amines. nitrogen-based functional groups amines as pharmaceutical agents

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  • Amines

  • Nitrogen-Based Functional Groups

  • Amines as Pharmaceutical Agents

  • 22.1Amine Nomenclature

  • The Naming of PartsAlkylamines

    Nitrogen atom isattached to alkyl group:

    Arylamines

    Nitrogen atom isattached to aryl group:

  • Nomenclature of Primary Alkylamines (RNH2)Two IUPAC styles1) analogous to alcohols: replace -e ending by -anamine2) name alkyl group and attach -amine as a suffix

  • Nomenclature of Primary Alkylaminesn-propylamineorpropanaminecyclopropylamineorcyclopetanamine2-bromo-3-chlorobutylamine

  • Nomenclature of Arylamines (ArNH2)aniline2,4-dibromoaniline4-bromo-2-ethylanilineThese compounds are named as derivatives of aniline

  • Amino Groups have Lower Priority than Alcoholsaminoethanolp-aminobenzoic acidWith regards to nomenclature, amines rank lower than alcohols and are named as substituents:

  • Secondary and Tertiary AminesN,N-diisopropylethylamine(a.k.a. Hnigs base)4-bromo-N,N-dimethyl-2-methylanilineName as N-substituted derivatives of parent primary amine. The longest chain takes the root name.

  • Ammonium Salts (R4-nHnN+ X-) Nitrogen atoms are positively charged when bonded to four substituents. The root name in this case is the ammonium ion (NH4+). Remember to name as a salt - two words.methylammonium acetateN-ethyl-N-methylbenzylammonium chloride

  • Quaternary Ammonium Salts (R4N+ X-) Nitrogen atoms are positively charged when bonded to four substituents: when all of these substituents are carbon, the molecule is referred to as a quaternary ammonium ion.tetrabutylammonium fluoride(TBAF)benzyltrimethylammonium hydroxideQuaternary ammonium salts are relatively soluble in organic solvents and consequently are used as phase transfer catalysts

  • 22.2Structure and Bonding of Amines

  • 147 pm106112Structure of Alkylamines

  • Note the high electron density on the nitrogen atom. The chemistry of amines is dominated by reactivity of the lone pair on this atom. Amines behave as nucleophiles and Bronsted bases.Alkylamines - Distribution of Electron Density

  • The hybridization adopted by nitrogen depends upon the nature of the N-substituents.Compare methylamine and formamide:Alkylamines - Hydridization at Nitrogen

  • the hybridization adopted by nitrogen depends upon the nature of the N-substituents - compare methylamine and formamide.Amines & Amides - Geometry at Nitrogen

  • Angle that the CN bond makes with bisector of HNH angle is a measure of the pyramidalization at nitrogen.sp3sp2~125180142.5Amines - Geometry at Nitrogen

  • Angle that the CN bond makes with bisector of HNH angle is a measure of the pyramidalization at nitrogen.142.5Amines - Geometry at NitrogenGeometry at the nitrogen atom in aniline is pyramidal; closer to methylamine than to formamide.

  • 142.5The hybridization of the nitrogen atom in aniline lies between sp2 and sp3

    Delocalization of the nitrogen lone pair into the aromatic ring is most effective if the nitrogen atom is sp2-hybridized and planar.

    2) A planar nitrogen atom increases repulsion between filled lone pair orbital and p-system of aromatic ring - sp3 hybridization reduces this bad interaction.Geometry of Aniline

  • Aniline - Distribution of Electron Density Enforce a non-planar geometry (sp3-like) at the nitrogen center

    - highest negative potential is on nitrogen.Enforce a planar geometry (sp2-like) at the nitrogen center

    - negative potential is shared by both nitrogen and ring.

  • 22.3Physical Properties of Amines

  • Amines - Physical Properties Amines are more polar and have higher boiling points than alkanes; but are less polar and have lower boiling points than alcohols.CH3CH2CH3CH3CH2NH2CH3CH2OHdipole moment ():boiling point:0 D1.2 D1.7 D-42C17C78C

  • Amines - Physical Properties Boiling points of isomeric amines decrease in going from primary to secondary to tertiary amines.Primary amines have two hydrogens on nitrogen capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds.CH3CH2NHCH3CH3CH2CH2NH2(CH3)3Nboiling point:50C34C3C

  • 22.4Basicity of Amines

  • Amines are Brnstead Bases and Nucleophiles

  • Brnstead Basicity of Amines

    1. Alkylamines are slightly stronger bases than ammonia.

    2.

  • Basicity of Amines in Aqueous Solution

    Amine

    Conjugate

    Acid

    pKa

    9.3

    10.8

    The ethylammonium ion (CH3CH2NH3+) is a weaker acid than ammonium (NH4+) therefore; ethylamine (H3CH2NH2) is a stronger base than ammonia (NH3)

  • The Relationship between pKa and Basicity

    Amine

    Conjugate

    Acid

    pKa

    9.3

    10.8

    The ethylammonium ion (CH3CH2NH3+) is a weaker acid than ammonium (NH4+) therefore; ethylamine (H3CH2NH2) is a stronger base than ammonia (NH3)

  • The Relationship Between Basicity and Structure

    1. Alkylamines are slightly stronger bases than ammonia.

    2. Alkylamines differ very little in basicity.

  • Basicity of Amines in Aqueous Solution

    Amine

    Conjugate

    Acid

    pKa

    9.3

    10.8

    11.1

    10.8

  • The Relationship Between Basicity and Structure

    1. Alkylamines are slightly stronger bases than ammonia.

    2. Alkylamines differ very little in basicity.

    3.Arylamines are much weaker bases than ammonia.

  • Basicity of Amines in Aqueous Solution

    Amine

    Conjugate

    Acid

    pKa

    NH3

    NH4+

    9.3

    CH3CH2NH2

    CH3CH2NH3+

    10.8

    (CH3CH2)2NH

    (CH3CH2)2NH2+

    11.1

    (CH3CH2)3N

    (CH3CH2)3NH+

    10.8

    PhNH2

    PhNH3+

    4.6

  • Arylamines are Relatively Weak Brnstead BasesAnilinium Ion

  • Arylamines are Relatively Weak Brnstead BasesIncreasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

    Amine

    Conjugate

    Acid

    pKa

    4.6

    0.8

    ~ -5.0

  • Arylamines - Effect of Substituents on Basicity1. Alkyl groups on the ring increase basicity by only one 1 pK unit.

    Amine

    Conjugate

    Acid

    pKa

    4.6

    5.3

  • 2. Electron withdrawing groups, especially ortho and/or para to amine group, decrease basicity and can have a large effect.Arylamines - Effect of Substituents on Basicity

    X

    pKa of conjugate acid

    H

    4.6

    CN

    3.5

    NO2

    1.0

  • Basicity of Arylamines - p-NitroanilineLone pair on amine nitrogen is conjugated with p-nitro groupmore delocalized than in aniline itself. This delocalization is lost upon protonation.

  • Electron Withdrawing Effects are Cumulative

  • Electron Withdrawing Effects are Cumulative

    Amine

    Conjugate

    Acid

    pKa

    10.3

    8.3

    3.1

  • Heterocyclic Amines

  • imidazolepyridinepKa of conjugate acid:7.0pKa of conjugate acid:5.2Heterocyclic Amines

  • q. Which nitrogen is protonated in imidazole?Protonation of Imidazole

  • Protonation in the direction shown gives a stabilized ion.Protonation of Imidazole - Resonance Picture

  • The Term Alkaloid

    The term alkaloid is composed from two words, the Arabic al-qualja (plant ashes) and the Greek (type, similarity).

  • The Term Alkaloid

    Meissner 1819: To me it seems wholly appropriate to refer to those plant substances currently known by the names of alkalis, but alkaloids, since some of their properties they differ from alkalis considerably, and would thus find their place before the plant acids in the field of plant chemistry.

    Jacobsen 1882: The bodies referred to as alkaloids are nitrogen-containing organic bases. The group, however, is in many respects not sharply defined.

  • The Term Alkaloid

    Pelletier 1983: An alkaloid is a cyclic organic compound containing nitrogen in a negative oxidation state, which is of limited distribution among living organisms.

  • Amines as Natural Products - AlkaloidsConium maculatum Hemlock contains the alkaloid coniine, among other compounds

    The man. laid his hands on him and after a while examined his feet and legs, then pinched his foot hard and asked if he felt it. He said No; then after that, his thighs; and passing upwards in this way he showed us that he was growing cold and rigid. And then again he touched him and said that when it reached his heart, he would be gone. The chill had now reached the region about the groin, ...the attendant uncovered him; his eyes were fixed. And Crito when he saw it, closed his mouth and eyes.

    [Plato's description of the death of Socrates, as witnessed by Crito in 399 B.C.]

  • The Toxic Alkaloids of Conium maculatum

  • Reduction of Nitroarenes - ExampleAromatic nitro compounds are easy to prepare and are readily reduced to the corresponding anilines under a wide range of conditions.

  • Reduction of Nitroarenes - Example

  • 18.9The Aldol Condensation

  • Aldol Condensation

  • Aldol Condensation of Butanal

  • dehydration of -hydroxy aldehyde can be catalyzed by either acids or basesDehydration of Aldol Addition Product

  • in base, the enolate is formed Dehydration of Aldol Addition ProductNaOH

  • the enolate loses hydroxide to form the ,-unsaturated aldehydeDehydration of Aldol Addition ProductNaOH

  • Aldol reactions of ketonesthe equilibriu

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