Nitrogen-Based Functional Groups!

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Harvey Allison
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1 Amines

2 itrogen-based Functional Groups! nitroarenes + R azides R C nitriles R' R R'' imines R R'' amides R' R R' R'' amines

3 Amines as Pharmaceutical Agents! C 3 C 3 Acetaminophen (analgesic) C 3 C 3 Pseudoephedrine (decongestant) 2 Aspartame (artificial sweetener) Cl Chlorpheniramine (blocks the effect of histamine)

4 22.1 Amine omenclature

5 The aming of Parts! Alkylamines itrogen atom is attached to alkyl group: Arylamines itrogen atom is attached to aryl group: R Alkyl R R = or Alkyl R R R =, Alkyl or Aryl

6 omenclature of Primary Alkylamines (R 2 ) Two IUPAC styles 1) analogous to alcohols: replace -e ending by -anamine 2) name alkyl group and attach -amine as a suffix

7 omenclature of Primary Alkylamines 3 C C 2 2 C n-propylamine or propanamine cyclopropylamine or cyclopetanamine Br 3 C 2-bromo-3-chlorobutylamine Cl

8 omenclature of Arylamines (Ar 2 ) These compounds are named as derivatives of aniline aniline Br 2,4-dibromoaniline Br Br C 3 4-bromo-2-ethylaniline

9 Amino Groups have Lower Priority than Alcohols With regards to nomenclature, amines rank lower than alcohols and are named as substituents: 2 aminoethanol p-aminobenzoic acid 2

10 Secondary and Tertiary Amines ame as -substituted derivatives of parent primary amine. The longest chain takes the root name. C 3 C 3 3 C C 3,-diisopropylethylamine (a.k.a. ünig s base) C 3 C 3 C 3 C 3 Br 4-bromo-,-dimethyl-2-methylaniline

11 Ammonium Salts (R 4-n n + X - ) itrogen atoms are positively charged when bonded to four substituents. The root name in this case is the ammonium ion ( 4+ ). Remember to name as a salt - two words. 3 C C 3 methylammonium acetate C 3 C 3 Cl -ethyl--methylbenzylammonium chloride

12 Quaternary Ammonium Salts (R 4 + X - ) itrogen 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. C 4 9 C 4 9 C 4 9 C 4 9 F tetrabutylammonium fluoride (TBAF) C 3 C 3 C 3 Quaternary ammonium salts are relatively soluble in organic solvents and consequently are used as phase transfer catalysts benzyltrimethylammonium hydroxide

13 22.2 Structure and Bonding of Amines

14 Structure of Alkylamines 147 pm

15 Alkylamines - Distribution of Electron Density ote 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.

16 Alkylamines - ydridization at itrogen The hybridization adopted by nitrogen depends upon the nature of the -substituents. Compare methylamine and formamide: methylamine C formamide Lone Pair sp 3 -hydridized tetrahedral C Lone Pair sp 2 -hydridized planar

17 Amines & Amides - Geometry at itrogen the hybridization adopted by nitrogen depends upon the nature of the -substituents - compare methylamine and formamide. methylamine C formamide Lone Pair sp 3 -hydridized tetrahedral C Lone Pair sp 2 -hydridized planar

18 Amines - Geometry at itrogen Angle that the C bond makes with bisector of angle is a measure of the pyramidalization at nitrogen. sp 3 sp 2 ~

19 Amines - Geometry at itrogen Angle that the C bond makes with bisector of angle is a measure of the pyramidalization at nitrogen Geometry at the nitrogen atom in aniline is pyramidal; closer to methylamine than to formamide.

20 Geometry of Aniline The hybridization of the nitrogen atom in aniline lies between sp 2 and sp 3 1) Delocalization of the nitrogen lone pair into the aromatic ring is most effective if the nitrogen atom is sp 2 -hybridized and planar. 2) A planar nitrogen atom increases repulsion between filled lone pair orbital and π-system of aromatic ring - sp 3 hybridization reduces this bad interaction

21 Aniline - Distribution of Electron Density Enforce a non-planar geometry (sp 3 -like) at the nitrogen center - highest negative potential is on nitrogen. Enforce a planar geometry (sp 2 -like) at the nitrogen center - negative potential is shared by both nitrogen and ring.

22 22.3 Physical Properties of Amines

23 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. dipole moment (µ): boiling point: C 3 C 2 C 3 C 3 C 2 2 C 3 C 2 0 D 1.2 D 1.7 D -42 C 17 C 78 C

24 Amines - Physical Properties boiling point: C 3 C 2 C 2 2 C 3 C 2 C 3 (C 3 ) 3 50 C 34 C 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.

25 22.4 Basicity of Amines

26 Amines are Brønstead Bases and ucleophiles X C X Amines behave as Brønstead Bases Amines behave as ucleophiles Amines are electron-rich and have a reactive lone pair, which can form a covalent bond to electrophiles C Amines behave as ucleophiles

27 Brønstead Basicity of Amines 1. Alkylamines are slightly stronger bases than ammonia. 2.

28 Basicity of Amines in Aqueous Solution Amine Conjugate Acid pk a C 3 C 10.8 The ethylammonium ion (C 3 C ) is a weaker acid than ammonium ( 4 + ) therefore; ethylamine ( 3 C 2 2 ) is a stronger base than ammonia ( 3 )

29 The Relationship between pk a and Basicity Amine Conjugate Acid pk a C 3 C 10.8 The ethylammonium ion (C 3 C ) is a weaker acid than ammonium ( 4 + ) therefore; ethylamine ( 3 C 2 2 ) is a stronger base than ammonia ( 3 )

30 The Relationship Between Basicity and Structure 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity.

31 Basicity of Amines in Aqueous Solution Amine Conjugate Acid pk a C 3 C C C 3 3 C C C 3 3 C C 3 C 3 3 C C

32 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.

33 Basicity of Amines in Aqueous Solution Amine Conjugate Acid pk a C 3 C 2 2 C 3 C (C 3 C 2 ) 2 (C 3 C 2 ) (C 3 C 2 ) 3 (C 3 C 2 ) Ph 2 Ph

34 Arylamines are Relatively Weak Brønstead Bases Anilinium Ion Stronger Acid Stronger Base pka = 4.6 Weaker Base Weaker Acid pka = 10.6

35 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 pk a ~ -5.0

36 Arylamines - Effect of Substituents on Basicity 1. Alkyl groups on the ring increase basicity by only one 1 pk unit. Amine Conjugate Acid pk a C 3 C

37 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. X X pk a of X conjugate acid 4.6 C

38 Basicity of Arylamines - p-itroaniline Lone pair on amine nitrogen is conjugated with p-nitro group more delocalized than in aniline itself. This delocalization is lost upon protonation.

39 Electron Withdrawing Effects are Cumulative is 3800 times more basic than... 2 aniline p-nitroaniline 2 is 1,000, 000, 000 times more basic than... 2 aniline 2,4-dinitroaniline

40 Electron Withdrawing Effects are Cumulative Amine Conjugate Acid pk a

41 eterocyclic Amines is more basic than... piperidine pyridine pk a of conjugate acid: pk a of conjugate acid: (an alkylamine) (resembles an arylamine in basicity)

42 eterocyclic Amines is more basic than... imidazole pyridine pk a of conjugate acid: pk a of conjugate acid:

43 Protonation of Imidazole q. Which nitrogen is protonated in imidazole? + + aromatic imidazolium ion nonaromatic iminium ion

44 Protonation of Imidazole - Resonance Picture Protonation in the direction shown gives a stabilized ion. + aromatic imidazolium ion aromatic imidazolium ion

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

46 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.

47 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. C 3 3 C (-)-yoscyamine (Atropa belladonna) (-)-Quinine (Cinchona pubescens)

Amines as atural 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.

48 Amines as atural 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. e said o ; 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 emlock contains the alkaloid coniine, among other compounds

49 The Toxic Alkaloids of Conium maculatum 2-Methylpiperidine Coniine γ-coniceine (+)-Pseudoconhydrine Conhydrinone Me (+)--Methylpseudoconhydrine (+)-α-conhydrine Me -Methylconiine

50 Reduction of itroarenes - Example Aromatic nitro compounds are easy to prepare and are readily reduced to the corresponding anilines under a wide range of conditions. C 3 C 3 Combretastatin A-2 a antineoplastic agent isloated from the South African bush willow tree

51 Reduction of itroarenes - Example C 3 Br PPh 3 C 3 P Ph phosphonium salt Ph Ph Br n-buli ylide (reactive nucleophile) Wittig Reaction C 3 P Ph Ph Ph C 3 2 Reduction C 3 C 3 Zinc metal acetic acid C 3 C 3 2

52 18.9 The Aldol Condensation

53 Aldol Condensation R K 2 Aldol Addition Reaction R β R α Aldol Condensation Reaction eat K R β α eat, - 2 Dehydration R Dehydration Product

54 Aldol Condensation of Butanal newly formed carbon-carbon double bond K 2 β 2 x n-butanal 100 C (86%) Aldol Condensation Reaction α α,β-unsaturated Ketone

55 Dehydration of Aldol Addition Product C C C C C C dehydration of β-hydroxy aldehyde can be catalyzed by either acids or bases

56 Dehydration of Aldol Addition Product C C a C C C C in base, the enolate is formed

57 Dehydration of Aldol Addition Product C C a C C C C the enolate loses hydroxide to form the α,β-unsaturated aldehyde

58 Aldol reactions of ketones 2% 3 C 3 C 2 x Acetone C 3 98% 3 C C 3 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

59 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 electrophilic alkene reacts with nucleophilic thiols (RS) on-toxic to worker termiotes

C 3 C 3 + Zn() 2 C 2 Zinc hydroxide neutralizes acid ( + ) in paper

60 Diethyl Zinc and Deacidification of Brittle Books Me Zn Me Diethylzinc (a volatile liquid) 2 (in paper) Ethane (a volatile gas) C 3 C 3 + Zn() 2 C 2 Zinc hydroxide neutralizes acid ( + ) in paper Zn(C 3 ) Unused zinc hydroxide reacts with carbon dioxide form zinc carbonate

61 14.13 Carbenes and Carbenoids

62 Carbene name to give to species that contains a divalent carbon (carbon with two bonds and six electrons) Br C Br dibromocarbene Carbenes are very reactive; normally cannot be isolated and stored. Are intermediates in certain reactions.

63 Generation of Dibromocarbene Br Br C Br + C(C 3 ) 3 Br Br C Br + C(C 3 ) 3

64 Generation of Dibromocarbene Br C Br + Br Br Br C Br

65 Carbenes react with alkenes to give cyclopropanes KC(C 3 ) 3 Br + CBr 3 (C 3 ) 3 C Br CBr 2 is a highly reactive (shortlived) intermediate (75%)

66 Why the synthesis of cyclopropanes is important? R Me Me Me Me Me Pyrethrin (atural Insecticide in RAID TM ) Chrysanthemum cinerariaefolium

67 Why the synthesis of cyclopropanes is important? Cl C 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

68 20.7 Sources of Esters

69 Esters are Commonly Found in atural Products! C 3 C 3 C 3 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate" contributes to characteristic odor of bananas

70 Esters of Glycerol! R' R R'' R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters

71 Fat & il are Mixtures of Glyceryl Triesters! (C 2 ) 16 C 3 C 3 (C 2 ) 16 (C 2 ) 16 C 3 Tristearin: found in many animal and vegetable fats

72 Lactones are Cyclic Esters! C 2 (C 2 ) 6 C 3 (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle)

22.1 Amine Nomenclature

Chapter 22 Amines 22.1 Amine Nomenclature Classification of Amines Alkylamine N attached to alkyl group Arylamine N attached to aryl group Primary, secondary, or tertiary determined by number of carbon