Cycloalkanes and Their Stereochemistry

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Amines and Heterocycles

• Amines are organic derivatives of ammonia
• Amines contain a nitrogen atom with a lone pair
  of electrons
• Amines are basic and nucleophilic
• Amines occur widely in both plants and animals

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18.1 Naming Amines

• Amines can be either alkyl-substituted
  (alkylamines) or aryl-substituted (arylamines)
• Amines are classified depending on the number of
  organic substituents attached to nitrogen
• Primary (RNH2)
• One organic substituent such as methylamine
  (CH3NH2)
• Secondary (R2NH)
• Two organic substituents such as dimethylamine
  (CH3)2NH
• Tertiary (R3N)
• Three organic substituents such as trimethylamine
  (CH3)3N

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Naming Amines

• Quaternary ammonium salts
• Nitrogen containing compounds with four organic
  (R) groups attached to the nitrogen atom
• Nitrogen carries a formal positive charge

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Naming Amines

• Primary amines are named in the IUPAC system in
  several ways
• For simple amines the
• suffix amine is added
• to the name of the alkyl
• substituent
• Aniline is an aryl amine
• The suffix amine can by
• used in place of the final
• e in the name of the
• parent compound

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Naming Amines

• Complex amines with more than one functional
  group are named by considering the NH2 as an
  amino substituent on the parent molecule

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Naming Amines

• Symmetrical secondary and tertiary amines are
  named by adding the prefix di- or tri- to the
  alkyl group

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Naming Amines

• Unsymmetrically substituted secondary and
  tertiary amines are named as N-substituted
  primary amines
• Largest alkyl group is chosen as the parent name
• Other alkyl groups are considered N-substituents
  on the parent
• N because they are attached to nitrogen

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Naming Amines

• Heterocyclic amines
• Compounds in which the nitrogen atom occurs as
  part of a ring
• Each different heterocyclic ring system has its
  own parent name
• The heterocyclic nitrogen atom is always numbered
  as position 1

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18.2 Properties of Amines

• Nitrogen atom in alkylamines is sp3-hybridized
• Three substituents occupy the three corners of a
  tetrahedron and the lone pair of electrons
  occupies the fourth corner
• Bond angles are close to 109

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Properties of Amines

• Nitrogen with three different substituents is
  chiral
• Chiral amines cannot be resolved because the two
  enantiomeric forms rapidly interconvert by a
  pyramidal inversion
• Inversion occurs by momentary rehybridization of
  nitrogen atom to planar, sp2 geometry, to give
  planar intermediate
• Rehybridization of planar intermediate occurs
  giving the tetrahedral, sp3 geometry
• Barrier to inversion is about 25 kJ/mol

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Properties of Amines

• Alkylamines are starting materials for
  insecticides and pharmaceuticals
• Labetalol is a b-blocker used for the treatment
  of high blood pressure
• Prepared by SN2 reaction of an epoxide with a
  primary amine

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Properties of Amines

• Amines with fewer than five carbons are generally
  water-soluble
• Amines form hydrogen bonds and are highly
  associated
• H-bonding results in higher boiling points than
  alkanes of similar molecular weights
• Amines possess characteristic odors

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18.3 Basicity of Amines

• Chemistry of amines dominated by the lone pair of
  electrons on nitrogen
• Lone pair makes amines both basic and
  nucleophilic
• Electrostatic potential surface of trimethylamine
  shows in red the region where the nonbonding
  electrons of nitrogen are located

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Basicity of Amines

• Amines are much stronger bases than alcohols and
  ethers
• Base strength measured by basicity constant, Kb

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Basicity of Amines

• Kb values are not often used
• Basicity of the amine is commonly measured by
  determining the acidity of its conjugate acid

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Basicity of Amines

• Weaker base Smaller pKa for ammonium ion
• Stronger base Larger pKa for ammonium ion

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Basicity of Amines

• Amides (RCONH2) are nonbasic
• Amides do not undergo substantial protonation
  when treated with acids
• Amides are poor nucleophiles
• Nitrogen lone-pair electrons are stabilized
  through orbital overlap with the carbonyl group

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Basicity of Amines

• Primary and secondary amines are very weak acids
• N-H proton can be removed by a sufficiently
  strong base
• Diisopropylamine (pKa 40) reacts with
  butyllithium to yield lithium diisopropylamide
  (LDA)

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18.4 Basicity of Arylamines

• Aryl amines are generally less basic than
  alkylamines
• Nitrogen lone-pair electrons are delocalized by
  interaction with the aromatic ring p electron
  system and less available for bonding to H

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Basicity of Arylamines

• Arylamines have a larger positive DG for
  protonation and are therefore less basic than
  alkylamines, primarily because of resonance
  stabilization of the ground state
• Nitrogen lone-pair electron density is
  delocalized in the amine but the charge is
  localized in the corresponding ammonium ion

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Basicity of Arylamines

• Electron-donating substituents which increase the
  reactivity for an aromatic ring toward
  electrophilic substitution also increase the
  basicity of the aryl amine
• Electron-withdrawing substituents which decrease
  ring reactivity toward electrophilic substitution
  also decrease arylamine basicity

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18.5 Biological Amines and the Henderson- Hasselba
lch Equation

• Amines exist essentially 100 in their protonated
  conjugate acid forms at physiological pH of 7.3
• Use Henderson-Hasselbalch equation to determine
  relative concentrations of amines and their
  conjugate acids

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Biological Amines and the Henderson-Hasselbalch
Equation

• For a 0.0010 M solution of methylamine at pH
  7.3
• pKa of methylammonium ion 10.64

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Biological Amines and the Henderson-Hasselbalch
Equation

• Cellular amines are written in their protonated
  forms
• Amino acids shown in their ammonium carboxylate
  form to reflect their structures at physiological
  pH

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18.6 Synthesis of Amines

• Reduction of Nitriles, Amides and Nitro Compounds
• Nitriles and amides are reduced by LiAlH4 into
  amines
• SN2 displacement with CN-
• followed by LiAlH4 reduction
• of the nitrile converts a
• primary alkyl halide into a
• primary alkylamine having
• one more carbon
• Carboxylic amides, formed
• from the reaction of the
• corresponding acid chloride
• with ammonia, are reduced
• with LiAlH4 into amines with
• the same number of carbons

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Synthesis of Amines

• Arylamines are usually prepared by nitration of
  an aromatic starting material, followed by
  reduction of
• the nitro group
• Reduction is accomplished by several methods

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Synthesis of Amines

• SN2 Reaction of Alkyl Halides
• Ammonia and other amines are good nucleophiles in
  SN2 reactions
• Alkylamines are synthesized most simply by SN2
  alkylation of ammonia or an alkylamine with an
  alkyl halide

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Synthesis of Amines

• Alkylations of ammonia and alkylamines often
  yield mixtures of products

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Synthesis of Amines

• Reductive Amination of Aldehydes and Ketones
• Amines can be synthesized in a single step from
  aldehydes or ketones with ammonia in the presence
  of a reducing agent
• Synthesis called a reductive amination

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Synthesis of Amines

• Mechanism of reductive amination
• Imine intermediate is
• formed by dehydration of the carbinolamine from
  the initial nucleophilic addition reaction
• CN bond of imine
• is then reduced

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Synthesis of Amines

• Ammonia, primary amines, and secondary amines can
  all be used in reductive amination yielding
  primary, secondary, and tertiary amines,
  respectively

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Synthesis of Amines

• Reductive aminations occur in biological pathways
• Biosynthesis of amino acid proline
• Glutamate 5-semialdehyde undergoes internal imine
  formation to give 1-pyrrolinium-5-carboxylate
• 1-pyrrolinium-5-carboxylate is reduced by
  nucleophilic addition of hydride ion by NADH

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Worked Example 18.1Using a Reductive
Amination Reaction

• How might you prepare N-methyl-2-phenylethylamine
  using a reductive amination reaction?

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Worked Example 18.1Using a Reductive
Amination Reaction

• Strategy
• Look at the target molecule, and identify the
  groups attached to nitrogen
• One of the groups must be derived from the
  aldehyde or ketone component and the other must
  be derived from the amine component
• In the case of N-methyl-2-phenylethylamine there
  are two combinations that can lead to the
  product
• Phenylacetaldehyde plus methylamine
• Formaldehyde plus 2-phenylethylamine
• In general, its usually better to choose the
  combination with the simple amine component
  methylamine in this case and to use an excess
  of that amine as reactant

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Worked Example 18.1Using a Reductive
Amination Reaction

• Solution

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18.7 Reactions of Amines

• Alkylation and Acylation
• Primary and secondary (not tertiary) amines can
  be acylated by reaction with acid chlorides or
  acid anhydrides to yield amides

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Reactions of Amines

• Hofmann Elimination
• Amines can be converted into alkenes by an
  elimination reaction
• NH2- is a poor leaving group and must be
  converted into a better leaving group
• Hofmann elimination
• Amine is methylated with excess iodomethane to
  produce a quaternary ammonium salt
• Quaternary ammonium salt undergoes elimination
  upon heating with silver oxide

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Reactions of Amines

• Silver oxide exchanges hydroxide ion for iodide
  ion in the quaternary salt
• Elimination is E2 and non-Zaitsev

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Reactions of Amines

• Major product is the less highly substituted
  alkene
• Base abstracts hydrogen from least hindered
  position due to the sterically bulky
  trialkylamine leaving group

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Reactions of Amines

• Biological eliminations analogous to the Hofmann
  elimination occur frequently
• In the biosynthesis of nucleic acids
  adenylosuccinate undergoes elimination of a
  positively charged nitrogen to give fumarate plus
  adenosine monophosphate

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Worked Example 18.2Predicting the Product of
a Hofmann Elimination

• What product would you expect from Hofmann
  elimination or the following amine?

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Worked Example 18.2Predicting the Product of
a Hofmann Elimination

• Strategy
• The Hofmann elimination is an E2 reaction that
  converts an amine into an alkene and occurs with
  non-Zaitsev regiochemistry to form the least
  highly substituted double bond. Look at the
  reactant and identify the positions from which
  elimination might occur (the positions two
  carbons removed from nitrogen). Carry out the
  elimination using the most accessible hydrogen.
  In the present instance, the primary (1o)
  position is the most accessible and leads to the
  least highly substituted alkene, ethylene.

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Worked Example 18.2Predicting the Product of
a Hofmann Elimination

• Solution

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Reactions of Amines

• Electrophilic Aromatic Substitution
• Amino substituents are strongly activating,
  ortho- and para-directing groups in electrophilic
  aromatic substitution
• Often give polysubstituted products
• Aryl amines do not undergo Friedel-Crafts
  reactions due to the acid-base reaction between
  the nonbonding electrons of the amino group and
  the AlCl3 catalyst

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Reactions of Amines

• Amido- substituted (-NHCOR) benzenes are less
  strongly activated because the nitrogen lone-pair
  electrons are delocalized by neighboring carbonyl
  group

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Reactions of Amines

• Sulfa drugs are prepared by chlorosulfonation of
  acetanilide
• Reaction of p-(N-acetylamino)benzenesulfonyl
  chloride with ammonia gives a sulfonamide
• Nitrogen of amide group is less basic that
  nitrogen of aryl amines
• Amide can be hydrolyzed in presence of
  sulfonamide group

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18.8 Heterocyclic Amines

• Heterocyclic amines are common in biological
  systems
• Most heterocycles have the same chemistry as
  their open-chain counterparts

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Heterocyclic Amines

• Pyrrole and Imidazole
• Many unsaturated ring heterocycles exhibit unique
  chemistry
• Pyrrole is an aromatic heterocycle prepared by
  reacting furan with ammonia over alumina

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Heterocyclic Amines

• Each carbon of pyrrole contributes one p electron
  and the sp2-hybridized nitrogen contributes two
  from its lone pair
• Pyrrole is a six p electron aromatic compound
• Nonbonding electrons of nitrogen are delocalized
  and less basic

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Heterocyclic Amines

• Nitrogen atom in pyrrole is less electron-rich,
  less basic, and less nucleophilic than nitrogen
  atom in an aliphatic amine
• Carbon atoms in pyrrole are more electron-rich
  and more nucleophilic than typical double-bond
  carbons

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Heterocyclic Amines

• Chemistry of pyrrole is similar to activated
  benzene rings
• Heterocycles are more reactive toward
  electrophiles than benzene rings and often
  require low temperatures
• Halogenation, nitration, sulfonation, and
  Friedel-Crafts acylation can all be accomplished
  with aromatic heterocycles

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Heterocyclic Amines

• Electrophilic substitution normally occurs at C2
  next to the nitrogen atom
• Substitution at C2 gives more stable intermediate
  with three resonance forms

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Heterocyclic Amines

• Imidazole (a constituent of histidine) and
  thiazole (on which the structure of thiamin is
  based) are common five-membered heterocyclic
  amines
• Only the lone-pair electrons of nitrogen atoms
  that are not participating in the aromatic p
  system are basic

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Heterocyclic Amines

• Pyridine and Pyrimidine
• The five carbon atoms and the sp2-hybridized
  nitrogen atom of pyridine contribute one p
  electron to the aromatic sextet
• The lone-pair electrons of nitrogen atom occupy
  an sp2 orbital in the plane of the ring
• Pyridine is less basic that alkylamines because
  the lone-pair electrons are in an sp2 orbital and
  are held more closely to the positively charged
  nucleus and thus less available for bonding

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Heterocyclic Amines

• Pyridine undergoes electrophilic aromatic
  substitution reactions with great difficulty

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Heterocyclic Amines

• Substitutions occur only slowly and usually at
  the C-3 of the ring
• Low reactivity of pyridine due to two factors
• Electrophile complexes in and acid-base reaction
  with the ring nitrogen placing a positive charge
  on the ring and deactivating it toward
  electrophilic aromatic substitution
• Electron density of the ring is decreased by the
  inductively withdrawing electronegative nitrogen
  atom
• Pyridine has substantial dipole moment (m 2.26
  D)

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Heterocyclic Amines

• Pyrimidine is a constituent of nucleic acids
• Pyrimidine is substantially less basic than
  pyridine due to the inductive effect of the
  second nitrogen atom

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18.9 Fused-Ring Heterocycles

• Quinoline, isoquinoline, indole, and purine are
  common fuse-ring heterocycles
• Quinoline alkaloid quinine is an antimalarial
  drug
• The amino acid tryptophan is an indole derivative
• The purine adenine is a constituent of nucleic
  acids

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Fused-Ring Heterocycles

• Quinoline and isoquinoline both undergo
  electrophilic substitutions less easily than
  benzene
• Reaction occurs on the benzene ring and produces
  a mixture of products

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Fused-Ring Heterocycles

• Indole has a nonbasic-pyrrole-like nitrogen and
  undergoes electrophilic substitution more easily
  than benzene
• Substitution occurs at C3 of electron-rich
  pyrrole ring

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Fused-Ring Heterocycles

• Purine has three basic, pyridine-like nitrogen
  atoms (1, 3, and 7) with lone-pair electrons in
  sp2 orbitals in the plane of the ring
• The remaining purine nitrogen atom (9) is
  non-basic and pyrrole-like with its lone-pair
  electrons part of the aromatic p system

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18.10 Spectroscopy of Amines

• Infrared Spectroscopy
• Primary amines show a pair of bands at about 3350
  and 3450 cm-1
• Secondary amines show a single band at 3350 cm-1
• Tertiary amines lack a N-H bond and do not absorb
  in this region of the IR spectrum

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Spectroscopy of Amines

• Nuclear Magnetic Resonance Spectroscopy
• Amine N-H absorptions can appear over a wide
  range and are best identified by adding a small
  amount of D2O to the sample tube
• N-H is exchanged for N-D and the N-H signal
  disappears from the 1H NMR spectrum

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Spectroscopy of Amines

• Hydrogens on the carbon next to nitrogen are
  deshielded because of the electron-withdrawing
  effect of the nitrogen
• Absorb at lower field than alkane hydrogens
• N-methyl groups are distinctive and absorb as a
  sharp three-hydrogen singlet at 2.2 to 2.6 d

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Spectroscopy of Amines

• Carbons next to amine nitrogens are slightly
  deshielded in the 13C NMR spectrum and absorb
  about 20 ppm downfield from where they would
  otherwise absorb in an alkane of similar structure

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Spectroscopy of Amines

• Mass Spectrometry
• Nitrogen rule of mass spectrometry
• A compound with an odd number of nitrogen atoms
  has an odd-numbered molecular weight
• Nitrogen is trivalent thus requiring an odd
  number of hydrogen atoms
• Alkylamines undergo characteristic a cleavage
• C-C bond nearest the nitrogen atom is broken

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Spectroscopy of Amines

• Mass spectrum of N-ethylpropylamine has peaks at
  m/z 58 and m/z 72 corresponding to the two
  possible modes of a cleavage