Dr. Wolf's CHM 201 & Chapter 21 Amines

Dr. Wolf's CHM 201 & Amine Nomenclature

Dr. Wolf's CHM 201 & Alkylamine N attached to alkyl group Arylamine N attached to aryl group Primary, secondary, or tertiary determined by number of carbon atoms directly attached to nitrogen Classification of Amines

Dr. Wolf's CHM 201 & Two IUPAC styles 1)analogous to alcohols: replace -e ending by -amine 2)name alkyl group and attach -amine as a suffix Nomenclature of Primary Alkylamines (RNH 2 )

Dr. Wolf's CHM 201 & Examples: some primary alkylamines CH 3 CHCH 2 CH 2 CH 3 NH2NH2NH2NH2 (RNH 2 : one carbon directly attached to N) CH 3 CH 2 NH 2 NH2NH2NH2NH2 ethylamine or ethanamine cyclohexylamine or cyclohexanamine 1-methylbutylamine or 2-pentanamine

Dr. Wolf's CHM 201 & Name as derivatives of aniline. Nomenclature of Primary Arylamines (ArNH 2 ) p-fluoroaniline 5-bromo-2-ethylaniline NH2NH2NH2NH2F NH2NH2NH2NH2Br CH 2 CH 3

Dr. Wolf's CHM 201 & Amino groups as substituents p-aminobenzaldehyde amino groups rank below OH groups and higher oxidation states of carbon in such cases name the amino group as a substituent NH2NH2NH2NH2 HCHCHCHCO HOCH 2 CH 2 NH 2 2-aminoethanol

Dr. Wolf's CHM 201 & Name as N-substituted derivatives of parent primary amine. (N is a locant-it is not alphabetized, but is treated the same way as a numerical locant) Parent amine is one with longest carbon chain. Secondary and Tertiary Amines

Dr. Wolf's CHM 201 & Examples CH 3 NHCH 2 CH 3 N-methylethylamine NHCH 2 CH 3 NO 2 Cl 4-chloro-N-ethyl-3-nitroaniline CH 3 N N,N-dimethylcycloheptylamine

Dr. Wolf's CHM 201 & A nitrogen with four substituents is positively charged and is named as a derivative of ammonium ion (NH 4 + ). Ammonium Salts CH 3 NH 3 + Cl– methylammonium chloride N CH 3 H CH 2 CH 3 + CF 3 CO 2 – N-ethyl-N-methylcyclopentylammonium trifluoroacetate

Dr. Wolf's CHM 201 & When all four atoms attached to N are carbon, the ion is called a quaternary ammonium ion and salts that contain it are called quaternary ammonium salts. Ammonium Salts + CH 2 N CH 3 I – benzyltrimethylammonium iodide

Dr. Wolf's CHM 201 & Structure and Bonding

Dr. Wolf's CHM 201 & pm 106° 112° Alkylamines

Dr. Wolf's CHM 201 & Most prominent feature is high electrostatic potential at nitrogen. Reactivity of nitrogen lone pair dominates properties of amines. Alkylamines

Dr. Wolf's CHM 201 & Compare geometry at N of methylamine, aniline, and formamide. sp 3 sp 2 Geometry at N Pyramidal geometry at sp 3 -hybridized N in methylamine. Planar geometry at sp 2 -hybridized N in formamide. C O NH2NH2NH2NH2 H C NH2NH2NH2NH2 H H H

Dr. Wolf's CHM 201 & Compare geometry at N of methylamine, aniline, and formamide. sp 3 sp 2 Geometry at N Pyramidal geometry at sp 3 -hybridized N in methylamine. Planar geometry at sp 2 -hybridized N in formamide.

Dr. Wolf's CHM 201 & Angle that the C—N bond makes with bisector of H—N—H angle is a measure of geometry at N. sp 3 sp 2 Geometry at N ~125° 180° Note: this is not the same as the H—N—H bond angle

Dr. Wolf's CHM 201 & Angle that the C—N bond makes with bisector of H—N—H angle is a measure of geometry at N. sp 3 sp 2 Geometry at N ~125° 180° 142.5°

Dr. Wolf's CHM 201 & Geometry at N in aniline is pyramidal; closer to methylamine than to formamide. Geometry at N 142.5°

Dr. Wolf's CHM 201 & Geometry at N 142.5° Hybridization of N in aniline lies between sp 3 and sp 2. Lone pair of N can be delocalized into ring best if N is sp 2 and lone pair is in a p orbital. Lone pair bound most strongly by N if pair is in an sp 3 orbital of N, rather than p. Actual hybridization is a compromise that maximizes binding of lone pair.

Dr. Wolf's CHM 201 & Electrostatic Potential Maps of Aniline Nonplanar geometry at N. Region of highest negative potential is at N. Planar geometry at N. High negative potential shared by N and ring.

Dr. Wolf's CHM 201 & Physical Properties

Dr. Wolf's CHM 201 & Amines are more polar and have higher boiling points than alkanes; but are less polar and have lower boiling points than alcohols. Physical Properties CH 3 CH 2 CH 3 CH 3 CH 2 NH 2 CH 3 CH 2 OH dipole moment (  ): boiling point: 0 D 1.2 D 1.7 D -42°C17°C78°C

Dr. Wolf's CHM 201 & Boiling points of isomeric amines decrease in going from primary to secondary to tertiary amines. Primary amines have two hydrogens on N capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds. Physical Properties CH 3 CH 2 NHCH 3 CH 3 CH 2 CH 2 NH 2 (CH 3 ) 3 N boiling point: 50°C34°C3°C

Dr. Wolf's CHM 201 & Basicity of Amines

Dr. Wolf's CHM 201 & Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia.

Dr. Wolf's CHM 201 & AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH Table 22.1 (page 920) Basicity of Amines in Aqueous Solution CH 3 CH 2 NH 3 + is a weaker acid than NH 4 + ; therefore, CH 3 CH 2 NH 2 is a stronger base than NH 3.

Dr. Wolf's CHM 201 & Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity.

Dr. Wolf's CHM 201 & AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH Table 22.1 (page 920) Basicity of Amines in Aqueous Solution Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units.

Dr. Wolf's CHM 201 & Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. 3. Arylamines are much weaker bases than ammonia.

Dr. Wolf's CHM 201 & AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH C 6 H 5 NH 2 C 6 H 5 NH Table 22.1 (page 920) Basicity of Amines in Aqueous Solution

Dr. Wolf's CHM 201 & H2NH2NH2NH2N Decreased basicity of arylamines + HNHH + NH2NH2NH2NH2 + + H3NH3NH3NH3N pK a = 4.6 pK a =10.6 Stronger acid Weaker acid Stronger base Weaker base

Dr. Wolf's CHM 201 & H2NH2NH2NH2N Decreased basicity of arylamines + HNHH + NH2NH2NH2NH2 + + H3NH3NH3NH3N Stronger acid Weaker acid When anilinium ion loses a proton, the resulting lone pair is delocalized into the ring.

Dr. Wolf's CHM 201 & H2NH2NH2NH2N Decreased basicity of arylamines + HNHH + NH2NH2NH2NH2 + + H3NH3NH3NH3N Aniline is a weaker base because its lone pair is more strongly held. Stronger base Weaker base

Dr. Wolf's CHM 201 & Decreased basicity of arylamines C6H5NH2C6H5NH2C6H5NH2C6H5NH2 (C 6 H 5 ) 2 NH (C 6 H 5 ) 3 N pK a of conjugate acid: ~-5 Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

Dr. Wolf's CHM 201 & Effect of Substituents on Basicity of Arylamines 1. Alkyl groups on the ring increase basicity, but only slightly (less than 1 pK unit). X NH 2 XpK a of conjugate acid H4.6 CH 3 5.3

Dr. Wolf's CHM 201 & Effect of Substituents on Basicity of Arylamines 2. Electron withdrawing groups, especially ortho and/or para to amine group, decrease basicity and can have a large effect. X NH 2 XpK a of conjugate acid H4.6 CF O 2 N1.0

Dr. Wolf's CHM 201 & p-Nitroaniline NH2NH2NH2NH2 O N O – + O N O – – NH2NH2NH2NH2 + + Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation.

Dr. Wolf's CHM 201 & Effect is Cumulative Aniline is 3800 times more basic than p-nitroaniline. Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

Dr. Wolf's CHM 201 & Heterocyclic Amines N H N is more basic than piperidinepyridine pK a of conjugate acid: (an alkylamine) (resembles an arylamine in basicity)

Dr. Wolf's CHM 201 & Heterocyclic Amines N is more basic than imidazolepyridine pK a of conjugate acid: NH N

Dr. Wolf's CHM 201 & Imidazole NH N Which nitrogen is protonated in imidazole? H+H+H+H+ H+H+H+H+ NH N H + N H N H +

Dr. Wolf's CHM 201 & Imidazole NH N Protonation in the direction shown gives a stabilized ion. H+H+H+H+ NH NH+ NH N H +

Dr. Wolf's CHM 201 & Tetraalkylammonium Salts as Phase-Transfer Catalysts

Dr. Wolf's CHM 201 & Phase-Transfer Catalysis Phase-transfer agents promote the solubility of ionic substances in nonpolar solvents. They transfer the ionic substance from an aqueous phase to a non-aqueous one. Phase-transfer agents increase the rates of reactions involving anions. The anion is relatively unsolvated and very reactive in nonpolar media compared to water or alcohols.

Dr. Wolf's CHM 201 & Phase-Transfer Catalysis Quaternary ammonium salts are phase-transfer catalysts. They are soluble in nonpolar solvents. N H3CH3CH3CH3C CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 + Cl – Methyltrioctylammonium chloride

Dr. Wolf's CHM 201 & Phase-Transfer Catalysis Quaternary ammonium salts are phase-transfer catalysts. They are soluble in nonpolar solvents. Cl – Benzyltriethylammonium chloride N CH 2 CH 3 +

Dr. Wolf's CHM 201 & Example The S N 2 reaction of sodium cyanide with butyl bromide occurs much faster when benzyl- triethylammonium chloride is present than when it is not. CH 3 CH 2 CH 2 CH 2 Br + NaCN CH 3 CH 2 CH 2 CH 2 CN + NaBr benzyltriethylammonium chloride

Dr. Wolf's CHM 201 & MechanismMechanism Cl – (aqueous) N CH 2 CH 3 + (aqueous) CN – + Cl – N CH 2 CH CN – (aqueous) (aqueous)

Dr. Wolf's CHM 201 & N CH 2 CH 3 + CN – (aqueous) (in butyl bromide) N CH 2 CH 3 + CN – MechanismMechanism

Dr. Wolf's CHM 201 & (in butyl bromide) N CH 2 CH 3 + CN – MechanismMechanism CH 3 CH 2 CH 2 CH 2 Br + N CH 2 CH 3 + Br – (in butyl bromide) CH 3 CH 2 CH 2 CH 2 CN +

Dr. Wolf's CHM 201 & Reactions of Amines: A Review and a Preview

Dr. Wolf's CHM 201 & Preparation of Amines Two questions to answer: 1) How is the C—N bond to be formed? 2) How do we obtain the correct oxidation state of nitrogen (and carbon)?

Dr. Wolf's CHM 201 & Methods for C—N Bond Formation Nucleophilic substitution by azide ion (N 3 – ) (Section 8.1, 8.13) Nitration of arenes (Section 12.3) Nucleophilic ring opening of epoxides by ammonia (Section 16.12) Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Nucleophilic acyl substitution (Sections 19.4, 19.5, and 19.11) Nucleophilic substitution by ammonia on  -halo acids (Section 20.15)

Dr. Wolf's CHM 201 & Preparation of Amines by Alkylation of Ammonia

Dr. Wolf's CHM 201 & Alkylation of Ammonia Desired reaction is: 2 NH 3 + R—X R—NH 2 + NH4XNH4XNH4XNH4Xvia: H3NH3NH3NH3N R X H3NH3NH3NH3N R + X – + + then: H3NH3NH3NH3N + H N H H R + H3NH3NH3NH3N H + + NHH R

Dr. Wolf's CHM 201 & Alkylation of Ammonia But the method doesn't work well in practice. Usually gives a mixture of primary, secondary, and tertiary amines, plus the quaternary salt. NH3NH3NH3NH3 RXRXRXRX RNH2RNH2RNH2RNH2 RXRXRXRX R2NHR2NHR2NHR2NH RXRXRXRX R3NR3NR3NR3N RXRXRXRX R4NR4NR4NR4N+ X–

Dr. Wolf's CHM 201 & Example CH 3 (CH 2 ) 6 CH 2 Br NH 3 CH 3 (CH 2 ) 6 CH 2 NH 2 (45%)+ CH 3 (CH 2 ) 6 CH 2 NHCH 2 (CH 2 ) 6 CH 3 (43%) As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine.

Dr. Wolf's CHM 201 & The Gabriel Synthesis of Primary Alkylamines

Dr. Wolf's CHM 201 & gives primary amines without formation of secondary, etc. amines as byproducts uses an S N 2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide Gabriel Synthesis

Dr. Wolf's CHM 201 & gives primary amines without formation of secondary, etc. amines as byproducts uses an S N 2 reaction on an alkyl halide to form the C—N bond the nitrogen-containing nucleophile is N-potassiophthalimide Gabriel Synthesis OO N – K +

Dr. Wolf's CHM 201 & the pKa of phthalimide is 8.3 N-potassiophthalimide is easily prepared by the reaction of phthalimide with KOH N-PotassiophthalimideOO N – K + O O NHNHNHNH KOH

Dr. Wolf's CHM 201 & N-Potassiophthalimide as a nucleophile O O N – R X +OO N R + X – SN2SN2SN2SN2

Dr. Wolf's CHM 201 & Cleavage of Alkylated Phthalimide OO N R + H2OH2OH2OH2O H2NH2NH2NH2NR + CO 2 H acid or base imide hydrolysis is nucleophilic acyl substitution

Dr. Wolf's CHM 201 & Cleavage of Alkylated Phthalimide hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative OO N R H2NH2NH2NH2NR +OO NH NH H 2 NNH 2

Dr. Wolf's CHM 201 & ExampleOO N – K + + C 6 H 5 CH 2 Cl DMFOO N CH 2 C 6 H 5 (74%)

Dr. Wolf's CHM 201 & Example + C 6 H 5 CH 2 NH 2 OO N CH 2 C 6 H 5 H 2 NNH 2 (97%)OO NH NH

Dr. Wolf's CHM 201 & Preparation of Amines by Reduction

Dr. Wolf's CHM 201 & almost any nitrogen-containing compound can be reduced to an amine, including: azides nitriles nitro-substituted benzene derivatives amides Preparation of Amines by Reduction

Dr. Wolf's CHM 201 & S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Azides CH 2 CH 2 Br CH 2 CH 2 N 3 NaN 3 (74%) CH 2 CH 2 NH 2 (89%) 1. LiAlH 4 2. H 2 O azides may also be reduced by catalytic hydrogenation

Dr. Wolf's CHM 201 & S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Nitriles CH 3 CH 2 CH 2 CH 2 Br NaCN (69%) CH 3 CH 2 CH 2 CH 2 CN CH 3 CH 2 CH 2 CH 2 CH 2 NH 2 (56%) H 2 (100 atm), Ni nitriles may also be reduced by lithium aluminum hydride

Dr. Wolf's CHM 201 & S N 2 reaction, followed by reduction, gives a primary alkylamine. Synthesis of Amines via Nitriles CH 3 CH 2 CH 2 CH 2 Br NaCN (69%) CH 3 CH 2 CH 2 CH 2 CN CH 3 CH 2 CH 2 CH 2 CH 2 NH 2 (56%) H 2 (100 atm), Ni the reduction also works with cyanohydrins

Dr. Wolf's CHM 201 & Synthesis of Amines via Nitroarenes HNO3HNO3HNO3HNO3 (88-95%) Cl Cl NO2NO2NO2NO2 H 2 SO 4 (95%) 1. Fe, HCl 2. NaOH Cl NH2NH2NH2NH2 nitro groups may also be reduced with tin (Sn) + HCl or by catalytic hydrogenation

Dr. Wolf's CHM 201 & Synthesis of Amines via Amides (86-89%) COHO 1. SOCl 2 2. (CH 3 ) 2 NH CN(CH 3 ) 2 O (88%) 1. LiAlH 4 2. H 2 O CH 2 N(CH 3 ) 2 only LiAlH 4 is an appropriate reducing agent for this reaction

Dr. Wolf's CHM 201 & Reductive Amination

Dr. Wolf's CHM 201 & The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. Synthesis of Amines via Reductive Amination O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine.

Dr. Wolf's CHM 201 & Synthesis of Amines via Reductive Amination O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O H 2, Ni NH2NH2NH2NH2RR' C H The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product.

Dr. Wolf's CHM 201 & Example: Ammonia gives a primary amine. O + NH3NH3NH3NH3H NH2NH2NH2NH2 H 2, Ni ethanol (80%) via: NHNHNHNH

Dr. Wolf's CHM 201 & Example: Primary amines give secondary amines H 2, Ni ethanol (65%) CH 3 (CH 2 ) 5 CH 2 NH + H2NH2NH2NH2N CH 3 (CH 2 ) 5 CH O via: N

Dr. Wolf's CHM 201 & Example: Secondary amines give tertiary amines H 2, Ni, ethanol (93%) + CH 3 CH 2 CH 2 CH O N H N CH 2 CH 2 CH 2 CH 3

Dr. Wolf's CHM 201 & Example: Secondary amines give tertiary amines CHCH 2 CH 2 CH 3 N + possible intermediates include: N CH CHCH 2 CH 3 CHCH 2 CH 2 CH 3 N HO

Dr. Wolf's CHM 201 & Reactions of Amines: A Review and a Preview

Dr. Wolf's CHM 201 & Reactions of Amines Reactions of amines almost always involve the nitrogen lone pair. N H X as a base: N C O as a nucleophile:

Dr. Wolf's CHM 201 & Reactions of Amines basicity (Section 21.4) reaction with aldehydes and ketones (Chapter 17) reaction with acyl chlorides, anhydrides, and esters Reactions already discussed

Dr. Wolf's CHM 201 & Reactions of Amines with Alkyl Halides

Dr. Wolf's CHM 201 & Reaction with Alkyl Halides Amines act as nucleophiles toward alkyl halides. X + N R H + X N R H + – + N R H +

Dr. Wolf's CHM 201 & Example: excess amine NH2NH2NH2NH2 + ClCH 2 NHCH 2 (85-87%) NaHCO 3 90°C (4 mol) (1 mol)

Dr. Wolf's CHM 201 & Example: excess alkyl halide + 3CH 3 I (99%) methanolheat CH 2 N (CH 3 ) 3 CH 2 NH 2 + I–

Dr. Wolf's CHM 201 & The Hofmann Elimination

Dr. Wolf's CHM 201 & The Hofmann Elimination a quaternary ammonium hydroxide is the reactant and an alkene is the product is an anti elimination the leaving group is a trialkylamine the regioselectivity is opposite to the Zaitsev rule.

Dr. Wolf's CHM 201 & Quaternary Ammonium Hydroxides Ag 2 O H 2 O, CH 3 OH CH 2 N (CH 3 ) 3 + HO – are prepared by treating quaternary ammmonium halides with moist silver oxide CH 2 N (CH 3 ) 3 I–

Dr. Wolf's CHM 201 & The Hofmann Elimination 160°C CH 2 N (CH 3 ) 3 + HO – on being heated, quaternary ammonium hydroxides undergo elimination CH 2 (69%) + N(CH 3 ) 3 + H2OH2OH2OH2O

Dr. Wolf's CHM 201 & Mechanism H CH2CH2CH2CH2+ N(CH 3 ) 3 –O H OH H N(CH 3 ) 3 CH2CH2CH2CH2

Dr. Wolf's CHM 201 & Regioselectivityheat Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule. N(CH 3 ) 3 + HO – CH 3 CHCH 2 CH 3 H2CH2CH2CH2C CHCH 2 CH 3 CH 3 CH CHCH 3 +(95%)(5%)

Dr. Wolf's CHM 201 & Regioselectivity Steric factors seem to control the regioselectivity. The transition state that leads to 1-butene is less crowded than the one leading to cis or trans-2-butene.

Dr. Wolf's CHM 201 & Regioselectivity N(CH 3 ) 3 + HHH H CH 3 CH 2 largest group is between two H atoms C H CHH CH 3 CH 2 major product

Dr. Wolf's CHM 201 & Regioselectivity N(CH 3 ) 3 +H H H CH 3 largest group is between an H atom and a methyl group C H C CH 3 H minor product CH 3

Dr. Wolf's CHM 201 & Electrophilic Aromatic Substitution in Arylamines

Dr. Wolf's CHM 201 & Nitration of Anililne NH 2 is a very strongly activating group NH 2 not only activates the ring toward electrophilic aromatic substitution, it also makes it more easily oxidized attemped nitration of aniline fails because nitric acid oxidizes aniline to a black tar

Dr. Wolf's CHM 201 & Nitration of Anililne Strategy: decrease the reactivity of aniline by converting the NH 2 group to an amide CH(CH 3 ) 2 NH2NH2NH2NH2 NHCCH 3 OO CH 3 COCCH 3 O (98%) (acetyl chloride may be used instead of acetic anhydride)

Dr. Wolf's CHM 201 & Nitration of Anililne Strategy: nitrate the amide formed in the first step CH(CH 3 ) 2 NHCCH 3 O HNO 3 CH(CH 3 ) 2 NHCCH 3 O NO 2 (94%)

Dr. Wolf's CHM 201 & Nitration of Anililne Strategy: remove the acyl group from the amide by hydrolysis CH(CH 3 ) 2 NHCCH 3 O NO 2 KOH ethanol, heat CH(CH 3 ) 2 NH2NH2NH2NH2 NO 2 (100%)

Dr. Wolf's CHM 201 & occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation Halogenation of Arylamines CO 2 H NH2NH2NH2NH2 Br 2 acetic acid (82%) CO 2 H NH2NH2NH2NH2BrBr

Dr. Wolf's CHM 201 & Monohalogenation of Arylamines Cl NHCCH 3 O CH 3 (74%) Cl 2 acetic acid NHCCH 3 O CH 3 Decreasing the reactivity of the arylamine by converting the NH 2 group to an amide allows halogenation to be limited to monosubstitution

Dr. Wolf's CHM 201 & Friedel-Crafts Reactions The amino group of an arylamine must be protected as an amide when carrying out a Friedel-Crafts reaction. NHCCH 3 O CH 3 CH 3 CCl O AlCl 3 (57%) NHCCH 3 O CH 3 CCH 3 O

Dr. Wolf's CHM 201 & Nitrosation of Alkylamines

Dr. Wolf's CHM 201 & Nitrite Ion, Nitrous Acid, and Nitrosyl Cation H+ –O NO O NO H H+O NO H H + + NO + O HH

Dr. Wolf's CHM 201 & Nitrosyl Cation and Nitrosation + NO

Dr. Wolf's CHM 201 & Nitrosyl Cation and Nitrosation + NO + N N NO +

Dr. Wolf's CHM 201 & Nitrosation of Secondary Alkylamines + NO N H + N NO + H + H + N NO nitrosation of secondary amines gives an N-nitroso amine

Dr. Wolf's CHM 201 & Example (CH 3 ) 2 NH NaNO 2, HCl H2OH2OH2OH2O (88-90%) (CH 3 ) 2 N NO

Dr. Wolf's CHM 201 & Some N-Nitroso Amines N-nitrosopyrrolidine (nitrite-cured bacon) N N O N-nitrosonornicotine (tobacco smoke) N N O N (CH 3 ) 2 N NO N-nitrosodimethylamine (leather tanning)

Dr. Wolf's CHM 201 & Nitrosation of Primary Alkylamines + analogous to nitrosation of secondary amines to this point + NO N H HR N NO + H HR+ H + N NO R H

Dr. Wolf's CHM 201 & Nitrosation of Primary Alkylamines N NO R H H + N NO RH H + this species reacts further N NO R H H + + H H + N NO RH

Dr. Wolf's CHM 201 & Nitrosation of Primary Alkylamines + H N NO RH + N N RH O H + nitrosation of a primary alkylamine gives an alkyl diazonium ion process is called diazotization

Dr. Wolf's CHM 201 & Alkyl Diazonium Ions +N N R alkyl diazonium ions readily lose N 2 to give carbocations R++NN

Dr. Wolf's CHM 201 & Example: Nitrosation of 1,1-Dimethylpropylamine NH2NH2NH2NH2 N N+ HONO H2OH2OH2OH2O OHOHOHOH (80%) + (2%)(3%) + – N 2

Dr. Wolf's CHM 201 & There is no useful chemistry associated with the nitrosation of tertiary alkylamines. Nitrosation of Tertiary Alkylamines N RRR N NO + RRR

Dr. Wolf's CHM 201 & Nitrosation of Arylamines

Dr. Wolf's CHM 201 & reaction that occurs is electrophilic aromatic substitution Nitrosation of Tertiary Arylamines N(CH 2 CH 3 ) 2 (95%) 1. NaNO 2, HCl, H 2 O, 8°C 2. HO – N(CH 2 CH 3 ) 2 N O

Dr. Wolf's CHM 201 & similar to secondary alkylamines; gives N-nitroso amines Nitrosation of N-Alkylarylamines NaNO 2, HCl, H 2 O, 10°C NHCH 3 (87-93%) NCH 3 NO

Dr. Wolf's CHM 201 & Nitrosation of Primary Arylamines gives aryl diazonium ions aryl diazonium ions are much more stable than alkyl diazonium ions most aryl diazonium ions are stable under the conditions of their formation (0-10°C) ArN N + RNRNRNRNN+fast slow R + + N2N2N2N2 Ar + + N2N2N2N2

Dr. Wolf's CHM 201 & Example: (CH 3 ) 2 CH NH2NH2NH2NH2 NaNO 2, H 2 SO 4 H 2 O, 0-5°C (CH 3 ) 2 CH N N + HSO 4 –

Dr. Wolf's CHM 201 & Synthetic Origin of Aryl Diazonium Salts ArH Ar NO2NO2NO2NO2 Ar NH2NH2NH2NH2 Ar N N+

Dr. Wolf's CHM 201 & Synthetic Transformations of Aryl Diazonium Salts

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Preparation of Phenols Ar N N+ Ar OHOHOHOH H 2 O, heat

Dr. Wolf's CHM 201 & Example 2. H 2 O, heat (CH 3 ) 2 CH NH2NH2NH2NH2 1. NaNO 2, H 2 SO 4 H 2 O, 0-5°C H 2 O, 0-5°C (CH 3 ) 2 CH OHOHOHOH (73%)

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Preparation of Aryl Iodides Ar N N+ ArI reaction of an aryl diazonium salt with potassium iodide KIKIKIKI

Dr. Wolf's CHM 201 & Example 2. KI, room temp. 1. NaNO 2, HCl H 2 O, 0-5°C H 2 O, 0-5°C (72-83%) NH2NH2NH2NH2Br I Br

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Preparation of Aryl Fluorides Ar N N+ ArF heat the tetrafluoroborate salt of a diazonium ion; process is called the Schiemann reaction

Dr. Wolf's CHM 201 & Example (68%) NH2NH2NH2NH2 CCH 2 CH 3 O 2. HBF 4 1. NaNO 2, HCl, H 2 O, 0-5°C H 2 O, 0-5°C 3. heat F CCH 2 CH 3 O

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Preparation of Aryl Chlorides and Bromides Ar N N+ ArBrArCl aryl chlorides and aryl bromides are prepared by heating a diazonium salt with copper(I) chloride or bromide substitutions of diazonium salts that use copper(I) halides are called Sandmeyer reactions

Dr. Wolf's CHM 201 & Example (68-71%) NH2NH2NH2NH2 NO 2 2. CuCl, heat 1. NaNO 2, HCl, H 2 O, 0-5°C H 2 O, 0-5°C Cl NO 2

Dr. Wolf's CHM 201 & Example (89-95%) 2. CuBr, heat 1. NaNO 2, HBr, H 2 O, 0-10°C H 2 O, 0-10°C NH2NH2NH2NH2Cl Br Cl

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Preparation of Aryl Nitriles Ar N N+ ArCN aryl nitriles are prepared by heating a diazonium salt with copper(I) cyanide this is another type of Sandmeyer reaction

Dr. Wolf's CHM 201 & Example (64-70%) 2. CuCN, heat 1. NaNO 2, HCl, H 2 O, 0°C H 2 O, 0°C NH2NH2NH2NH2 CH 3 CN

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH Ar OHOHOHOH ArI ArF ArBrArCl ArCN

Dr. Wolf's CHM 201 & Transformations of Aryl Diazonium Salts Ar N N+ ArH hypophosphorous acid (H 3 PO 2 ) reduces diazonium salts; ethanol does the same thing this is called reductive deamination

Dr. Wolf's CHM 201 & Example (70-75%) NaNO 2, H 2 SO 4, H 3 PO 2 H 3 PO 2 NH2NH2NH2NH2 CH 3

Dr. Wolf's CHM 201 & Value of Diazonium Salts 1) allows introduction of substituents such as OH, F, I, and CN on the ring 2) allows preparation of otherwise difficultly accessible substitution patterns

Dr. Wolf's CHM 201 & Example BrBrBr NH2NH2NH2NH2Br Br Br (74-77%) NaNO 2, H 2 SO 4, H 2 O, CH 3 CH 2 OH NH2NH2NH2NH2 Br 2 H2OH2OH2OH2O (100%)

Dr. Wolf's CHM 201 & Azo Coupling

Dr. Wolf's CHM 201 & Azo Coupling Diazonium salts are weak electrophiles. React with strongly activated aromatic compounds by electrophilic aromatic substitution. Ar N N+Ar' H + Ar N N Ar' an azo compound Ar' must bear a strongly electron-releasing group such as OH, OR, or NR 2.

Dr. Wolf's CHM 201 & ExampleOH+ C6H5NC6H5NC6H5NC6H5N N+ OHN NC 6 H 5 Cl –

Dr. Wolf's CHM 201 & Spectroscopic Analysis of Amines

Dr. Wolf's CHM 201 & the N—H stretching band appears in the range cm -1 primary amines give two peaks in this region, one for a symmetrical stretching vibration, the other for an antisymmetrical stretch Infrared Spectroscopy R NHH symmetric R NHH antisymmetric

Dr. Wolf's CHM 201 & Infrared Spectroscopy RNH 2 R 2 NH primary amines give two N—H stretching peaks, secondary amines give one

Dr. Wolf's CHM 201 & compare chemical shifts in: 1 H NMR H3CH3CH3CH3C CH 2 NH 2 H3CH3CH3CH3C CH 2 OH N C H is more shielded than  3.9 ppm  4.7 ppm O C H

Dr. Wolf's CHM 201 & C NMR Carbons bonded to N are more shielded than those bonded to O. CH 3 NH 2 CH 3 OH  26.9 ppm  48.0 ppm

Dr. Wolf's CHM 201 & max 204 nm 256 nm max 204 nm 256 nm max 230 nm 280 nm max 230 nm 280 nm max 203 nm 254 nm max 203 nm 254 nm An amino group on a benzene ring shifts max to longer wavelength. Protonation of N causes UV spectrum to resemble that of benzene. UV-VIS NH 2 NH 3 +

Dr. Wolf's CHM 201 & Mass Spectrometry Compounds that contain only C, H, and O have even molecular weights. If an odd number of N atoms is present, the molecular weight is odd. A molecular-ion peak with an odd m/z value suggests that the sample being analyzed contains N.

Dr. Wolf's CHM 201 & Mass Spectrometry Nitrogen stabilizes carbocations, which drives the fragmentation pathways. (CH 3 ) 2 NCH 2 CH 2 CH 2 CH 3 e–e–e–e– + CH 2 CH 2 CH 3 CH 2 CH 2 CH 3 + (CH 3 ) 2 N CH 2 +

Dr. Wolf's CHM 201 & Mass Spectrometry Nitrogen stabilizes carbocations, which drives the fragmentation pathways. CH 3 NHCH 2 CH 2 CH(CH 3 ) 2 e–e–e–e– + CH 2 CH(CH 3 ) 2 CH 2 CH(CH 3 ) 2 + CH 3 NH CH 2 +

Dr. Wolf's CHM 201 & End of Chapter 21