Exam 5 Study Guide Chapter 21 Amines I Naming 1 Substituted Amines of groups on N 2 As alkanamines N alkyl amines 3 As amino substituents 4 As alkyl amines II Nucleophilicity and Basicity 1 Amines are good nucleophiles and bases A Lone pair on N can act as a nucleophile by attacking an electrophile B Lone pair on N can act as a base by grabbing a proton more steric hinderance leads to greater basicity except tertiary 2 Amides are formed from deprotonated primary and secondary amines stronger nucleophiles and bases than neutral amines 3 Alkyl vs Aryl Amines A Alkyl Amine N is attached to an alkyl group B Aryl Amine N is attached to an aromatic ring less nucleophilic and basic than alkyl amines because lone pair is delocalized into the aromatic ring III Synthesis of Amines 1 Alkylation of Amines A Direct alkylation through SN2 leads to polyalkylations this does multiple alkylation because the product is still nucleophilic and will react again with the electrophile B Indirect alkylation is required for monoalkylations Cyanide Displacement Reduction Azide Displacement Reduction Gabriel Synthesis primary amines from primary alkyl halides mechanism works best with primary alkyl halides as it relies on SN2 reaction Secondary alkyl halides work but not as well as primary and tertiary alkyl halides do not work at all Also it will not work for aryl halides 2 Reductive Amination forming an amine from an imine via reduction A This is useful because the starting material is an aldehyde or ketone and we know many ways to makes them 3 Preparation of Amines from Carboxylic Amides A Reduction with LAH B Ho man Rearrangement this involves a loss of one carbon atom useful because it gives us a way to make an amine from any carboxylic acid derivative IV Reactions of Amines 1 Acylation of Amines converting an amine into an amide the addition and removal of an acyl group to an amine can be useful in synthesis problems The addition of this group can turn a strong activator into a moderate activator For example imagine you want to make this The problem is the amino group is TOO strong of an activator group and will lead to unwanted products Therefore by adding an acyl group to the amine and then adding nitric acid we can get our desired product 2 Ho man Elimination A Elimination of tetraalkylammonium hydroxides B Gives least stable alkene anti zaitsev TS Anti Zaitsev Zaitsev 3 Mannich Reaction enol iminium mechanism 4 Nitrosation amines react with nitrosyl cations NO A Nitrosyl cation formation NaNO2 HCl B Tertiary Amine Attack C Secondary amines lead to N nitrosamines D Primary amines lead to carbocations Chapter 22 Benzene Substituents I Reaction at the Benzyl Position 1 Radical Halogenation 2 Solvolysis SN1 3 SN2 100x faster more reactive than primary sp3 4 Acidity of Benzylic Hs 5 Oxidation A Oxidative cleavage of alkyl groups must have at least one benzylic H the second benzylic position will undergo oxidation if the reaction is allowed to react for a long time B Selective Benzylic Oxidation of OHs 6 Reduction of the Benzylic Carbon 7 Benzyl Ethers as Protecting Groups II Phenols conjugate base is resonance stabilized 1 Preparation of Phenols A Nucleophilic Aromatic Substitution NAS NO2 is a strong deactivating group and electron withdrawing this reaction will not go through SN2 as there s no backside attack available and it will not go through SN1 because the ring is very high in energy Would go by addition elimination mechanism Mechanism Idea Rate of Formation NaOCH3 F 312 small and electronegative Cl 1 0 Br 0 8 I 0 4 best LG 2 NAS Benzyne elimination addition do not need electron withdrawing groups need very extreme conditions for reaction to occur A Example label using carbon 14 3 Aryl Diazonium Ions A Mechanism nitrosyl cation formation mechanism B Diazonium Ions as Electrophiles in EAS Reactions mechanism III Reactions of Phenols 1 Acidic Cleavage of Aryl Ethers A Mechanism 2 Formation of Ethers A Mechanism 3 Phenols as Nucleophiles in EAS A Phenol is a strong activator sometimes can observe multiple additions of electrophile 4 Base Mediated Substitution IV Electrocyclic Reactions 1 Claisen Rearrangement A Mechanism 2 Cope Rearrangement C O stability makes equilibrium lie to the right proceeds through chairlike TS A Claisen Rearrangement V Benzoquinones 1 Radical Oxidation of Phenols 2 Reactions of Benzoquinones VI Biological Reactions certain vitamins can stabilize free radicals all has to do with resonance stability Chapter 15 Heterocycles I Naming 1 Named as heterocycloalkanes aza N oxa O thia S phospha P 2 Common names to memorize II Reactivity of Nonaromatic Heterocycles 1 5 membered rings unreactive towards nucleophiles usually used as bases and solvents 2 3 4 membered rings undergo ring opening ring strain drives this reaction Nucleophile attacks the least substituted side because of sterics and basic conditions proceeds through carbocation TS Nucleophile attacks more substituted side due to acidic conditions III Properties of 5 Membered Aromatic Heterocycles 1 Aromaticity and Electron Count only one lone pair counts towards aromaticity remember 4n 2 is aromatic more electronegative atoms are less aromatic S N O other heteroatoms do not contribute to resonance Neutral sp2 lone pairs do NOT contribute to resonance Neutral sp3 lone pairs DO contribute to resonance 2 General Synthesis Paal Knorr Conditions X R NH2 N R P2O5 O P2S5 S A Example for synthesis problems can add di erent R groups to the ends of the 1 4 dicarbonyl to get desired product IV Reactions of 5 membered Aromatic Heterocycles 1 EAS Analogs A C2 Substitution furan is electron rich therefore no catalyst is needed for this reaction to proceed B Mechanism and Stability attack at C2 produces three resonance structure with the last being most stable as it has all octets attack at C3 produces two resonance structures again with the last being most stable as it has all octets the attack at C2 is the major product because it produces more resonance structures than attack at C3 does making it the most stable C Rates of Reactions Benzene S O N D Indole will attack at C3 intermediates with attack at C3 the aromaticity of benzene is retained however attack at C2 would not retain aromaticity of the benzene ring this is why indole attacks at C3 not C2 2 Acidity and Basicity A Pyrrole is a weak base H on C the product on the right has a pka of about the same as HCl and is therefore a very strong acid B Pyrrole is a good acid