amines and heterocycles
DESCRIPTION
Naming Amines Alkyl-substituted (alkylamines) or aryl-substituted (arylamines) Classified as primary (RNH2), secondary (R2NH), and tertiary (R3N) Depends on number of organic substituents attached to nitrogenTRANSCRIPT
Amines and Heterocycles
Chapter 24 Amines and Heterocycles Suggested Problems
1-24,30-33,47-49,53-64,66 Naming Amines Alkyl-substituted
(alkylamines) or aryl-substituted (arylamines) Classified as
primary (RNH2), secondary (R2NH), and tertiary (R3N) Depends on
number of organic substituents attached to nitrogen Naming Amines
Quaternary ammonium salts: Compounds that carry a positively
charged nitrogen atom with four attached groups Simple amines are
named by adding the suffix -amine to the name of the alkyl
substituent Adding amine to the name of the alkyl substituent is
one way to name amines. Naming Amines The suffix -amine can be used
in place of the final -e in the name of the parent compound Amines
with more than one functional group are named by considering the
NH2 as an amino substituent A second way to name amines is to
replace the e at the end of the parent name with amine. Naming
Amines Symmetrical secondary and tertiary amines are named by
adding the prefix di- or tri- to the alkyl group Naming Amines
Unsymmetrically substituted secondary and tertiary amines Named as
N-substituted primary amines Largest alkyl group is the parent
name, and other alkyl groups are considered N-substituents The
compound at left could also be named N,N-dimethylpropanamine and
the compound at right could also be named
N-ethyl-N-methylcyclohexanamine. Naming Amines Heterocyclic amines:
Compound in which the nitrogen atom occurs as part of a ring Each
ring system has its own parent name Nitrogen atom is always
numbered as position 1 Heterocyclic rings are defined as ring which
are comprised of at least two different types of atoms here N and
C. Worked Example Name the following compounds: Solution: a)
CH3NHCH2CH3
b) Solution: a) N-Methylethylamine b)
N-Ethyl-N-methylcyclohexylamine Or N-methylethanamine and
N-ethyl-N-methylcyclohexanamine Structure and Properties of
Amines
Bonding in alkylamines is similar to that in ammonia N is
sp3-hybridized CNC bond angles are close to 109 tetrahedral value
Structure and Properties of Amines
An amine with three different substituents on nitrogen is chiral
The two enantiomeric forms rapidly interconvert by a pyramidal
inversion at room temperature Structure and Properties of
Amines
Amines with fewer than five carbon atoms are water-soluble Primary
and secondary amines form hydrogen bonds, increasing their boiling
points Basicity of Amines Lone pair of electrons on nitrogen makes
amines basic and nucleophilic React with acids to form acid-base
salts and they react with electrophiles Basicity of Amines Amines
are stronger bases than alcohols, ethers, or water Amines establish
an equilibrium with water in which water acts as an acid and
transfers a proton to the amine Basicity constant Kb is used to
measure the base strength of an amine High pKa weaker acid and
stronger conjugate base Basicity of Amines Basicity of an amine
(RNH2) can be measured by looking at the acidity of the
corresponding ammonium ion (RNH3+) The higher the Kb the more basic
the amine.The lower the pKb the more basic the amine. Typically we
think of the protonated amine and consider its pKa.If an amine is
weakly basic, its conjugate acid, the protonated amine, will be
strongly acidic and have a high Ka and a low pKa. Basicity of
Amines Weaker base - Smaller pKa for ammonium ion
Stronger base - Larger pKa for ammonium ion Basicity of Some Common
Amines
Note that the pKas of the amines listed here correspond to the
ammonium salts the protonated amines. Most simple alkylamines are
similar in their base strength, with pKas for their ammonium ions
in the narrow range 10 to 11.Arylamines, however, are considerably
less basic than alkylamines, as are the heterocyclic amines
pyridine and pyrrole. Basicity of Amines Amides (RCONH2) are
nonbasic, in contrast with amines Amides are stabilized by
delocalization of the nitrogen lone-pair electrons Amides are more
stable than amines Stability is lost when protonated Basicity of
Amines Primary and secondary amines can act as very weak acids N-H
proton can be removed by a sufficiently strong base (eg. LDA)
Butyllithium is a very strong base with a pKa on the order of 50.It
can easily pull a proton from a primary or secondary amine. Worked
Example Which compound in the following pair is more basic
CH3NHCH3 or pyridine Solution: CH3NHCH3 is more basic than pyridine
pKa of CH3NHCH3 is 10.73 pKa of pyridine is 5.25 Basicity of
Arylamines
Arylamines are less basic than alkylamines The N lone-pair
electrons in arylamines are delocalized by interaction with the
aromatic rings electron system Are less able to accept H+ Energy
difference between protonated and nonprotonated forms is higher for
arylamines Electrostatic Potential Maps Basicity of
Arylamines
Substituted arylamines can be either more basic or less basic than
aniline Electron-donating substituents increase the basicity of the
corresponding arylamine Electron-withdrawing substituents decrease
arylamine basicity Worked Example Rank the following compounds in
order of ascending basicity p-nitroaniline, p-aminobenzaldehyde,
p-bromoaniline Solution: Least basic Most basic All of these groups
withdraw electrons by resonance.The nitro group is the most
electron withdrawing.Remember that it directs electrophilic
aromatic substitution into the meta position by deactivating the
ring.The aldehyde behaves similarly but not to the extent the nitro
group does.The bromide is electron withdrawing but not nearly to
the extent of the other two groups. Biological Amines and the
Henderson-Hasselbalch Equation
To reflect structures at physiological pH: Cellular amines are
written in their protonated form Amino acids in their ammonium
carboxylate form The Henderson-Hasselbalch equation can be used to
calculate the extent of dissociation of an acid (in this case a
protonated amine) at a given pH if the pKa is known. Because
alkylamines have high pKa values (10-11), it is possible to
determine the predominant form (ionized or unionized) at
physiologic pH of 7.3. Worked Example Calculate the percentages of
neutral and protonated forms present in a solution of M pyrimidine
at pH = 7.3 The pKa of pyrimidinium ion is 1.3 Solution: At pH =
7.3, virtually 100% of the pyrimidine molecules are in the neutral
form In contrast, alkylamines with pKas of 10 to 11 exist almost
exclusively in their ionized protonated form. Amino acids then
exist as zwitterions with the amine protonated and the acid
deprotonated. Synthesis of Amines Reduction of nitriles, amides,
and nitro compounds
Amines can be prepared by reduction of nitriles and amides with
LiAlH4 The use of an SN2 displacement of an alkyl halide by cyanide
allows for the synthesis of a primary amine with one additional
carbon. Primary amides are reduced to primary amines with the same
number of carbons. Synthesis of Amines Arylamines are prepared from
nitration of anaromatic compound and reduction of the nitro group
Reduction by catalytic hydrogenation over platinumis suitable if no
other groups can be reduced Iron, zinc, tin, and tin(II) chloride
are effective inacidic solution Tin(II) chloride is particularly
mild and is often used when other reducible functional groups are
present. Worked Example Propose structures for either a nitrile or
an amide that might be a precursor of N-ethylaniline Solution: The
compound can be synthesized only by amide reduction Amide reduction
can be used to synthesize most amines, but nitrile reduction can be
used to synthesize only primary amines SN2 Reactions of Alkyl
Halides
Simplest method of alkylamine synthesis is by SN2 alkylation of
ammonia or an alkylamine with an alkyl halide Ammonia and other
amines are good nucleophiles These reactions dont stop cleanly
after a single alkylation has occurred, however. SN2 Reactions of
Alkyl Halides
Primary, secondary, and tertiary amines all have similar reactivity
Initially formed monoalkylated substance undergoes further reaction
to yield a mixture of products Secondary and tertiary amines
undergo further alkylation SN2 Reactions of Alkyl Halides
Azide ion, N3, displaces a halide ion from a primary or secondary
alkyl halide to give an alkyl azide Alkyl azides are not
nucleophilic Reduction gives only the primary amine Although this
method works well, low molecular weight alkyl azides are explosive
and must be handled carefully. SN2 Reactions of Alkyl Halides
Gabriel amine synthesis: A phthalimide alkylation for preparing a
primary amine from an alkyl halide N-H in imides (CONHCO) can be
removed by KOH followed by alkylation and hydrolysis Worked Example
Show two methods for the synthesis of dopamine, a neurotransmitter
involved in regulation of the central nervous system Use any alkyl
halide needed Worked Example Upper reaction is azide
synthesis
Lower reaction is Gabriel synthesis Reductive Amination of
Aldehydes and Ketones
Reductive amination: Treatment of an aldehyde or ketone with
ammonia or an amine in the presence of a reducing agent Mechanism
Reductive Amination Ammonia, primary amines, and secondary amines
through reductive amination reaction yield primary, secondary, and
tertiary amines, respectively Worked Example How might the
following amine be prepared using a reductive amination reaction?
Solution: Amine Precursor - Carbonyl Precursor - CH3CHO One could
envision that ethylamine and benzaldehyde would be effective
partners in this reaction as well.These partners would lead to the
same product. Hofmann and Curtius Rearrangements
Carboxylic acid derivatives can be converted into primary amines
with loss of one carbon atom by both the Hofmann rearrangement and
the Curtius rearrangement Both involve the loss of carbon dioxide
but their mechanisms are different.Both involve the migration of
the R group onto nitrogen atom. Mechanism Hofmann Rearrangement
Mechanism Hofmann Rearrangement
With heat carbamic acids lose carbon dioxide. Despite its
mechanistic complexity, Hofmann rearrangement often gives high
yields of both arylamines and alkylamines. Curtius
Rearrangement
Heating an acyl azide prepared from an acid chloride Migration of R
from C=O to the neighboring nitrogen with simultaneous loss of a
leaving group Worked Example How is the following amine prepared
using Curtius rearrangements on a carboxylic acid derivative?
Worked Example Solution:
The precursor is an acid chloride, which is treated with NaN3, then
with H2O and heat Note the lowermost path is the Curtius
rearrangement and the uppermost path is the Hofmann rearrangement.
Reactions of Amines Primary and secondary amines can also be
acylated by nucleophilic acyl substitution reaction Whereas
overalkylation of ammonia, primary, and secondary amines with alkyl
halides is a problem, overacylation of these amines is not a
problem because the amide nitrogen is insufficiently nucleophilic
to react further. Hofmann Elimination Converts amines into
alkenes
NH2 is very a poor leaving group; it is converted to an
alkylammonium ion, which is a good leaving group An amine is
completely methylated by reaction with an excess amount of
iodomethane to produce the corresponding quaternaryammonium salt
Hofmann Elimination Silver oxide is used for the elimination
step
Exchanges hydroxide ion for iodide ion in the quaternary ammonium
salt, thus providing the base necessary to cause elimination The
actual elimination step is an E2 elimination in which hydroxide ion
removes a proton while the positively charged nitrogen atom leaves.
Orientation in Hofmann Elimination
Major product is the less highly substituted alkene Non-Zaitsev
result is probably steric Due to the large size of the
trialkylamine leaving group The base must abstract a hydrogen from
the most sterically accessible Least hindered position Orientation
in Hofmann Elimination Worked Example What products would you
expect from Hofmann elimination of the following amine? If more
than one product is formed, indicate which is major Worked Example
Solution:
The first pair of products results from elimination of a primary
hydrogen and are the major products The second pair of products
results from elimination of a secondary hydrogen Reactions of
Arylamines
Electrophilic aromatic substitution Amino substituents are strongly
activating and ortho- and para-directing groups in electrophilic
aromatic substitution reactions Reactions are controlled by
conversion to amide Because amines are so strongly activating,
polysubstitution in electrophilic aromatic substitution reactions
is a problem.In the case of aniline, it is impossible to get solely
the monosubstituted product. Converting the NH2 to an amide
decreases the activation provided by the NH2 group substantially
without affecting the substitution pattern (ortho, para). Reactions
of Arylamines
The amino group forms acid-base complex with the AlCl3 catalyst
preventing further reaction Therefore, we use the corresponding
amide Similarly, anilines cannot undergo Friedel-Craft type
reactions because the basic nitrogen effectively ties up the Lewis
acid catalyst. Again, conversion to the amide solves the problem.
Reactions of Arylamines
Modulating the reactivity of an amino-substituted benzene allows
many kinds of electrophilic aromatic substitutions to be carried
out Sulfa drugs were among the first pharmaceutical agents to be
used clinically against bacterial infection Note here that
hydrolysis of the amide occurs preferentially over hydrolysis of
the sulfonamide; sulfonamides hydrolyze very slowly. Worked Example
Propose syntheses of m-chloroaniline from benzene
Solution: Chlorination occurs before reduction so that chlorine can
be introduced in the m-position Neither the NH2 group nor the
chlorine substituent can be present initially in the reactant
because both of these groups direct ortho, para.An amide does
similarly.So both the NH2 and Cl must be introduced at a later
stage.Since the nitro group directs meta and can be easily
converted into an aniline, its introduction permits meta
chlorination.It is important to use tin in the reduction step
because catalytic hydrogenation with a nickel catalyst could remove
the chlorine substituent. Reactions of Arylamines
Diazonium salts: The Sandmeyer reaction Primary arylamines react
with HNO2 yielding stable arenediazonium salts Corresponding
alkanediazonium can not be isolated Arenediazonium salts are useful
because the diazonio group can be replaced by a nucleophile in a
substitution reaction The process of forming a diazonium salt by
reaction of an aniline with nitrous acid is referred to as
diazotization. Reactions of Arylamines
Sandmeyer reaction: Reaction of an arenediazonium salt with the
corresponding copper(I) halide to yield aryl chlorides and bromides
Aryl iodides can be prepared by direct reaction with NaI Copper(I)
salts are not required in the synthesis of aryl iodides. Reactions
of Arylamines
An arenediazonium salt and CuCN yield the nitrile, ArCN, which can
be hydrolyzed to other functional groups The diazonio group can be
replaced by OH to yield a phenol and by H to yield an arene Note in
the first reaction above, the product cannot be prepared from
o-xylene by the usual side-chain oxidation because both methyl
groups would be oxidized. Reactions of Arylamines
Reaction of arenediazonium salt with copper(I) oxide in an aqueous
solution of copper(II) nitrate yield phenols This is a useful
reaction because few other general methods exist for introducing an
OH group onto an aromatic ring. Reduction to a Hydrocarbon
By treatment of a diazonium salt with hypophosphorous acid, H3PO2
Diazonium replacement takes place through radical pathways This
reaction is used primarily when there is a need for temporarily
introducing an amino substituent onto a ring to take advantage of
its directing effect.By incorporating an amino group in the para
position of toluene, dibromination in the two ortho positions is
possible.Removal of the amino group by diazotization effectively
removes the amine substituent to afford 3,5-dibromotoluene. Worked
Example How is p-bromobenzoic acid prepared from benzene using a
diazonium replacement reaction Solution: Use of the diazonium
replacement reaction that substitutes bromine for a nitro group
Both the carboxy and bromo substituents on an aromatic ring are
ortho, para directing.One would find it very difficult to separate
the isomers that would be generated by effecting electrophilic
aromatic substitution reactions on one or the other.Nitro isomers
tend to be easily separable either via chromatography or by
recrystallization.Nitrating toluene would lead to the para isomer
being the predominant product for steric reasons.There still would
be some ortho isomer but that could be readily separated by
recrystallization.Conversion to the diazonium salt allows for the
introduction of the bromine. Diazonium Coupling Reactions
Arenediazonium salts undergo a coupling reaction with activated
aromatic rings to yield azo compounds, ArN=NAr Are typical
electrophilic aromatic substitutions Diazonium Coupling
Reactions
The electrophilic diazonium ion reacts with the electron-rich ring
of a phenol or arylamine Usually occurs at the para position but
goes ortho if para is blocked Diazonium Coupling Reactions
Azo-coupled products have extended conjugation that lead to low
energy electronic transitions that occur in visible light
Azo-coupled products are widely used as dyes for textiles because
of their extended conjugation. Worked Example Propose a synthesis
of p-(dimethylamino)azobenzene with benzene as organic starting
material Solution: Heterocyclic Amines A cyclic organic compound
that contains atoms of two or more elements in its ring Most
heterocyclic compounds possess same chemistry as their open-chain
counterparts Lactones and acyclic esters behave similarly, lactams
and acyclic amides behave similarly, and cyclic and acyclic ethers
behave similarly. Where the ring is unsaturated, however,
heterocycles have unique and interesting properties. Heterocyclic
Amines Pyrrole
Simplest five-membered unsaturated heterocyclic amine Undergoes
electrophilic substitution reactions Chemical properties are not
consistent with the structural features of amine or a conjugated
diene Pyrrole has six pi electrons and is aromatic.Thus it does not
react as a diene or as a typical aliphatic amine. Protonation on
nitrogen would destroy the aromaticity so pyrrole is not basic nor
is it nucleophilic. Halogenation, nitration, sulfonation, and
Friedel-Crafts acylation can all be accomplished. Heterocyclic
Amines Ring is reactive toward electrophiles
Electrophilic substitutions occur at C2 Reaction leads to
intermediate cation having 3 resonance forms Reaction at C3 gives
only 2 resonance forms Heterocyclic Amines Imidazole Common
five-membered heterocyclic amine
Constituent of the amino acid histidine One of two nitrogens is
basic One of the nitrogen atoms in imidazole and the lone nitrogen
atom in thiazole are basic and can be protonated.Imidazole is a
very mild base which is often used to scavenge protons in some
organic reactions. Worked Example Draw an orbital picture of
thiazole Solution:
Assume that both the nitrogen and sulphur atoms are sp2-hybridized
Show the orbitals that the lone pairs occupy Solution: Contains six
electrons Each carbon contributes one electron, nitrogen
contributes one electron, and sulfur contributes two electrons to
the ring system The overall result is there are six pi electrons
and thiazole is aromatic. Worked Example Sulfur and nitrogen have
lone electron pairs in sp2 orbitals that lie in the plane of the
ring Heterocyclic Amines Pyridine
Nitrogen-containing heterocyclic analog of benzene The
sp2-hybridized nitrogen atom is less basic than the sp3-hybridized
nitrogen in an alkylamine Pyridine is aromatic.The lone pair on
nitrogen is in an sp2 orbital.Having less s character than an sp3
orbital the lone pair is held closer to the nitrogen nucleus
accounting for the diminished basicity. Heterocyclic Amines
Undergoes electrophilic aromatic substitution reactions with
difficulty Acid-base complexation between the basic rings nitrogen
atom and the incoming electrophile High dipole moment pulls density
out of ring Six-membered diamine pyrimidine is found commonly in
biological molecules Worked Example Electrophilic aromatic
substitution reactions of pyridine normally occur at C3 Draw the
carbocation intermediates resulting from reaction of an
electrophile at C2, C3, and C4 Explain the observed result
Solution: Worked Example Reaction at C3 is favored over reaction at
C2 or C4 Worked Example Positive charge of the cationic
intermediate of reaction at C3 is delocalized over three carbon
atoms rather than over two and the electronegative pyridine
nitrogen as occurs in reaction at C2 or C4 Heterocyclic Amines
Polycyclic heterocycles
Quinoline, isoquinoline, and indole contain both a benzene ring and
a heterocyclic aromatic ring Purine contains two heterocyclic rings
joined together Quinoline and isoquinoline are less reactive
towards electrophilic substitution Indole undergoes electrophilic
substitution more easily than benzene Heterocyclic Amines
Heterocyclic Amines Purine has three basic, pyridine-like nitrogen
atoms Worked Example Which nitrogen atom in the hallucinogenic
indole alkaloid N,N-dimethyltryptamine is more basic? Explain
Worked Example Solution:
Side chain nitrogen atom of N,N-dimethyltryptamine is more basic
than the ring nitrogen atom Aromatic nitrogen electron lone pair is
part of the ring electron system Spectroscopy of Amines
Infrared spectroscopy 1 and 2 amine are identified by
characteristic NH stretching absorptions at 3300 to 3500 cm1 Amine
absorption bands are sharper and less intense than hydroxyl bands
NH bend (scissor) is noticed above 1600 cm1 Generally primary
amines exhibit two bands in the 3300 to 3500 region.Secondary
amines exhibit only one band.Since tertiary amines do not have an
N-H bond they do not absorb in this area. Nuclear Magnetic
Resonance Spectroscopy
NH hydrogens appear as broad signals without clear-cut coupling to
neighboring CH hydrogens In D2O exchange of ND for NH occurs, and
the NH signal disappears Hydrogens on the carbon next to nitrogen
are deshielded due to the electron-withdrawing effect of nitrogen
Carbons next to amine nitrogens absorb about 20 ppm further
downfield than would otherwise be expected if they were not
deshielded by the nitrogen atom. Nuclear Magnetic Resonance
Spectroscopy
Hydrogens on C next to N absorb further downfield than alkane
hydrogens N-CH3 gives a sharp three-H singlet at 2.2 to 2.6 Worked
Example Compound A, C6H12O, has an IR absorption at 1715 cm-1 and
gives compound B, C6H15N, when treated with ammonia and NaBH4 What
are the structures of A and B? Worked Example Solution:
It is inferred that B is a primary amine, from the spectrum 1H NMR
spectrum shows a 9-proton singlet, a one-proton quartet, and a
3-proton doublet Absorption due to the amine protons is not visible
Mass Spectrometry Compound with odd number of nitrogen atoms has
odd-numbered molecular weight Presence of N can be detected
observing the spectrum Alkylamines cleave at the CC bond nearest
the nitrogen to yield an alkyl radical and a nitrogen-containing
cation Mass Spectrum of N-ethylpropylamine
The two main modes of a cleavage give fragment ions at m/z = 58 and
m/z = 72