate alkoxide

Step 2: An acid/base reaction. Protonation of the alkoxide oxygen creates the cyanohydrin product.

Reactions of RLi and RMgX with Aldehydes and Ketones

(review of Chapter 14)

Reactions usually in Et2O or THF followed by H3O+ work-ups

Reaction type: Nucleophilic Addition

NUCLEOPHILIC ADDITION OF RLi or RMgX TO AN ALDEHYDE

Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=Omove to the electronegative O creating an intermediate metal alkoxide complex.

Step 2: This is the work-up step, a simple acid / base reaction. Protonation of the alkoxide oxygen creates the alcohol product from the intermediate complex.

Chapter 17: Aldehydes and Ketones. Nucleophilic Addition to C=O

The Wittig Reaction

ylide aldehyde or ketone alkene

Reaction type: Nucleophilic Addition then Elimination

THE WITTIG REACTION

Step 1: The nucleophilic C of the ylid Wittig reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=O bond are used to form a bond to the +ve P atom. This creates a cyclic intermeiate called anoxaphosphetane.

Step 2: Decomposition of the intermediate by breaking the C-P andC-O bonds leads to the formation of the C=C bond of the alkene and triphenyl phosphine oxide.

Reactions of Primary Amines

imine

Reaction type: Nucleophilic Addition then Elimination

NUCLEOPHILIC ADDITION OF A PRIMARY AMINE GIVING AN

IMINE

Step 1: An acid/base reaction. Protonation of the carbonyl activates it and makes it more susceptible to attack by a neutral nucleophilic like the N of a primary amine.

Step 2: Attack of the N nucleophile at the electrophilic C of theC=O group with the electrons from the bond going to the +ve O.

Step 3: An acid/base reaction. Removal of the proton neutralises the +ve charge on the N and forms the carbinolamine intermediate.

Step 4: To form the imine we need to dehydrate. However, before -OH leaves it needs to be protonated, so a simple acid/base reaction.

Step 5: Use the electrons of the N to help push out the leaving group, a neutral water molecule, forming a C=N in the form of an iminium ion.

Step 6: An acid/base reaction. Deprotonation of the iminiumN reveals the imine product and regenerates the acid catalyst.

NUCLEOPHILIC ADDITION OF A SECONDARY AMINE GIVING AN ENAMINE

Step 1: An acid/base reaction. Protonation of the carbonyl activates it and makes it more susceptible to attack by a neutral nucleophilic like the N of a secondary amine

Step 2: Attack of the N nucleophile at the electrophilic C of theC=O group with the electrons from the bond going to the +ve O.

Step 3: An acid/base reaction. Removal of the proton neutralises the +ve charge on the N and forms the carbinolamine intermediate.

Step 4: To form the enamine we need to dehydrate. However, before -OH leaves it needs to be protonated, so a simple acid/base reaction.

Step 5: Removal of a proton from an adjacent C allows theC=C bond to form and loss of the leaving group, a neutral water molecule, creating the enamine.

MECHANISM FOR THE ACID CATALYSED FORMATION OF HYDRATES Step 1:

An acid/base reaction. Since there is only a weak nucleophile we need to activate the carbonyl by

protonating on O. Step 2: The nucleophilic O in the water attacks the electrophilic C in the C=O, breaking the bond and giving the electrons to the positive OStep 3: An acid/base reaction. Deprotonation of the oxonium ion neutralises the charge giving the hydrate.

MECHANISM FOR THE ACID CATALYSED FORMATION OF ACETALS

Step 1: An acid/base reaction. Since there is only a weak nucleophile we need to activate the carbonyl by protonating on O.

Step 2: The nucleophilic O in the alcohol attacks the electrophilic C in the C=O, breaking the bond and giving the electrons to the positive O.

Step 3: An acid/base reaction. Deprotonation of the alcoholic oxonium ion neutralises the charge giving the hemi-acetal. Now we need to substitute the -OHby -OEt.

Step 4: An acid/base reaction. In order for the -OH to leave we need to make it into a better leaving group by protonation.

Step 5: Using the electrons from the other O, the leaving group departure is facilitated.

Step 6: We now have what resembles a protonated ketone (compare with step 2). The nucleophilic O of the alcohol attacks the electrophilic C and the electrons of the bond move to neutralise the charge on the positive O.

Step 7: An acid/base reaction. Deprotonation of the alcoholic oxonium neutralises the charge and produces the acetal product and regenerates the acid catalyst.

OXIDATION OF ALDEHYDES

Part 1: Formation of the hydrate (mechanism) occurs first.

Part 2: Now we essentially have an alcohol which reacts with the chromium species to form a chromate ester.

Part 3: A base (here a water molecule) abstracts a proton from the chromate ester, the C=Oforms and a Cr species leaves. This is really an E2 elimination reaction. Note the importance of the original aldehyde H... if its' missing, no oxidation can occur.

THE BAEYER-VILLAGER REACTION

Step 1: An acid/base reaction. Protonation of the carbonyl activates it while creating a more reactive nucleophile, the percarboxylate.

Step 2: Now the nucleophilic O attacks the carbonyl C with the electrons from the C=O bond going to the positive O.

Step 3: Electrons from the O come back (this reforms the bond of the C=O) and we migrate the C-Celectrons to form a new C-O bond displacing the carboxylate as a leaving group.

Step 4: Finally an acid/base reaction reveals the C=Oand therefore the ester product.