Carbonyls and Amines

A carbonyl is a carbon double bonded to an oxygen. The double bond is shorter

and stronger than the double bond of alkenes!!
Aldehydes, ketones, carboxylic acids, amides and esters all have carbonyls.
Aldehydes and ketones typically undergo nucleophilic addition, while other
carbonyl compounds prefer nucleophilic substitution!!!
Whenever you see a carbonyl on the MCAT you should think two(2) things:
1) planar stereochemistry
a. The planar stereochemistry of a carbonyl leaves open space above
and below, making it susceptible to a chemical attack. This is
because there is no steric hindrance.

b. Because of this planar stereochemistry a substance can attack

from both sides of a carbonyl therefore creating a racemic
mixture which is optically inactive!!

2) partial positive charge on the carbon

a. the partial positive charge on the carbon means that any attack on
the carbonyl carbon will be from a nucleophile
b. The partial negative charge on the oxygen means that it is easily
protonated.

Formaldehyde = methanal
Acetalaldehyde = ethanal
Acetone = 2-propanone  polar aprotic solvent in SN2 reactionas

Aldehyde and Ketone physical properties

Aldehydes and Ketones are more polar than alcohols.

- Higher boiling points than alkanes and alkenes of similar molecular weight.
- Lower boiling points than alcohols (because they cant hydrogen bond with each
other)

- Aldehydes and ketones with up to four carbons are water soluble

Chemical Properties
On the MCAT an aldehyde or ketone will most of the time be acting as either a substrate
in nucleophilic addition or as a Bronsted-Lowery acid by donating one of its a-
hydrogens.

The alpha carbon in organic chemistry refers to the first carbon that attaches to a
functional group (the carbon is attached at the first, or alpha, position).[1] By extension,
the second carbon is the beta carbon, and so on. This nomenclature can also be applied
to the hydrogen atoms attached to the carbons. A hydrogen attached to an alpha carbon is
called an "alpha-hydrogen" (α-hydrogen), a hydrogen on the beta-carbon is a beta-
hydrogen, and so on.

- Normal hydrogen’s aren’t easily removed from carbons because carbon anions are
very strong bases and unstable. However, a-carbons are stabilized through
resonance. This anion is called an enolate ion. En from alkene and ol from
alcohol.

- When the B-carbon also a carbonyl, the enol form becomes more stable
due to internal hydrogen bonding and resonance
- Alpha hydrogen’s are acidic and a dicarbonyl on the beta-carbon
makes it more acidic!!!
- Since ketones have two alkyl groups next to the carbonyl and these groups are
electron donating, it can’t distribute the negative charge as well and is slightly less
stable than aldehydes. Thus aldehydes are slightly more acidic than
ketones and more reactive than ketones.
 a) any electron withdrawing groups attached to the a-carbon or the
carbonyl tend to stabilize the conjugate base and thus increase
acidity

- Both aldehydes and ketones are less acidic than alcohols, and alcohols are less
acidic than water.

- Keto-enol tautomerism is a reaction at equilibrium and NOT a

resonance!!
o Tautomerism involves a proton shift, in this case from the a-carbon
position to the carbonyl oxygen position.

o The ketone or aldehyde tautomer is usually favored!!!

o Remember that in resonance structures atoms can’t move!!

There are other forms of tautomerization but keto-enol tautomerization is the most
likely form to be tested on the MCAT. In order to recognize other forms, simply
watch for the proton shift in equilibrium!!

Formation of Acetals
Aldehydes and ketones react with alcohols to form hemiacetals and hemiketals,
respectively.

When aldehydes and ketones are attacked by a nucleophile, they undergo

addition!!
Aldehydes and hemiacetals, and ketones and hemiketals, exist in equilibrium
when an aldehyde or ketone is dissolved in an alcohol. However, usually the
hemiacetal or hemiketal is too unstable to isolate unless it exists as a ring structure.
- The aldehyde products can be easily distinguished from the ketone products
by the lone hydrogen.

- The hemi products can be distinguished from the acetals and ketals because the
hemi products both have an alcohol while the full acetals don’t

- Hemi formation is catalyzed by an acid or base, while the acetal

formation is catalyzed by only acid because we have to protonate the
OH group.
a) In acid catalyzed the reactant is the nucleophile and the acid
protonates the carbonyl.
b) In base catalyzed the base abstracts a proton from the
reactant that is going to attack the ketone/aldehyde and that
ion attacks the carbonyl carbon.
hemiacetal formation:
 hemiketal formation:

- If a second molar equivalent of alcohol is added an acetal is formed from a

hemiacetal or ketal is formed from a hemiketal.

a) Hemiacetal + Alcohol <===> Acetal + H2O

b) Hemiketal + Alcohol <===> Ketal + H2O

- Because the acetals and ketals are unreactive toward bases, they are
often used as a blocking group (protecting group).
Diol alcohol and Acetal protection of a ketone during reduction of an ester:

To remove the acetal protecting group we must use and acid.

In a similar reaction, when aldehydes or ketones are dissolved in aqueous

solution they establish an equilibrium with their hydrate, a geminal diol.

Aldol Condensation
Aldol condensation is a favorite on the MCAT, because it demonstrates both a-hydrogen
activity and the susceptibility of carbonyl carbons to a nucleophile.
Aldol (ald from aldehyde and ol from alcohol) condensation occurs when one aldehyde
reacts with another, when one ketone reacts with another, or when an aldehyde reacts
with a ketone.

- There must be a alcohol at the carbon beta to the carbonyl or a double

bond in between the beta and alpha carbon to the carbonyl, in the end
product
- If two aldehydes react there must be an alcohol and an aldehyde in the
end product!!
- If two ketones react there must be an alcohol and a ketone in the end
product!!

The reaction is catalyzed by an acid or base. The first part of this reaction is
technically called aldol addition but it is sometimes referred to as aldol condensation.
The aldol to enal step is actually the condensation and almost always accompanies
aldol addition.
The first step of the base catalyzed reaction, the base abstracts an a-hydrogen leaving an
enolate ion (negative charge on the a-carbon). In the second step, the enolate ion acts
as a nucleophile and attacks the carbonyl carbon to form an alkoxide ion.
The alkoxide ion is a stronger base than a hydroxide ion and thus removes a proton
from water to complete the aldol.

- Notice that the alkoxide ion is stronger because it has an electron donating
alkyl group attached to the oxygen, thus increasing its negative charge.
The aldol is unstable and is easily dehydrated by heat or a base to become an enal. The
enal is stabilized by its conjugate double bonds.
Note: Formaldehyde cannot provide an enolate anion because it doesn’t
have an -hydrogen, but it can function as a particularly good
enolate anion acceptor.
 Under base catalysis, the carbon-carbon bond-forming step involves the
attack of an enolate anion (a nucleophile) on the uncharged carbonyl carbon
(an electrophile) of a second molecule of the aldehyde or ketone.

Under acid catalysis, it involves the attack of the enol of one molecule on the
protonated carbonyl group (an electrophile) of the second molecule.

The aldol reaction may occur between two molecules of the same aldehyde or the
same ketone, or between different molecules (crossed aldol reaction).
- You can also have intramolecular aldol reactions!!
This is an example commonly given in most organic texts:

Ethanal reacting with itself provides one product.

Propanal reacting with itself provides one product.
Ethanal reacting with propanal where ethanal acts as a nucleophile will produce a
different product than if propanal reacts as the nucleophile.
The reactions of ethanal and propanal with themselves are still considered products
of the crossed aldol reaction (although maybe not the desired ones).

MECHANISM OF THE ALDOL CONDENSATION

Step 1:
First, an acid-base reaction. Hydroxide functions as a base and
removes the acidic -hydrogen giving the reactive enolate.
Step 2:
The nucleophilic enolate attacks the aldehyde at the electrophilic
carbonyl C in a nucleophilic addition type process giving an
intermediate alkoxide.
Step 3:
An acid-base reaction. The alkoxide deprotonates a water
molecule creating hydroxide and the hydroxyaldehydes or
aldol product.
 MECHANISM OF THE DEHYDRATION OF THE ALDOL PRODUCT

 
Step 1:
First, an acid-base reaction. Hydroxide functions as a base and
removes an acidic -hydrogen giving the reactive enolate.

Step 2:
The electrons associated with the negative charge of the enolate
are used to form the C=C and displace the leaving group,
regenerating hydroxide giving the conjugated aldehyde.

A racemic mixture also is produced in aldol condensations

Halogenation and the Haloform Reaction

Halogens add to ketones at the alpha carbon in the presence of a base or an acid.

 Under acidic reaction conditions, selective monohalogenation at the α-

postion is observed!!!


 Under basic conditions polyhalogenation occurs, base is consumed by

the water as well so its not a true catalyst!!!


 This is because each electronegative halogen further enhances the stability of

the enolate!!!


 The halogenations get faster since the halogen stablizes the enolate
negative charge and makes it easier to form. The reaction proceeds via
 successively faster halogenations at the -position until the 3 H have
been replaced.


 Chlorination, bromination and iodination all occur at the same rate.

When a base is used with a methyl ketone, the alpha carbon will become completely
halogenated (-CX3). This trihalo product reacts further with the base to
produce a carboxylic acid ion and a haloform (HCX3)
Haloform Reaction:

The iodoform test or reaction is a chemical reaction where iodoform (CHI3)

is produced by the multiple halogenation of a methyl ketone (a molecule
containing the R-CO-CH3 group) in the presence of a base. R may be alkyl or aryl.
The reaction can be used to produce CHCl3, CHBr3 or CHI3. To get a positive test a
yellow ppt will form!!!

The Wittig Reaction

The Wittig reaction converts a ketone/aldehyde to an alkene.
A phosphorous ylide is used. An ylide is a neutral molecule with a negatively
charged carbanion (neutrophile).

        ylide     aldehyde or ketone            alkene 

Reaction type:  Nucleophilic Addition then Elimination

 The double bond forms specifically at the location between the original aldehyde
or ketone and the incoming group.
Whenever possible, a mixture of both cis (Z) and trans (E) isomers are
formed by the Wittig reaction!!!

As a general rule, those Wittig reagents with anion stabilizing substituents

(EWD groups) on the phosphorous ylide, such as carbonyl groups, adjacent
to the negative charge are E (trans) selective!!!

Reductions of Aldehydes and Ketones

  Reduction of methanal (formaldehyde) gives methanol.
 Reduction of other aldehydes gives primary alcohols.
 Reduction of ketones gives secondary alcohols.

You CANT hydrogenate a carbonyl to form an alcohol you have to use a

reducing agent!!!

Note: Zn(Hg) & HCL and H2NNH2 (hydrazine) & KOH reduce the
carbonyl group to a alkane!!!

 O2 and Tollens’ reagent, Ag(I), also oxidizes aldehydes to carboxylic

acids!!!

- Tollens reagent doesn’t oxidize acetals!!!

a-B Unsaturated Carbonyls

α,β-Unsaturated carbonyl compounds are an important class of carbonyl compounds
with the general structure Cβ=Cα−C=O.

In order to form a α,β-Unsaturated carbonyl compound via a dehydration

reaction the alpha carbon must have an alpha hydrogen!!

In these compounds the carbonyl group is conjugated with an alkene (hence the adjective
unsaturated), from which they derive special properties. Unsaturated carbonyls can be
prepared in the laboratory in an aldol reaction!!!

The carbonyl group, be it an aldehyde or acid or a ketone, draws electrons

away from the alkene and the alkene group in unsaturated carbonyls are
therefore deactivated towards an electrophile such as bromine or
hydrochloric acid (electrophilic addition)!!!

On the other hand, these compounds are activated towards nucleophiles in

nucleophilic addition!!!

Conjugate addition, as it is known, is the addition of a carbon nucleophile to an

electrophilic carbon-carbon double or triple bond conjugated with a carbonyl or other
electron-withdrawing group.

Summary
 Conjugate or 1,4-addition tends to occur with nucleophiles that are
weaker bases!!!
 Examples: thiols RSH, cyanide ion -CN, organocopper reagents R2CuLi, and
enolates.
  Direct or 1,2-addition tends to occur with nucleophiles that are
stronger bases!!!
 Examples : Organolithiums RLi, lithium aluminium hydride, LiAlH4 and
Grignard reagents, RMgX.
 Direct addition (1,2 addition) adds to the carbonyl carbon!!

A 1,2 nucleophillic addition is when a Nuc: attacks the C of the carbonyl. The
1,4 conjugate addition occurs when the Nuc: attacks the Beta carbon in an
alpha-beta unsaturated carbonyl compound!!!

 The product of conjugate addition (1,4 addition) is usually more stable

(i.e. the thermodynamic product) as it still contains the strong C=O
bond the 1,2 addition is the kinetic product as it occurs faster!!! (less
stable, because when it attacks the carbonyl carbon oxygen has a negative on it
but in the 1,4 conjugation there is a resonance between the double bond and the
oxygen thus stabilizing the negative charge more).

Two interesting conjugate addition reactions are the Michaels reactions and with Gilman
reagents (orgolithium and orgomagnesium reactants)

Michaels’ reaction

Reaction type : Conjugate addition

Summary

 Reagents : commonly bases such as NaOH or KOH.

 The first step is the formation of the enolate.

 Enolates tend to react with -unsaturated ketones via conjugate addition.

 A conjugate addition with a carbanion nucleophile is known as the Michael
reaction or Michael addition.
 MECHANISM OF THE MICHAEL
ADDITION
Step 1:
First, an acid-base reaction. Hydroxide functions as
a base and removes the acidic -hydrogen giving
the reactive enolate.
Step 2:
The nucleophilic enolate attacks the conjugated
ketone at the electrophilic alkene C in a
nucleophilic addition type process with the
electrons being pushed through to the
electronegative O, giving an intermediate enolate.
Step 3:
An acid-base reaction. The enolate deprotonates  a
water molecule recreating hydroxide and the more
favorable carbonyl group.

Michael reactions are an example of 1,4

conjugate addition reactions!!!

The Robinson Annulation reaction

Reaction type: Conjugate addition, then intramolecular Aldol and finally an

Elimination!

Summary
 A complex sequence that can be used to form bicyclic systems containing a
substituted cyclohexenone system.
 These products are important systems in various natural products, for example
within steriods.
 "Annulation" means "building a ring"
 The reaction is named after Sir Robert Robinson.
 The sequence involves the following steps:
o Michael addition of an enolate on a conjugated ketone

o An intramolecular Aldol reaction

o An elimination (dehydration) of an alcohol to give a conjugated ketone

The Diels-Alder reaction

The dienophile has an electron-withdrawing group conjugated to the alkene and is the
electrophile
The diene component in the Diels-Alder reaction, is the nucleophile, and can be open-
chain or cyclic and it can have many different kinds of substituents.

- There is only one limitation: the diene must be able to exist in the s-cis
conformation!!

Carboxylic Acids
Should recognize and give the common name for the two simplest carboxylic acids:

Formic Acid, (Methanoic acid) Acetic acid, (Ethanoic acid) Benzoic acid

Carboxylic Acid physical properties

Carboxylic acids where the R group is an alky group are called aliphatic acids.

Formic acid (methanoic acid) acetic acid (ethanoic acid)

The salts of carboxylic acids are named with the suffix –ate. The –ate replaces the –
ic, so that “acetic” becomes “acetate”. Acetate is sometimes abbreviated –OAc.
Sodium acetate/Sodium Ethanoate (NaOAc)
In IUPAC rules, the carbonyl carbon of a carboxylic acid takes priority over
all groups discussed so far!!!
Carboxylic acids undergo nucleophilic substitution!!!
Like any carbonyl compound, its stereochemistry makes it susceptible to nucleophiles.
When the hydroxyl group is protonated, the good leaving group, water, is formed
and substitution results.
As far as organic acids go, carboxylic acids are very strong. When the proton is
removed, the conjugate base is stabilized by resonance.
Electron withdrawing groups on the a-carbon help to further stabilize the conjugate base
and thus increase the acidity of the corresponding carboxylic acid.

Physical Properties
In a pure carboxylic acid, double hydrogen bonding can occur between two molecules of
acid to produce a dimer.

This doubles the size of the molecule and so increases the van der Waals
dispersion forces between one of these dimers and its neighbors.

- This results in a high boiling point.

Saturated carboxylic acids with more than 8 carbons are generally solids. The
double bonds in unsaturated carboxylic acids impede crystal lattice formation and lower
the melting point.

Carboxylic acids with four carbons or less are miscible (soluble) with water.
Carboxylic acids with 5 carbons or more are increasingly less soluble with water.

Carboxylic acids with 10 carbons or more are insoluble with water.

Carboxylic acids are soluble in most nonpolar solvents because the dimer
form allows the carboxylic acid to solvate without disrupting the hydrogen
bonds of the dimer!!

Decarboxylation

Summary

 Loss of carbon dioxide is called decarboxylation and is an exothermic

reaction!
 Simple carboxylic acids rarely undergo decarboxylation, the energy of
activation is high.
 Carboxylic acids with a carbonyl group at the b position readily undergo
thermal decarboxylation, e.g. derivatives of malonic acid. A carboxylic acid
with a carbonyl B-carbon is called a B-keto acid.

 The energy of activation is lowered when the B-carbon is a carbonyl

because either the anion intermediate is stabilized by resonance or a
hydrogen bond between the carboxyl hydrogen atom and the B-
carbonyl oxygen promotes the reaction by favoring a conformation on
the path to a six membered ring.

 Decarboxylation releases CO2!!

 The reaction proceeds via a cyclic transition state giving an enol intermediate that
tautomerises to the carbonyl
Carboxylic Acid Derivatives
Derivatives of carboxylic acid contain the acyl group.

(acyl group)

Carboxylic acid derivatives

acyl chlorides

acid anhydrides

esters

amides

carboxylates
Acyl chlorides are Bronsted-Lowry acids and, just like aldehydes, they donate
a a-hydrogen. The electron withdrawing chlorine stabilizes the conjugate base
more than the lone hydrogen of an aldehyde, making acyl chlorides significantly
stronger acids than aldehydes!!
Acyl chlorides are the most reactive of the carboxylic acid derivatives because
of the stability of the Cl- leaving group. They love nucleophiles.

- To make the derivatives convert to acyl chloride first!!

All carboxylic acid derivatives hydrolyze to give the carboxylic acid. Typically,
hydrolysis can occur under either acidic or basic conditions

Esterification: Acid + alcohol => ester +H2O

Esterification

The strong acid-catalyzed esterification of carboxylic acids with alcohols to give esters
is a typical reaction in which the products and reactants are in equilibrium.

The equilibrium may be influenced by either removing one product from the reaction
mixture (for example, removal of the water by azeotropic distillation or absorption by
molecular sieves) or by employing an excess of one reactant. This is in accordance with
LeChatlier’s principle.

A more effective method for preparing esters is to use an anhydride instead of a

carboxylic acid in the above reaction!!

Transesterification is the process of exchanging the alkoxy group of an ester compound

with another alcohol. These reactions are often catalyzed by the addition of an acid or
base.

Transesterification
An equilibrium results in this reaction as well, where the result can be controlled
by adding an excess of the alcohol in the product or the reactant

Acetoacetic ester synthesis is the production of a ketone from acetoacetic ester due to
the strongly acidic properties of the alpha hydrogen. A base is added to remove the
alpha hydrogens.

Acetoacetic ester synthesis

Reaction type: Nucleophilic substitution, then ester hydrolysis and finally

decarboxylation(!)

The sequence of reactions:

o Alkylation of an active methylene enolate

o Hydrolysis of an ester to a carboxylic acid

o Decarboxylation of a -ketoacid

Step 1:
First, an acid-base reaction. Ethoxide functions
as a base and removes the acidic -hydrogen
giving the reactive enolate which is then
alkylated.

Step 2:
Acid or base catalysed hydrolysis of the ester to
the parent carboxylic acid.
Step 3:
Loss of CO2 = decarboxylation, readily occurs
giving a substituted ketone.

Reactivity of Carboxylic acid derivatives:

Carboxylate ion is even less reactive than the amide

The weakest base is usually the best leaving group
** The less reactive it is the more stable the derivative **
Many of these reactions are reversible, but equilibrium will prefer the more stable
products. In other words, since a strong base makes a poor leaving group, the
equilibrium will favor the formation of the compound whose leaving group is a stronger
base. This explains the order of reactivity of carboxylic acid derivatives.
Oxidation/Reduction of Carboxylic Acids

Instead of remembering all these reactions, you should remember that carboxylic
acids and their derivatives undergo nucleophilic substitution; aldehydes and ketones
prefer nucleophilic addition

Amines
Amines are derivatives of ammonia.

Ammonia:

Primary amine Secondary amine Tertiary amine

Nitrogen is capable of taking 3 or four bonds. When nitrogen takes four bonds it has a
positive charge. When you see nitrogen on the MCAT and it only have 3 bonds
you should draw the extra lone pair of electrons immediately.
There are three important considerations when dealing with nitrogen containing
compounds:

1) They may act as a Lewis base donating their lone pair of

electrons (Lewis base)
2) They may act as a nucleophile where the lone pair attacks a
positive charge
3) Nitrogen can take on a fourth bond (becoming positively
charged)

Ammonia and amines act as weak bases by donating their pair of electrons. EWG’s
decrease the basicity of an amine while EDG’s increase the basicity of the amine!!

Steric hindrance created by bulky functional groups also tends to hinder the
ability of an amine to donate a lone pair, thus decreasing its basicity!

Amine Basicity from highest to lowest goes in this order (where the functional groups
are EDG):
Secondary > Primary > ammonia
Aromatic amines (amines attached directly to a benzene ring) are much weaker bases
than non-aromatic amines because the electron pair can delocalize around the benzene
ring. Substituents that withdraw electrons from the benzene ring will further weaken the
aromatic ring.
Since amines like to donate their negative electrons, they tend to stabilize
carbocations when they are part of the same molecule.

Physical Properties
Given the shape of amines we might expect some secondary and tertiary amines to be
optically active. However, at room temperature the lone pair of electrons moves
very rapidly from one side of the molecule to the other, inverting the configuration.
Thus each chiral molecule spends equal time as both its enantiomers (racemic
mixture sort of). Therefore, amines aren’t optically active.

- So a tertiary amine isn’t optically active

Ammonia, primary amines and secondary amines can hydrogen bond with each
other. All amines can hydrogen bond with water. This makes the lower molecular
weight amines very soluble.
Amines with comparable weights have higher boiling points than alkanes but lower
boiling points than alcohols

This is consistent with the polarity of the bonds:

Amide > Acid > Alcohol > Ketone ~ Aldehyde > Amine > Ester > Ether > Alkane

Condensations with ketones

Amines react with aldehydes and ketones losing water to produce imines and enamines
(substituted imines are sometimes referred to as Schiff bases).
In this reaction the amine acts as a nucleophile, attacking the electron deficient carbonyl
carbon of the ketone. As expected, the ketone undergoes nucleophilic addition. The
acid protonates the product to form an unstable intermediate. The intermediate loses
water and a proton to produce either an enamine or imine.
Reaction type:  Nucleophilic Addition then Elimination

If the original amine is primary, it gives up its proton to form an imine.

If the original amine is secondary, it has no proton to give up, so the ketone must
give up its alpha proton, as a result, an enamine is produced.

                                                Enamine

Imine mechanism Enamine mechanism

If too much acid is used in this reaction, the amine will become protonated
before the first step. The protonated amine will have a positive charge and
thus a poor nucleophile, preventing the first step in this reaction from
occurring.

The imine product shown exists as a tautomer with its corresponding enamine.

Wolff-Kishner Reduction

Wolff-Kishner is the reduction of aldehydes and ketones to alkanes.

We use this method because another way of reducing aldehydes and ketones is to
treat it with hot acid in the presence of amalgamated zinc (zinc treated with
mercury), the problem with this is that some ketones and aldehydes may not survive
the treatment of hot acid.

The first step of Wolff-Kishner Reduction follows the same mechanism as imine
formation, shown before, only a hydrazine is used rather than an amine. The addition of
hydrazine to the ketone or aldehyde produces a hydrozone by nucleophilic addition.

A hot strong base is added to the hydrazone to deprotonate the NH2 nitrogen
and produce the desired product with water and nitrogen gas as by products .
A high boiling solvent is usually used to facilitate the high tempterature.
Condensation of the carbonyl compound with hydrazine forms the hydrazone, and
treatment with base induces the reduction of the carbon coupled with oxidation of the
hydrazine to gaseous nitrogen, to yield the corresponding alkane.

Alkylation and Hofmann Elimination

Amines can be alkylated with alkyhaldes:

Reaction type: Nucleophilic Substitution

- The amine acts as a nucleophile

As a leaving group, an amino group would be –NH2, so amino groups are very poor
leaving groups. However, an amino group can be converted to a quartenary
ammonium salt by repeated alkylations.

NH2- and NR2-  are very poor leaving groups (both anionic), but NR3 is much
better (neutral)!!!
- Note that every time we add a –R to the ammonia we produce a strong
acid therefore a base must be used to neutralize it!!

The quartenary alkal halide, typically an ammonium iodide, is converted to a

quartenary ammonium hydroxide using silver oxide. Heating the quartenary
ammonium hydroxide results in the Hoffman elimination.
Hoffman elimination

Reaction type: Elimination

Summary

 Quaternary ammonium salts undergo an E2 elimination when heated

with silver oxide, Ag2O, in water!!
 Amines can readily be converted into quaternary ammonium iodides by treating
them with excess methyl iodide (as shown above).
 Ag2O / H2O reacts giving the quaternary ammonium hydroxide, silver iodide
precipitates.

 When heating the quartenary ammonium hydroxide results in Hofmann

Elimination (E2 mechanism)
 The less highly substituted alkene is sometimes referred to as the
Hofmann product.

Notice that the LEAST stable alkene is the major product in the Hofmann
Elimination!!

Amines and Nitrous Acid

Nitrous acid is a weak acid. A strong acid can dehydrate nitrous acid to produce
nitrosonium ion and water.
Most reactions with amines and nitrous acid involve the nitrosonium ion.
Another form of the nitrosonium ion

Primary amines react with nitrous acid to form diazonium salts. Alphiphatic
(nonaromatic) amines form extremely unstable salts that decompose spontaneously
to form nitrogen gas. Aromatic amines also form unstable diazonium salts, but
at a temperature below 5 Celc. they decompose very slowly!!!

Secondary amines have an extra R group instead of the tautomeric proton so

NO tautomer can form. Therefore it will stop at N-nitrosamine!!! Whenever
nitrous acid is added to a secondary amine the product is N-nitrosoamine

Mechanism:
The most useful reactions are probably those of primary aryl amines, Ar-
NH2, which give aryl diazonium salts, Ar-N2+ which can then be used to
prepare substituted benzenes!!!
 Note: Notice how all of the additional reactions with Ar-N2+ are
replacements but only the reaction with an aromatic ring
is an addition.

REMEMBER: That only aromatic amines work, and for primary think of the
diazonium ion.

Amides
Amides that have no substituent on the nitrogen are called primary amides.
Primary Amide:
Primary amides are named by replacing the –ic in the corresponding acid with
amide. Substituents on the nitrogen are prefaced by N-. For instance, if one
hydrogen on acetamide is replaced by an ethyl group, the result is N-ethylacetamide.
N-ethylacetamide

Amides can behave as a weak acid or a weak base!

They are less basic than amines due to the electron withdrawing properties of
the carbonyl.
Amides are hydrolyzed by either strong acids or strong bases.

Amides with a hydrogen attached to the nitrogen are able to hydrogen bond to each other.
Recall: They are the least reactive of the carboxylic acid derivatives and
therefore the most stable.

B-Lactams
Cyclic amides are called lactams. A Greek letter is assigned to the lactam to denote
the size. B-lactams are 4 membered rings, y-lactams have 5 members, and sigma-lactams
have 6 members and so on.
Although amides are the most stable of the carboxylic acid derivatives, B-lactams
are highly reactive due to the large ring strain (high heat of combustion).
Nucleophiles easily react with B-lactams via nucleophilic substitution.
B-lactams are found in several types of antibiotics!!

Hofmann Degradation
Primary amides react with strongly basic solutions of chlorine or bromine to
form primary amines with carbon dioxide as a by-product!!!
The N-haloamide is more acidic than the original primary amide and is
deprotonated as well!!

mechanism:

The advantage of the Hofmann degradation over other methods of producing

amines is that other amines rely upon an SN2 mechanism. This prevents the
production of amines on a tertiary carbon.
The Hofmann degradation can produce amines with a primary, secondary, or
tertiary alkyl position!!!

Phosphoric Acid
When heated phosphoric acid forms Phosphoric anhydride, Phosphoric
anhydride is a solid, which is very strongly moisture-absorbing and is used as a
desiccant.

Note: A desiccant is a hygroscopic substance that induces or sustains a

state of dryness (desiccation) in its local vicinity in a
moderately well- sealed container
The -OH groups in phosphoric acids can also condense with the hydroxyl groups of
alcohols to form phosphate esters. Since phosphoric acid has three -OH groups, it can
esterify with one, two, or three alcohol molecules to form a mono-, di-, or triester.
Phosphate ester

In a living cell at a pH about 7, triphosphates exist negatively charged ions,

making them less susceptible to nucleophilic attack and relatively stable!!
ATP is an example of an important triphosphate.