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Amines Nitrogen-Based Functional Groups! O N+ O– R N N N azides R C N nitriles nitroarenes N O R' R R R'' imines N R'' amides R' R' R N R'' amines Amines as Pharmaceutical Agents! O OH HN CH3 CH3 HN CH3 Pseudoephedrine (decongestant) OH Acetaminophen (analgesic) NH2 Cl O H N OH N N O O O CH3 Aspartame (artificial sweetener) Chlorpheniramine (blocks the effect of histamine) 22.1 Amine Nomenclature The Naming of Parts! Alkylamines R N Nitrogen atom is attached to alkyl group: Arylamines Nitrogen atom is attached to aryl group: Alkyl R R = H or Alkyl R N R R = H, Alkyl or Aryl Nomenclature of Primary Alkylamines (RNH2) Two IUPAC styles 1) analogous to alcohols: replace -e ending by -anamine 2) name alkyl group and attach -amine as a suffix Nomenclature of Primary Alkylamines H3C H2 C C H2 n-propylamine or propanamine H N H H cyclopropylamine or cyclopetanamine N H Br H3C H N H Cl 2-bromo-3-chlorobutylamine Nomenclature of Arylamines (ArNH2) These compounds are named as derivatives of aniline H N aniline H Br H N H Br 2,4-dibromoaniline H N H Br CH3 4-bromo-2-ethylaniline Amino Groups have Lower Priority than Alcohols With regards to nomenclature, amines rank lower than alcohols and are named as substituents: OH H2N aminoethanol O OH H2N p-aminobenzoic acid Secondary and Tertiary Amines Name as N-substituted derivatives of parent primary amine. The longest chain takes the root name. CH3 H3C CH3 CH3 N N,N-diisopropylethylamine (a.k.a. Hünig’s base) CH3 CH3 CH3 N CH3 4-bromo-N,N-dimethyl-2-methylaniline Br 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. H N H3C H O methylammonium acetate H O CH3 N CH3 Cl H CH3 N-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. C4H9 N C4H9 C4H9 F C4H9 N CH3 tetrabutylammonium fluoride (TBAF) CH3 CH3 OH Quaternary ammonium salts are relatively soluble in organic solvents and consequently are used as phase transfer catalysts benzyltrimethylammonium hydroxide 22.2 Structure and Bonding of Amines Structure of Alkylamines 147 pm 112° 106° Alkylamines - Distribution of Electron Density 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 - Hydridization at Nitrogen The hybridization adopted by nitrogen depends upon the nature of the N-substituents. Compare methylamine and formamide: formamide methylamine H H O H C H N N H H H H Lone Pair H H sp3-hydridized tetrahedral N H H H Lone Pair O C N H H H sp2-hydridized planar Amines & Amides - Geometry at Nitrogen the hybridization adopted by nitrogen depends upon the nature of the N-substituents - compare methylamine and formamide. formamide methylamine H H O H C H N N H H H H Lone Pair H H sp3-hydridized tetrahedral N H H H Lone Pair O C N H H H sp2-hydridized planar Amines - Geometry at Nitrogen Angle that the C—N bond makes with bisector of H—N—H angle is a measure of the pyramidalization at nitrogen. sp3 sp2 180° ~125° 142.5° Amines - Geometry at Nitrogen Angle that the C—N bond makes with bisector of H—N—H angle is a measure of the pyramidalization at nitrogen. 142.5° Geometry at the nitrogen atom in aniline is pyramidal; closer to methylamine than to formamide. Geometry of Aniline The hybridization of the nitrogen atom in aniline lies between sp2 and sp3 1) 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 π-system of aromatic ring - sp3 hybridization reduces this “bad” interaction. 142.5° Aniline - Distribution of Electron Density Enforce a non-planar geometry (sp3-like) at the nitrogen center Enforce a planar geometry (sp2-like) at the nitrogen center - highest negative potential is on nitrogen. - negative potential is shared by both nitrogen and ring. 22.3 Physical 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. CH3CH2CH3 CH3CH2NH2 CH3CH2OH dipole moment (µ): 0D 1.2 D 1.7 D boiling point: -42°C 17°C 78°C Amines - Physical Properties CH3CH2CH2NH2 CH3CH2NHCH3 boiling point: 50°C 34°C (CH3)3N 3°C 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. 22.4 Basicity of Amines Amines are Brønstead Bases and Nucleophiles N H X N X Amines behave as Nucleophiles Amines behave as Brønstead Bases Amines are electron-rich and have a reactive lone pair, which can form a covalent bond to electrophiles C N C Amines behave as Nucleophiles O Brønstead Basicity of Amines 1. Alkylamines are slightly stronger bases than ammonia. 2. …… Basicity of Amines in Aqueous Solution Amine Conjugate Acid H H N N H H H N 9.3 H H H H3C H pKa H3C H N H H 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 H H N N H H H N 9.3 H H H H3C H pKa H3C H N H H 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 H H N N H H H H N H3C N H N H H H 10.8 H H H3C 9.3 H H H3C pKa CH3 H3C N CH3 11.1 H CH3 CH3 H3C N CH3 H3C N H CH3 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 Brønstead Bases Stronger H Acid N H H H Anilinium Ion Stronger Base N H pKa = 4.6 Weaker Base H N H H H Weaker Acid N H pKa = 10.6 Arylamines are Relatively Weak Brønstead Bases Increasing delocalization makes diphenylamine a weaker base than a n i l i n e , a n d triphenylamine a weaker b a s e t h a n diphenylamine. Amine Conjugate Acid H H N N H H H H N N H N H N H pKa 4.6 0.8 ~ -5.0 Arylamines - Effect of Substituents on Basicity 1. Alkyl groups on the ring increase basicity by only one 1 pK unit. Conjugate Acid Amine H H N N H H H H H3C pKa 4.6 H H H N N H H H H3C 5.3 Arylamines - Effect of Substituents on Basicity 2. Electron withdrawing groups, especially ortho and/or para to amine group, decrease basicity and can have a large effect. H pKa of conjugate acid 4.6 CN 3.5 NO2 1.0 X H N X H N H H H X Basicity of Arylamines - p-Nitroaniline Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. This delocalization is lost upon protonation. O O N O N H H H N O N H Electron Withdrawing Effects are Cumulative H H N N H is 3800 times more basic than....... H O2N H p-nitroaniline aniline NO2 H N H is 1,000, 000, 000 times more basic than....... H N O2N H aniline 2,4-dinitroaniline H Electron Withdrawing Effects are Cumulative Conjugate Acid Amine H N H H N N H H pKa H 10. 3 H N 8.3 H N N H 3.1 Heterocyclic Amines is more basic than...... N N H piperidine pyridine pKa of conjugate acid: 11.2 pKa of conjugate acid: 5.2 (an alkylamine) (resembles an arylamine in basicity) Heterocyclic Amines N N H is more basic than...... N imidazole pyridine pKa of conjugate acid: 7.0 pKa of conjugate acid: 5.2 Protonation of Imidazole q. Which nitrogen is protonated in imidazole? N N N N H H H+ H+ H H N N H aromatic imidazolium ion N N H nonaromatic iminium ion Protonation of Imidazole - Resonance Picture Protonation in the direction shown gives a stabilized ion. N N H H+ H N N H aromatic imidazolium ion H N N H aromatic imidazolium ion The Term ‘Alkaloid’! The term ‘alkaloid’ is composed from two words, the Arabic ‘al-qualja’ (plant ashes) and the Greek ‘ειδοσ’ (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. OCH3 H3C N OH H HO H N O O (-)-Hyoscyamine (Atropa belladonna) N H (-)-Quinine (Cinchona pubescens) Amines as Natural Products - Alkaloids! 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.] Conium maculatum Hemlock contains the alkaloid coniine, among other compounds The Toxic Alkaloids of Conium maculatum N N H N H 2-Methylpiperidine γ-Coniceine Coniine HO H HO H N H (+)-Pseudoconhydrine N H O Conhydrinone N Me (+)-N-Methylpseudoconhydrine H N N H OH (+)-α-Conhydrine Me N-Methylconiine Reduction of Nitroarenes - Example Aromatic nitro compounds are easy to prepare and are readily reduced to the corresponding anilines under a wide range of conditions. O O OCH3 OH OCH3 Combretastatin A-2 a antineoplastic agent isloated from the South African bush willow tree Reduction of Nitroarenes - Example O Br PPh3 O O Ph P Ph O OCH3 H H H Ph n-BuLi Br O Ph O ylide (reactive nucleophile) OCH3 OCH3 Ph P O Ph H phosphonium salt Wittig Reaction NO2 OCH3 O Reduction O Zinc metal O acetic acid OCH3 N OCH3 H H O OCH3 NO2 OCH3 18.9 The Aldol Condensation Aldol Condensation O OH KOH H2O R H H H Aldol Addition Reaction β O H R H α R Heat KOH Heat, -H2O Dehydration Aldol Condensation Reaction O β R α H R Dehydration Product Aldol Condensation of Butanal newly formed carbon-carbon double bond KOH H2O O H 2 x n-Butanal 100 °C (86%) Aldol Condensation Reaction O β α H α,β-Unsaturated Ketone Dehydration of Aldol Addition Product C H C O C C C OH dehydration of β-hydroxy aldehyde can be catalyzed by either acids or bases C O Dehydration of Aldol Addition Product C H O NaOH C C OH in base, the enolate is formed – C O C OH C •• Dehydration of Aldol Addition Product C H O NaOH C C OH the enolate loses hydroxide to form the α,β-unsaturated aldehyde – C O C OH C •• Aldol reactions of ketones O H3C CH3 2 x Acetone OH 2% H3C 98% H3C O CH3 Formation of Aldol product is not thermodynamically favorable [4-hydroxy-4-methylpentan-2-one] the equilibrium constant for aldol addition reactions of ketones is usually unfavorable Termite Self-Defense! Toxic compound produced by soldier termites of the species Schedorhinotermes lamanianus nucleophilic alkenes are not reactive to nucleophiles conjugated alkene is reduced by enyzme expressed by worker termites O electrophilic alkene reacts with nucleophilic thiols (RSH) O Non-toxic to worker termiotes Diethyl Zinc and Deacidification of Brittle Books Me Zn Me Diethylzinc (a volatile liquid) H2O (in paper) Ethane (a volatile gas) CH3 CH3 + Zn(OH)2 CO2 Zn(CO3) Unused zinc hydroxide reacts with carbon dioxide form zinc carbonate Zinc hydroxide neutralizes acid (H+) in paper 14.13 Carbenes and Carbenoids Carbene name to give to species that contains a divalent carbon (carbon with two bonds and six electrons) •• C Br Br dibromocarbene Carbenes are very reactive; normally cannot be isolated and stored. Are intermediates in certain reactions. Generation of Dibromocarbene Br Br H C + – •• •• OC(CH3)3 •• Br Br Br C •• Br – + H •• OC(CH3)3 •• Generation of Dibromocarbene •• C Br Br Br Br C •• Br – + Br – Carbenes react with alkenes to give cyclopropanes KOC(CH3)3 Br (CH3)3COH Br + CHBr3 CBr2 is a highly reactive (shortlived) intermediate (75%) Why the synthesis of cyclopropanes is important? R Me Me O O Me Me O Me Pyrethrin (Natural Insecticide in RAIDTM) Chrysanthemum cinerariaefolium Why the synthesis of cyclopropanes is important? Cl O H CN O Cl Me Me Cypermetrin is an insecticide with contact and stomach action and is highly effective against a wide range of chewing and sucking insects in various crops. It is also active against mosquit.oes O 20.7 Sources of Esters Esters are Commonly Found in Natural Products! O CH3 CH3 O CH3 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate" contributes to characteristic odor of bananas Esters of Glycerol! O R' O O R O O R'' O R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters Fat & Oil are Mixtures of Glyceryl Triesters ! O (CH2)16CH3 O O CH3(CH2)16 O O (CH2)16CH3 O Tristearin: found in many animal and vegetable fats Lactones are Cyclic Esters! O O CH2(CH2)6CH3 H H (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle)