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Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Summary Amines eg RNHZ are organic derivatives of ammonia NH replace the NH With NC bonds and so have certain similarities With ammonia eg basicity nucleophilicity Nitrogen containing compounds are biologically very important examples amines amino acids amides proteins vitamins etc The important organic reactions of amines nucleophiles are With the common electrophiles as we have already encountered via nucleophilic substitution With alkyl halides via nucleophilic addition aldehydes or ketones via nucleophilic acvl substitution With carboxylic acid derivatives especially acid chlorides or anhydrides Amines o Nomenclature o thsical Pronerties m 0 Reactivity o Basicity Preparation of Amines 0 Overview of alkvlations Alkylation of Ammonia by Alkyl Halides o Alkylation of Phthalimide Gabriel synthesis of primary amines o Reductions of nitrogen containing functional groups 0 m o Nitriles o m o Amides Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o Reductive Amination Via Imines Reactions of Amines Alkylation of Amines by Alkyl Halides Reaction of Amines with Aldehydes and Ketones 0 Preparation of Amides Hofmann Elimination o Electrophilic Aromatic Substitution of Aryl Amines Nitrosation o Transformations of Aryl Diazonium salts Amines Nomenclature Functional group suffix amine reView Functional group prefix amino Primary secondary tertiary or quaternary Amines are described as primary 1 secondary 2 tertiary 3 or quaternary 4 depending on how many alkyl substituents are attached to the N atom note the difference compared with alcohols Quaternary amines are also known as ammonium cations Physical Properties 0 The polar nature of the NH bond due to the electronegatiVity difference of the two atoms results in the formation of hydrogen bonds with other amine molecules see below or other Hbonding systems 6 g water The implications of this are 0 high melting and boiling points compared to analogous alkanes 0 high solubility in aqueous media Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand H H 5 a 5 H Nr39H N 5 intermolecular Hbonding in amines Structure The amine functional group consists of an N atom bonded either to C or H atoms via 0 bonds Both the CN and the NH bonds are polar due to the electronegatiVity of the N atom The trigonal pyramidal arrangement of bonds around nitrogen is shallower in aryl amines vs alkyl amines This is a result of resonance delocalisation of the lone pair into the aromatic H system such delocalisation is also responsible for the decreased basicity of aryl vs alkyl amines 312 NH2 NH2 HHH 13 Reactivity The image shows the electrostatic potential for methylamine CH3NH2 The more red an area is the higher the electron density and the more blue an area is the lower the electron density 0 The amine N atom is a region of high electron density red due to the lone pair 0 Amine N atoms are Lewis bases alkyl ammonium pK1 10 aryl ammonium pKa 5 Amines can react as either bases or nucleophiles at the nitrogen Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand There is low electron density blue on H atom of the NH group Removal of the proton generates the amide ion care not to be confused with the carboxylic acid derivative RCONHZ The NH group is a very poor leaving group and needs to be converted to a better leaving group before substitution can occur The image shows the electrostatic potential for methylammonium CH3NH3 The more red an area is the higher the electron density and the more blue an area is the lower the electron density Basicity The ammonium N atom is a region of low electron density blue due to the positive charge Ammonium ions are not nucleophilic There is low electron density blue on H atom of the NH3 group Removal of the proton regenerates the amine The NH3 group is a potential leaving group Amines are more basic than analogous alcohols RNH3 pKa 10 ROHz pKa 3 0 Factors e g resonance electronegativity that affect the availability of the lone pair will affect the basicity o N is less electronegative than 0 and therefore N is a better electron donor 0 alkyl and nonaromatic heterocyclic amines are slightly stronger bases than ammonia o aryl amines are much weaker bases than ammonia a result of the delocalisation of the lone pair into the H system of the ring 0 The anion derived by the deprotonation of an amine is the amide ion NH239 4 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o Amide ions are important bases in organic chemistry example 0 Amines react With Na or K to give the amide ion 0 The basicity ofaryl amines is 0 Increased by the presence of electrondonating substituents on the ring by counteracting the delocalisation of the lone pair into the Hsystem of the r1ng 1 1le o Decreased by the presence of electronWithdrawing substituents Which enhance the delocalisation of the lone I39 pair into the Hsystem of the ring N especially those ortho or para to the quot amine functional group see right ng 0 Inclusion of a heteroatom into an aromatic ring generally decreases basicity unless protonation leads to an ion that can be stabilised by electron delocalisation H N ivFE HmeE H H quotWIRE Alkvlation of Ammonia RK ENE 1 Eli I ll39ILE NH 4 Reaction type Nucleophilic Substitution Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Summary 0 Ammonia reacts as a nucleophile With alkyl halides to give primary amines in a nucleophilic substitution reaction Yields are often poor as the product a primary amine RNHZ is itser a nucleophile and can react With more alkyl halide o The result are mixtures containing primary amines secondary amines tertiary amines and quaternary ammonium salts o This can be avoided if a large excess of ammonia is used R39CHZK R39c R39CH i HRH mtcmm HEX RECHER39JE CHZR39MK Prim31F secondmy Emmy watermaij As aryl halides do not undergo simple nucleophilic substitution they cannot be prepared using this method Related reactions 0 Alkylation of Amines Acylation of Amines Williamson ether synthesis Substitution reactions of Alle Halides MECHANISM OF AMMONIA ALKYLATION Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Step 1 The N in ammonia functions as the nucleophile and 1 33 attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new CN bond 3 H Step 2 An acidbase reaction The base excess ammonia deprotonates the positive N ammonium center creating the alkylation product the primary amine Alkvlation of Phthalimide Gabriel synthesis of Primary Alkvl Amines o o 1 EDII 2 11 15 Tm N I I RI39TH I 3 I ZIHZI ZI39IIz NH 3 o Phthalimide Reaction type Nucleophilic substitution then Nucleophilic Acyl Substitution Summary 0 The advantage of this method is that over alkylation is avoided see previous page 0 Reaction of phthalimide With KOH removes the NH proton giving an imide ion a good nucleophile Nucleophilic substitution by the imide ion on the alkyl halide generates an intermediate Nalkyl phthalimide o Hydrolysis or hydrazinolysis liberates a primary alkyl amine Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o Aryl amines cannot be prepared Via this method since aryl halides do not undergo simple nucleophilic substitution Related reactions Alkylation of Ammonia Substitution reactions of Alle Halides MECHANISM OF THE GABRIEL SYNTHESIS Step 1 An acidbase reaction Deprotonation of the imide NH 39339 proton by the base hydroxide This proton is more acidic than a simple amine due to the resonance stabilisation by ll J II the two adjacent CO groups This generates a strong nucleophile the Ve N Step 2 The N nucleophile attacks the electrophilic C of the alkyl halide displacing the bromide and creating the new CN bond This product can be compared to an Nalkyl N amide 39 39 Step 3 D The imide can be cleaved Via a mechanism analogous to that of amides Hydrolysis creates the dicarboxylic acid CECE Elf and the required amine 1 III II I lequot h df ljFSiS CDEH HENquot CH CDEII Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Reduction of Azides R RNNN R I TH Alkyl Primary Azide Amine Reaction type Oxidation Reduction Summary 0 Azides RN3 can be reduced to primary amines RNH2 Reagents either lithium aluminum hydride LiAlH4 ether solvent or catalytic hydrogenation eg HzPd o Alkyl azides are prepared by nucleoDhilic substitution 132 by azide ion N339 of prima or secondary alle halides Related reactions 0 Reduction of Nitriles Reduction of Nitro compounds 0 Reduction of Amides Reduction of Nitriles R R CEN R CIIzl lTI Nit le Primary Amine Reaction type Oxidation Reduction or Nucleophilic Addition Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Summary 0 The nitrile RC EN is reduced to the l0 amine by conversion of the CEN to RCHzNHZ Reagents either lithium aluminum hydride LiAlH4 ether solvent or catalytic hydrogenation eg HzPd o Alkyl nitriles are prepared by nucleophilic substitution S52 by cyanide ion CN39 of primary or secondary alkyl halides o Aryl nitriles can also be reduced to aryl amines QUESTIONS 0 What is the oxidation state of the nitrile C in acetonitrile CH3CN o What is the oxidation of the same C atom in acetonitrile CH3CN after reaction With LiAlH4 Related reactions 0 Reduction of Azides Reduction of Nitro compounds 0 Reduction of Amides Reduction of Nitro Compounds shun NDI R Arl lHI Mitrearena pri iargir aryl amine Reaction type Oxidation Reduction Summary Nitroarenes can be reduced to primary aryl amines see scheme 0 Typical reducing agents include Fe H Sn H or catalytic hydrogenation eg H2 Pd Nitroarenes are prepared by the nitration of aromatics 10 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o This is probably the most important method for the synthesis of anilines ArNHZ and therefore accessing the chemistry of diazonium compounds see later Related reactions 0 Reduction of Azides Reduction of Nitriles 0 Reduction of Amides Reduction of Amides 1 R I Li lH I C HIEIZ I39il39II2 R I ll H2 H Reactions usually in EtzO or THF followed by H30 workups quota Reaction type Nucleophilic Acyl Substitution then Nucleophilic Addition Summary 0 Amides RCONR39Z can be reduced to the amine RCHZNR39Z by conversion of the CO to 39CH2 0 Amides can be reduced by LiAlH4 but NOT the less reactive NaBH4 0 Typical reagents LiAlH4 ether solvent followed by aqueous workup Note that this reaction is different to that of other CO compounds which reduce to alcohols for example esters The nature of the amine obtained depends on the substituents present on the original amide Look at the N substituents in the following examples those bonds don39t change 11 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand D H II I H eCe H 3quot H C N R N I H H H l39z39amide 1El amine i I R39 LiMH4 Rd MNR39 HIFIJI II I H H H 2 amide 2 amine i If R39 Rf ENJI39L39 HI39f H I H Rquot Rquot 3 amide 3 amine o R R39 or Rquot may be either alkyl or aryl substituents o In the potential mechanism shown below note that it is an 0 system that leaves 0 This is consistent With 0 systems being better leaving grougs that the less electronegative N systems Related reactions 0 Reduction of Azides Reduction of Nitriles Reduction of Nitro compounds 0 Reduction of Carboleic acids and Esters REACTION OF LiAlH4 WITH AN AMIDE 12 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Step 1 if The nucleophilic H from the hydride reagent adds to the 3 M electrophilic C in the polar carbonyl group of the ester Electrons SI Ia NHZ from the CO move to the electronegative 0 creating an x intermediate metal alkoxide complex Step 2 3132 The tetrahedral intermediate collapses and displaces the O as part F C of a metal alkoxide leaving group this produces a highly reactive C I NH iminium ion an intermediate H Step 3 Rapid reduction by the nucleophilic H from the hydride reagent as it adds to the electrophilic C in the iminium system H electrons from the CN move to the cationic N neutralising the charge gig creating the amine product CI I3 H l a am Reductive Amination via Imines I than reduce Elmquot EC Rquot H R C RI R R39 I I I H aldahj da ammnnia or katana at amine amine Reaction type Nucleophilic Addition then Oxidation Reduction Summary 13 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o Aldehydes and ketones react chapter 17 with 10 amines to give substituted imines and 2 amines to give enamines a IE3quot REE Rquot IT JH ICE HID R R39 R 1139 These N species can then be reduced to amines The method provides access to 1 2 or 30 amines Typical reagents step 1 acidic buffer step 2 most commonly catalytic hydrogenation eg HzPd gt Sodium cyanoborohydride NaBHgCN Which is like NaBH4 can be used for smaller scale reductions gt R R39 and Rquot may be either hydrogen alkyl or aryl VVV Related reactions 0 Reduction of Aldehvdes and Ketones Reduction of Alkenes Overview of Amine reactions The important organic reactions of amines nucleophiles are With thecommon electrophiles 0 alkyl halides via nucleophilic substitution aldehydes or ketones via nucleophilic addition carboxylic acid derivatives especially acid chlorides or anhydrides vianucleonhilic acvl substitution 14 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand 1L 1139 R X z I H 3 1 DH R H RI 39NJ further Ell NH 39 I x reaction H H D IPE 3 R 31 HER R 1139 I ll H Alkylation of Amines R 11 arr NH II I H RTE325i Reaction type Nucleophilic Substitution Summary 0 Amines can react as a nucleophiles With alkyl halides Via substitution reactions SEQ Yields are often poor as the product amines are still nucleophilic and can react With more halide The result is often a mixture of amines in various states of alkylation R39CHQK R39C 1139ch RI39iIH a RI HILfCIIzH39j HEX Extrema CHZR39jSK Primal SEE daI39jf martian watemaxy Related reactions Alkylation of Ammonia Acylation of Amines o Williamson Ether synthesis Substitution reactions of Alle Halides 15 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand MECHANISM OF AMINE ALKYLATION Step 1 The amine N functions as the nucleophile and attacks I33 121511 12 the electrophilic C of the alkyl halide displacing the bromide and creating the new CN bond 1 CI H I CHSCHZIIJECJ H Step 2 An acidbase reaction The base excess amine deprotonates the positive N ammonium center B creating the alkylation product here a secondary H amine I CC H C E II Reactions of Primary Amines with Aldehydes and Ketones review of Chapter 17 3 I311quot run Ell NH ICE R R39 R R39 imjne Reaction type Nucleophilic Addition then Elimination Summary 0 Primary amines RNH2 or ArNHz undergo nucleophilic addition with aldehydes or ketones to give carbinolamines which then dehydrate to give substituted imines The reactions are usually carried out in an acidic buffer to activate the CO and facilitate dehydration but without inhibiting the nucleophile Systems of the general type ZNH2 review table in Ch17 undergo this type of reaction and can be used as derivatives to aid in the identification of aldehydes and ketones Related Reactions 16 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand 0 Formation of Acetals o Dehvdration of Alcohols Formation of Enamines NUCLEOPHILIC ADDITION OF A PRIMARY AMINE GIVING AN IMINE Step 1 An acidbase reaction Protonation of the carbonyl activates it and makes it more susceptible to attack by a neutral nucleophilic like the N of a primary amine Step 2 Attack of the N nucleophile at the electrophilic C of the CO group With the electrons from the H bond going to the ve 0 Step 3 An acidbase reaction Removal of the proton neutralises the ve charge on the N and forms the carbinolamine intermediate Step 4 To form the imine we need to dehydrate However before OH leaves it needs to be protonated so a simple acidbase reaction Step 5 Use the electrons of the N to help push out the leaving group a neutral water molecule this leaves us With an iminium ion Step 6 An acidbase reaction Deprotonation of the iminium N reveals the imine product and regenerates the acid catalyst 17 Organic Chemistry 233 Amines Lecture Notes I D rug II C H 18 Dr Farshid Zand Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Reactions of Secondarv Amine Derivatives with Aldehvdes and Ketones review of Chapter 17 quot HEN H ER CHZR R CHEL39 enamine Reaction type Nucleophilic Addition then Elimination Summary 0 Secondary amines R2NH react With aldehydes or ketones to give carbinolamines Which then dehydrate to give enamines o The carbinolamine in these reactions can only eliminate to give a CC since there is no NH in the carbinolamine The products are called enamines because they are quotalkene aminesquot Enamines are useful reagents in synthetic organic chemistry and biochemical transformations Related Reactions 0 Formation of Aceta1s o Dehydration of Alcohols Formation of Imines 19 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand NUCLEOPHILIC ADDITION OF A SECONDARY AMINE GIVING AN ENAMINE Step 1 An acidbase reaction Protonation of the carbonyl activates it and makes it more susceptible to attack by a neutral nucleophilic like the N of a secondary amine Step 2 Attack of the N nucleophile at the electrophilic C of the CO group with the electrons from the H bond going to the ve 0 Step 3 An acidbase reaction Removal of the proton neutralises the ve charge on the N and forms the carbinolamine intermediate Step 4 To form the enamine we need to dehydrate However before OH leaves it needs to be protonated so a simple acidbase reaction Step 5 Removal of a proton from an adjacent C allows the H bond to form and loss of the leaving group a neutral water molecule creating the enamine 20 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Preparation of Amides reVieW of Chapter 20 21 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand J D a RP a E quotEl base Rf RNR acid chlu dea E 5 w E R H 1 11 base Rf ENE armyd dES Reaction type Nucleophilic Acyl Substitution Summary 0 Primary amines RNH2 and secondary amines RzNH undergo nucleonhilic acvl substitution With carboxylic acid derivatives to give amides The most common examples are the reactions of acid chlorides and anhydrides though esters do react With amines Hofmann Elimination 1 eaceaa CH3 quota I CC N133th H20 l I a 320 Iago I 1 Reaction type Elimination Summary 0 Like alcohols amines can undergo elimination reactions Quaternary ammonium salts undergo an E2 elimination When heated With silver oxide AgzO in water 0 Amines can readily be converted into quaternary ammonium iodides by treating them With excess methvl iodide o AgzO H20 reacts giving the quaternary ammonium hydroxide silver iodide precipitates eaceaa AK AgECI gal NH CHJI CHGLJII39 HE39S CIGkth 22 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand When heated the hydroxide induces a base promoted 12 or Belimination giving an amine and alkene o The regioselectivity is opposite to that predicted by Zaitsevs rule in that it leads to the less highly substituted alkene o The less highly substituted alkene is sometimes referred to as the Hofmann product M WJF Nl ala CIIgh DH heat major minor o The outcome is dictated by steric effects of the large leaving group and the alkyl chain more details NH239 and NR239 are very poor leaving groups both anionic but NR3 is much better neutral 0 Compare this With With OH and H20 in the dehvdration of alcohols Related reactions 0 Dehvdration of Alcohols o DehvdrohaIOgenation of Alkvl Halides MECHANISM OF THE HOFMANN ELIMINATION The initial steps are an example of the alkylation of an amine by methyl iodide The mechanism of the elimination step is shown H CHECHZ ITIJQH When heated the hydroxide removes the more accessible proton the H bond of the alkene CC GEE H forms and the leaving group a neutral amine departs Ctrjcrgmzcm 03313 ngfj 23 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Electrophilic Aromatic Substitution of Arvl Amines 1 1le NHz NH2 pam arma Summary Arylamines are potentially very reactive towards electrophilic aromatic substitution 0 This is because NH2 NHR2 and NR2 are verv strong activators and are ortho Dara directing 0 However the basicity of the amino group means it is unsuitable for reactions With acids e 3 H2804 or A1C13 such as nitration sulfonation and FriedelCrafts alkylation or acylation Polysubstitution can also be a problem For example bromination is very rapid even in the absence of a catalyst leading to bromination in all available ortho and para positions NHz 2 Br Br Br Br 0 To avoid these problems it is customary to quotprotectquot aryl amines by converting them to their Nacvl derivatives ie amides o The protecting group an amide can later be removed by either acid or base hvdrolvsis 24 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand H quotII D a an min MHz H3CI er aq NaCJII heat amine amide o The amide is a less powerful activating group than the simple amino group NH2 since resonance Within the Nacetyl group of the amide see below competes With delocalisation of the N lone pair into the ring 3ij Ha HER Steric effects in the amide also often lead to a decrease in the amount of the ortho products 0 In principle the sequence protect substitute deprotect is equivalent to being able to substitute the aniline directly Nitrosation of Amines HI IIEJII Eli I ll39II2 339 RNEN 2112 139539 amine rdiareenium ien Rx R HNIEJII FI HI HNND H20 1139 R 2 amine N nitre aeamine Summary 0 Typical reagents sodium nitrite and aq HCl or H2804 this mixture yields nitrous acid HNOz 25 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand The most useful reactions are probably those of primary aryl amines ArNH2 Which give aryl diazonium salts ArNz Which can then be used to prepare substituted benzenes see next page 0 The actual nitrosation reagent is the nitrosyl cation NO Which is formed in situ m H H H I H2C39 IEZIJ HZCI i H Q Hz iIr H Ow Hzl j 1IIr Hz Nitrite anien Mittens aeid Mitre33d entien The nature of the product depends on the nature of the initial amine 0 Primary alkyl or aryl amines yield diazonium salts hence the diazotisation reaction H H l H R bII f NZD H R le NZCI iii NEH H H2D Dineeninni Primer Nitreejrl E tl 39 alkyl ainine eatinn o Alkyl diazonium salts are very unstable and yield carbocationderived products by loss of the very good leaving group N2 RTFM N R N1 Alkyl Carbe enti en Nitre gen dineeninin inn 0 Secondary alkyl or aryl amines yield Nnitrosoamines H Rglwll ng Fi N13 RZN Hzci H H Seeen deny l itreej H l itre eeainine alkylainine e atien o Tertiary alkyl amines do not react in a useful fashion 0 Tertiary aryl amines undergo nitrosation of the ring an electrophilic aromatic substitution reaction 26 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand rsrlgcrl2 a HZCHB CHgCHg H xCI39ECHS szj Svntheticallv Useful Transformations Involving Arvl Diazonium Ions Cl GE 0 DH RED camp uund Cull Cu Er H N I H3PD2 1 E11 IZII39 EtCIII mast WEI C en EN F g 6 CH 0 Aryl diazonium salts can be converted into a range of systems as shown above 0 These reactions can be useful as the methodology can be complementary to other methods of introducing aromatic substitutents Summary 0 Of particular note are the methods for introducing F using HBF4 the Schiemann reaction and OH using H20 27 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand The reactions of copper salts CuCl CuBr and CuCN are known as the Sandmeyer reactions Coupling With phenols gives azocompounds Which are important as yellowred dyes or pigments Aryl diazonium salts are prepared from aryl amines previous page Which in turn can be obtained by the reduction of nitrobenzene Spectroscopic Analysis IR The NH should be apparent NH one band NH2 two bands symmetric and asymmetric Absorbance cm39l Interpretation 3500 3100 NH stretch 1350 1000 CN stretch 1H NMR The NH protons tend to be broad peaks N is less electronegative than 0 so it deshields less Resonance ppm Interpretation 05 50 broad exchangeable NH proton 15 30 CHzNRZ 13 C NMR CN typically 35 50 ppm deshielding due to N note the deshielding is less than that observed in alcohols CO 50 65 ppm UVVIS maxima due to n gts 190 nm 0 n electron from N lone pair 28 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand o s antibonding CN 0 Mass Spectrometry Peak for the molecular ion M is usually apparent The nitrogen rule compounds composed of only C H 0 have an even molecular weight If a compound contains an odd number of N atoms will have an odd molecular weight the Nitrogen rule Since N is very good at stabilising positive charge cleavage at the bcarbon are common Cw q39gr qmcmcm CHs r I CHCHCH3 M 101 I39 fE 53 Amine Questions Q For each of the following series of compounds arrange the molecules in order of Q decreasing basicity most basic to least basic m4 NHS ll 12 a b NH2 NH2 NH2 1 1le No Me 12143 Cl C 29 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand a E d pipendine aniline pyridine pyrrnle 2 Q What would be the major products of the following reactions LillillILI a CI ISCHZCHZCHZC EN 339 TIIF b GAE ennessl l CHE Linirni an in CF 3 HQ 1 539 2 SanICI n innlfnngjg c1 7 angina P Q Design syntheses of the following amines using ethene as the only source of Q 3 carbon atoms 1 aminoethane 1 aminopropane 1 aminobutane Q What would be the major products of the reactions of cyclohexylamine with each 9 4 of the following a ethanoy1 chloride Et3N b hydrogen bromide c cyclohexanone in an acidic d ethylene oxide followed by dilute buffer acid workup 3O Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand f excess methyl iodide then AgzO e excess ethyl 10d1de H20 mat Amine Answers 31 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand a NHE NHS 3 m4 Use the Lewis base definition to start and try to look at the lone pair availability more available stronger base Each system in N centered so we can ignore that as a factor The amide ion is the strongest base since it has two pairs of nonbonding electrons more electronelectron repulsion compared to ammonia which only has one Ammonium is not basic since it has no lone pair to donate as a base b CECE 1 3H3 EH2EJH it CHFPEEH Amines are stronger bases than alcohols Again we can use lone pair availability N is less electronegative than 0 so it is a better electron donor What about the alcohol and the thiol Acidity increases down a group so the thiol is a worse base than the alcohol larger atoms tend to form weaker bonds with the small proton DCH3 Me c1 Ho Since these are all substituted anilines we need to look at the role of the substituent after all it is the only thing changing across the series Substituents that are electron donors will make the N lone pair more available electron donating ability OCH3 gt CH3 whereas electron withdrawing groups will make the N lone pair less available electron withdrawing ability N02 gt C1 32 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand W H H We can still use lone pair availability Piperidine is the most basic conjugate acid pKa 112 The lone pair is in an sp3 hybrid orbital and there is no resonance no H system In pyridine conjugate acid pKa 52 the N lone pair is in an sp2 hybrid orbital but is not part of the 6139I electron aromatic system nor is it involved in any resonance perpendicular The sp2 hybrid is smaller than the sp3 hybrid so there is a stronger attraction to the nucleus so less basic In aniline conjugate acid pK1 52 the N lone pair can interact With the H system of the aromatic ring Which makes them less available for donation In pyrrole is a very weak base conjugate acid pKa 4 The N lone pair is involved in the 6H electron aromatic svstem Protonation Will destroy the aromaticity of the 6H electron aromatic system and this makes it an unfavourable process 33 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Lisls ta CI ISCIIZCHZCHZCEN E CI ISCHZCHZCHZCHZN reduction Nitriles RCEN are reduced to 10 amines by conversion of the RCEN to RCHzNHZ so the product would laminopentane Er s sssss I ll H3 NH Us F I nuslsoph m substitution Benzyl bromide is an alkyl halide and will therefore undergo nucleophilic substitution by the nucleophilic N of ammonia giving benzylamine C CH3 MESH123E314 CHs SanICI H3 393 I quot mtrstmn ND rsdususn NH Toluene undergoes nitration to give mainly paranitrotoluene Reduction of the nitro group gives the amine paraaminotoluene or para methylaniline if you prefer CH3 C a 0 NEWS sHB HM is ac I CH3 U Pf parstisn sf 0 H3 redusssn U snsnsmins 34 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand Cyclohexanone a ketone will react with a secondary amine to give an enamine more stable alkene preferred which on catalytic hydrogenation reduces to the tertiary amine NNdimethylaminocyclohexane m First note that we have a homologous series of C2 to C4 amines we are trying to make Here is a scheme collecting possible syntheses together These are based on important reactions and to be short syntheses 35 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand eleetrephili e edditl en 1 eeeee e eleetrephili e PEI C39 reagent g 4 MEET eubetimtien r M3 El 239J eeeeee eubeti tien G g d NHg NaCN reeeti en MOE In N redeetien WES W melteteeylete MAEl4 PBI glEEN TeCl f Et3N ME MEETS I39 eubetituti e11 eeeeee MNHQ We WNHZ a laminoethane we can39t add NH3 directly to the alkene so introduce a halogen bromide is a good choice as it is a good leaVing group then substitute using excess ammonia b laminopropane we need to add a C atom to get from C2 to C3 For an amine a good way to do that is Via the nitrile So after preparing ethyl bromide nucleophilic substitution with NaCN in a polar aprotic solvent 36 Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand such as DMSO will give the nitrile which can be reduced to the amine c laminobutane now we need to add 2C to get to C4 addition of the Grignard ethyl magnesium bromide to ethylene oxide gives lbutanol Ammonia will not react with an alcohol to give substitution poor leaving group our best choice here is either to convert the alcohol to the bromide or we could use a tosylate both better leaving groups then substitute with the ammonia SH Q1 each of the reactions the primary amine is the nucleophilic species reacting with a variety of electrophiles 37 Organic Chemistry 233 Amines Lecture Notes D An quotIf Et3N HEr quotII39 39II39 EEC ass CH3 CHZI excess CHJI 38 Dr Farshid Zand Craft UN U H 0 Uri laggcj r r120 heat 0 I NICHGJE Organic Chemistry 233 Amines Lecture Notes Dr Farshid Zand 39