Y ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE SYLLABUS (6 Lecturers) Introduction to reactions involving substitution, addition, elimination, oxidation, reduction, cyclization and ring openings. Synthesis of a commonly used drug molecule. 9.1 INTRODUCTION All chemical reactions involve the breaking of existing bond in the reactant molecules and formation of new bonds in the product of the molecules. An intermediate transition complex is first formed during the reaction, which is immediately change to final products. In the covalent bond, the shared electrons are held together by mutual attraction of the two atomic nuclei of the concerned atoms. So, it is important to know in what ways the bonds are broken and transition state is formed. When a bond between the two atoms breaks in such a way that one electron of the shared pairs remains with each of the two atoms, we call it homolytic fission and it results into the formation of free radicals. The free radicals are high! ly reactive due to the presence of unpaired electrons with them. Alternatively, when the two shared electrons remains associated with only one of two atoms, the type of fission is heterolytic fission. It results into the formation ofa cation and an anion which type of fission will take place depends upon the nature of bond and the prevailing conditions. Mostly, it depends upon the electronegativity of the two concerned atoms. Homolytic fission will appear when the electronegativities are equal or almost equal. For example, molecules like Cl, Br, CCl, ete. undergo homolytic fission. but when the clectronegativity differs, heterolytic fission results, e.g. in HCI, HBr, H,0, HN; ete. The carbon atoms carrying a negative charge due to the presence of electron pair with it is called carbanion and other carbon atoms carrying a positive charge is called carbonium ion (or carbocation). The stability of carbanions follow the order given below: CH; (Primary)> RCH; (Primary)> RCH (Secondary) > R; C~ (Tertiary) (376)ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE m The stability of carbocations follows the reverse order as given below: R3C* (Tertiary) > RCH (Secondary) > RCH} (Primary) > CHS (Primary) ; In this chapter, we are Going to discuss the details of the above noted types of organic reactions particular Tegarding the mechanism of these reactions. In studying the mechanisms of any organic Feactions, it is essential to know about the different types of attaching agents also because the mechanism of the reaction is named on the attacking agent. The following are some important types of attaching reagents 9.2 TYPES OF ATTACHING REAGENTS 1. Electrophilic reagents (Electrophiles) It is an electron-deficient (or electron-loving) chemical species. Due to the electron- effenciecy, it always attacks at the centre of high electron-density. Electrophiles are further classified as: (Positive electrophites, c.g, H*, Hx0*, CI’, Br*, I*, N*Os, RY (carbocation) te (i) Neutral electrophiles, e.g. R (free radical), BF3, AICI, SnCly, RCOCI, S03, :CRy (carbene), :NR (nitrine), ete. 2. Nucleophilic reagent (Nucleophiles) It is an electron-rich (or nucleus loving) chemical species. Due to the presence of a Pair of free electrons, it always attacks at the centre of low electron density, Nuclophiles are: (Negative nuctophiles, e.g. F, Cl- , Br ,1~ , OH- , CN-, OR“ ,NH~ , RCOO-, R~ (carbonion) etc. Gi) Neural nuclophiles, e.g. H,0, ROH, NH, KOH, R.NH3, ROR etc. (il) Ambident nucleophiles: When an electron rich species Hy ca react from both sides it is known as ambident nucleophiles, such as CN- and NO~ . For exampe, cyanide ion (CN-) can reach from carbon side as well as nitrogen side. Likewise, NO can react from oxygen side as well as nitrogen side. R-X +K*CN (alc) 4 5R-C=N +K*X Haloakane Alkyl eyanide R-X +Agt CN" Am, R_CZN 4 AgX Haloakane Alkyl isooyanide 9.3 | SUBSTITUTION REACTIONS On the basis of mechanism of the reaction, the substitution reactions of the following two types: 1. Electrophilic substitution reaction 2. Nucleophilic substitution reaction| 1 78 CONCEPTUAL ENGINEERING CHEMISTRY 3 1. Electrophilic substitution reactions Substitution reaction of benzene are summarised as below: (i) Halogenation by Cly: Ch, 22-4 GH, Cl + HCI (ii) Halogenation by Br, : Br, —229C, He Br + HBr (iii) Nitration: HNO, 4289: _¢, H,NO, + H,O0 (iv) Sulphonation: H,$0,———> H,0 + C,HsSO3H (Benzene sulphonic acid) (v) Acetylation: cH,cocl““s_, HCl + C,HsCOCH, (Acetophenone) This reaction is called Friedel-Craft acylation. (vi) Alkylation: — CH,CI—*S3-4 HCI + Cg HsCHy (Toluene) This reaction is called Friedel-Craft alkylation. 2. Nucleophilic substitution reaction Alkyl halides are highly reactive in nature. This is due to the fact that halogen atom is held rather loosely in the carbon atom and hence can be easily removed. (i) Fora given alkyl group, the order of reactivity is: iodides > bromides > chlorides. (ii) Among the primary alkyl halides the order to reactivity is: CH;-X > CH; -X > CyH, - x Explanation for reactivity of alkyl halides: The C-X bond in R-X is polar, ie. 6+ 8 R-X Due to the presence of partial negative charge on halogen, it behaves as a Lewis base. This weak basic halogen atom can be readily displaced by stronger bases (nucleophile), which are also electron-rich and possess at least one lone pair of electrons as shown below: fh -8 f Nu? Rox — Renu +X® (Attacking ~ Halide ion nucleophile) leaving group 9.3.1 Types of Nucleophilic Substitution Reactions There are mainly two types of nucleophilic substitution reactions. They are: (i) SN (nucleophilic substitution, bimolecular) reactions (ii) SN, (nucleophilic substitution, unimolecular) reactionseras ORGANIC REACTIONS AND SYNTHEsis. OF ADRUG MOLECULE a Kinetics of nucleophilic Substitution reactions It seems probable that the two mechanisms involved in are the same with other nucleophiles. The two types of the res CHBr + KOH (a 9) — CH,OH + KBr Methyl bromi - ce, " " bromide Methyl alcohol 3)3 CBr + KOH (ag) —5 ‘ (CH); COH + KBr tert-Butyl bromide tertButyl alcohol alkyl halides with hydroxy! ions ‘actions are as follows: These two reactions appear to be similay path. However, both the reactions follow The rate of the first reaction is: Rate = k [CH,Br] [KOH] Ttmeans that the reaction results from the collision between methyl bromide and hydroxy! ion. This is found to be so. ir and are expected to follow similar mechanistic different kinetic order as illustrated below: In second reaction, the rate is de independent of base concentration, ive, Rate = k [(C,HBr] Hence, first reaction follows second-order kinetics and second reaction follows first- order kinetics. To account for this difference, two different mechanisms are proposed for these reactions: pendent on the concentration of alkyl halide only and is (i) SN, Reactions: Tertiary alkyl halides undergo nucleophilic substitution reactions by a first-order mechanism. (ii) SN, Reactions: Primary alkyl halides undergo nucleophilic substitution reactions by a second-order mechanism. The details of SN, and SN reactions are explained at a later stage in this chapter. 9.4 MECHANISMS OF ELECTROPHILIC MONO-SUBSTITUTION IN BENZENE RING In monosubstitution, two steps are involved: The key step is considered to be the attack of an electrophile at carbon of the Ting to form a cationic intermediate. This step may be represented by the following general equation in which the attacking reagent is represented either as a electrophile (Y*) or as a neutral but polarized (y*8 — 2-4) molecule. H + on CesHe + Y ——> HCE (Slow; rate determining) Y Be + Z” ——> CgHsY + H—Z (Fast)i, 380 CONCEPTUAL ENGINEERING CHEMistRy Y HY Slow ® + Y'oRY?-z*) ——> — +H Step (i) Step (i) Intermediate Substituted carbonium ion product The overall mechanism is as follows: . o A s Celle + YY —e | Hcg |—> caiky + ‘Y This is based upon the fact that when a aromatic compounds labelled with deuterium or tritium were subjected to nitration, bromination and Friedel—Crafts alkylation, deuterium and tritium are replaced at the at same rate as protium H. This conclusively proves that the above reactions whose rate we are comparing do not involve the breaking of the carbon—hydrogen bond. The rate of the overall substitution is determined by the slow attachment of the electrophile, Y*, to the aromatic Ting to form the carbonium ion. Once formed, the carbonium ion rapidly loses hydrogen ion to form the products. Step (i) is thus the rate-determining step. Since it does not involve the breaking off carbon—hydrogen bond, its rate is independent of the particular hydrogen isotope which is present Thus the absence of isotopic effect establishes not only the two-step nature of electrophilic aromatic substitution but also the relative speeds of the steps Mechanisms of Some Electrophilic Substitution Reactions of Benzene 1. Mechanism of halogenation The commonly accepted mechanism for aromatic halogenation, illustrated for chlorination, involves the following steps: The first step generates the attacking electrophile CI* by an acid-base equilibrium (Lewis acid). Metallic iron, which is added as a catalyst, is converted into ferric chloride by chlorine. The ferric chloride, in turn, polarizes the chlorine molecule yielding an electrophile which brings about the further reaction, €.g., generation of the electrophile a & ® ° C1—Cl + FeClh —> Cl... Ch... FeCl; —> Cl + FeCl Chloroniurn ion In the second step, chloronium (Cl*) ion attacks the 1-electron cloud of benzene ring forming a carbocation, which is stabilized by resonanceJIC REACTIONS AND SYNTHESis or GAN OF ADRUG 4 lOLECULE + ¢; _Slow H +c (S cl Oe Abstraction of proton from the from the carbocati abstracted cation interm chlorobenzene. diate by the ba H H Ch = er carbocation: In the third step, the proton is then se FeCl; to form the final product, cl ch = + Fei, oO + FeCl, + HC! Tt may be pointed out here that in actual practic the free chloroniu | tual practice, ¢ chloronium ion may not be lectrophile is the com, ‘ plex between the Lewis acid and the chlorine molecule, whose positive end attacks the r-clectrons of the benzene ring, i.c. H St & . Slow Chen ChumBeCh, SOV, © cl + FeCl, 2. Mechanism of nitration The following steps were involved. In the first step, nitronium ion NO, which is electrophilic reagent that attacks the benzene ring is obtained, The reaction is simply acid—base equilibrium in which H,S0, serves as the acid and HNO serves as a base. * HNO, +2H,S0, — NO, + 2HS0; + H,0* In the second step, the nitronium ion reacts with benzene to form as intermediate carbonium ion, which is stabilized due to resonance. + oH H H H + w ‘oh: pa eh — 6h — Ch — Eh. In the third step, the hydrogen ion is removed from the carbonium ion by the basic ion (HS ) to yield the final substitution product. NO, ——> + Hy NOp + SO} <———— Oo #80,i CONCEPTUAL ENGINEERING CHEMIstay 382 3. Mechanism of sulphonation The commonly accepted mechanism fr sulphonation of aromatic cmpoundg involves | the following steps: In the first step, electrophilic sulphur trioxide i between two molecules of sulphuric acid 2H80,-—~+ 4 B80; + Hot + so, In the second step, SO; deficient sulphur atom. It is cleat s produced by an acid—base equilibrium molecule is a neutral molecule but it h: ‘as a powerful clectron. from its resonance hybrid structures shown below: ° ° 0 oO | | | | 8 st ee So b | J \ J \ . a / \\ J \ H 80, H So, H So, H & + so, Slow, Co — =n = In the third step, th of benzene sulphonic acid H e : Slow ve) 803 + HSO? + HS0, In the fourth step, sulphonic acid. ere is a loss of hydrogen ion to form the Tesonance-stabilized anion the benzene sulphonic acid anion Teacts with H,0* ee $0, SO3H @ » O SS O ee Benzene sulphonic acid to form benzene 4. Mechanism of Friedel—Crafts alkylation reaction Benzene on treatment with an alkyl halide in the presence of a Lewis acid like AlCl, yields an alkyl benzene, In this reaction, a nuclear hydrogen is replaced by an alkyl. This Feaction is known as Friedel—Crafis alkylation reactionORGANIC REACTIONS any SYNTHESIS OF A DRUG MOLECULE = Until recently the Commonly a i iedel—Crafts alkylation is shown inthe following equation, '’ accepted mechanism of Friedel—Crafts alky In the first step, the Lew: carbonium ion. 's acid AICL, converts the alkyl chloride into an alkyl 45 ~6 e aie’ IC, — (R, AIC] —+ R* + AlCl, The alkyl ¢; ; SH carbonium ion attacks to benzene to form a carbonium ion. Ron Reaea Rey RH + Slow ® +R 1 Oo O-H =O @ . 8 The hydrogen ion from the carbonium ion is removed by the basic AICI, to produce the final substitution alkyl Product, @H R 8 ‘ij == + Alc, + HCL 4 Shown above, Friedel—Crafis alkylaions are reversible Again the rate determining step is (b). 5, Friedel—Crafts acylation . 0 ll The R-C— group is called an acy! group, and a reaction whereby an acyl group is introduced into a compound is called an acylating agent. Two common acylating agents are acid chlorides and carboxylic acid anhydrides. In most Friedel—Crafts acylations, the electrophile appears to be acylium ion formed from acyl chloride or acid anhydride with the help of Lewis acids in the following ways: 0: 0 0: Il. oom eG R- C-Cl:+AIC ==R-C-Cl-AIC, —=R- CO+AICL, 0 0 { rt ° ae Ne «ho 8 Sr he, — PP Aly == R—-C +Re O—AICl; R—C R-Cmi CONCEPTUAL ENGINEERING CHEMistay 3 An acylium ion is the resonance hybrid of the following two resonating structures: + + R-C=0:e—>R-C=0 The remaining steps in the Friedel-Crafts acylation of benzene are as follows R gl a b Slow —C—R mma Il I) Us \ R ® i / I Slow —C—R i i | i ZA | 0 i o #H H H H 9 | I | C—R CR C—R C tooo oa Il = 0 o 0 ln 0 R 8 —— C—R+AICI, Fast C—R+ HCI + AICI, pee = OT Alternatively, it has been suggested that the true tiectrophile in acylation reactions is actually the positive end of the complex between the acid chloride (or aahydride) and the Lewis acid. Oo oO ll [+8 5 R-C-Cl+AICl; —>R-C - Cl-Al Cl; It may be pointed out here that since the aromatic Ting is deactivated by the introduction of an electron withdrawing acyl group, unlike alkylation, there is no chance of polysubstitution in acylation reactions. Besides, the acylium ion does not undergo any rearrangement. It is on this account that this reaction is often employed for the preparation of alkylbenzenes by reduction of acylbenzenes (aliphatic aromatic ketones) by Clemensen reduction. 9.5 __ MECHANISMS OF SN, (Substitution Nucleophilic Bimolecular) It is clear that in such reactions the nucleophile (OH) collides with the reactant (CH;Br) molecule by the back side attack from the halogen atom (Br) and possesses sufficient energy385 ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE to break the C—Br bond and form C—OH bond. Hence the reaction (SN2) proceeds through a fransition state involving two reactant molecules. Thus a complete inversion of configuration . takes place, H HoH H - \A b= \/ 8 7S S HOrH=¢-B > (Bt > HO-G-H + Br H H Backside attack of methyl bromide Transition state of a ‘SN, reaction In the transition state, the central carbon atom is sp2-hybridized and the three hydrogen atoms attached to it lie in a plane at bond angles of 120°. The OH group and the Br atom are Partially bonded to each lobe of the p-orbital, which is perpendicular to the plane of three H atoms. The C—OH bond is partly formed and the C—Br bond is partly broken H. H ‘sp*-hybridized \o carbon 3 c 8S 8 / H \ cabon and p-Otbital of three H-atom Spt-carbon —_WaRsifon-statefora SN, reaction jana pane 9.5.1 Factors which influence SN, reactions <1 Reactivity of alkyl halides: The basic requirement of mechanism is the backside attack of the incoming nucleophile on the carbon atom carrying the halogen atom. This type of attack is quite easy in the case of primary halides as the small size of hydrogen atom does not hinder the attack. However, in case of tertiary alkyl halides, there are three bulky groups attached to carbon atom carrying a halogen atom. These alkyl groups cause overcrowding and hinder the incoming nucleophile. This type of hindrance is called steric hindrance. So the rate of SN, reaction decreases as the bulk of the substituents increases. CH,X > Primary alkyl halide > Secondary alkyl halide > Tertiary alkyl halides > Neopentyl halides \2. Nature of the halogen atom: In the transition state for SN, reactions, the negative charge is normally distributed over the nucleophile and the leaving group, The better the leaving group, more stable is the transition state due to greater stabilization of the negative charge by the leaving group and hence more rapid is the reaction. 6 i 3] Nu:+R-XLNu -XJ>Nu-R+:XSleble the jug at bover 4 re us Ahe Maid rrr: : ate CONCEPTUAL ENGINEERING CHEMISTRY “groups are of weak-bases. The order of increasing basic strength of halide ions is: 1° R-Br>R-CI>R-F Nucleophilicity or strength of the nucleophile: Since the transition state ina SN, reaction is formed by the attack of the nucleophilic reagent on alkyl halide, stronger the nucleophilic reagent, more rapid would be SN> reaction. The nucleophilicity of a reagent may be defined as its ability to donate a pair of electrons to the carbon atom. Thus, greater is the nucleophilicity of a nucleophile, the more rapid should be its SN, reaction. As the nucleophiles have complete octet and a lone pair of electrons, therefore, all the nucleophilies should be basic in nature. However, their nucleophilicity does not always parallel their base strength. For instance, the hydroxide ion is a strong base and is also a good nucleophile but iodide ion is a very good nucleophile though it is very weak base. In a series oftucleophiles belonging to the same family; the nucleophilicity increases with the increase in the size of the atom bearing the unshared pair (Ione pair) of electrons, Therefore, the nucleéphilicity of halide ions in the decreasing order is; 1° > Br° > CI° > F® 9.5.2 Effect of solvent on SN, reaction As the transition state in SNy reaction is non-polar, therefore, non-polar sclvent will stabilize it and will lower the activation energy of the SN, reaction. Hence non-polar solvent will favour SN, reaction, Stereochemistry of SN, Reaction: Due to the attack of incoming nucleophile on the alkyl halide from the backside, the configuration of the molecule in inverted. This is proved when (-)-2-bromooctane is hydrolysed under SN) conditions (high concentration of hydroxide ion), it gives exclusively, (+)-octan-2-ol as shown below: ones chy Apedlic ne 1g, ‘HAC * CH, Cn Beal C-Br High con. of OH” 44g pH om Tas SNp cue 0, cH,te Cots (4-2-Bromooctane (#}-Octan-2-017 ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE * __ Thus if the alkyl halide is optically active and laevorotatory, the substitution product is also optically active and Aextrorotatory, This inversion of configuration is known as Walden inversion. 9.6 SN, REACTION A nucleophilic substitution Teaction in which the rate of kinetics depends upon the concentration of only one reactant i s called an SN, reaction. Rate = k [RX] , (Substitution nucleophilic unimolecular) reaction , The mechanism suggested for the Teaction between tert-butyl bromide and hydroxide jon is as under: Mechanism of SN. CH, CH, fers Slow if 1 WjC—C—pr —— me—e + Bro CH, CH, tert-Butyl bromide Carbonium ion 2 (CHs)3C* + OH Ft, (CH,),c— on As the rate-determining ste P is only the slowest one, it means that the rate of reaction depends upon the concentration of tert-butyl bromide only, Rate = & (CH3),CBr. 9.6.1 Factors which influence SN, reactions & Effect of solvent: As the transition vent: solvents will stabilize it and SN, reaction. state of SN; reaction is polar, therefore polar lower its activation energy. Hence polar solvents favour (i) Nature of nucleophiles: As the nucleop! hhiles do not take part in the rate-determining step of SN, reaction, the strength of the nucleophile has no effect the rate o reaction. iii) Effect on structure of alkyl halides: We have discussed above that the carbocations ~~ are be intermediates in SN, reactions. Therefore, the more stable the carbocation formed, the more rapid should be the SN, reaction. As the order of the stability of various carbocations follows be order: Benzyl > Allyl > Tertiary > Secondary > Primary > Methyl carbocation Therefore, the order of reactivity of alkyl halides in SN, reactions follows the same sequences: Benzyl > Allyl > Tertiary > Secondary > Primary » Methyl halides However, it may be noted here that this order of reactivity of alkyl halides is opposite to that of the SN, reactions. Effect of nature of the leaving group: Evidently, better the leaving group, lesser is the E,,, for the zansition state leading to the formation of the carbocation and hence more should be the reactivity of the alkyl halide in SN, reactions. Thus the order of 8. Bsc? reactivity of the different leaving groups follows the sequence: 1° >Br® >CI° >F°ae CONCEPTUAL ENGINEERING CHEMIsTRy Stereochemistry of SN. 4 As the carbonium ion has a flat structure, therefore nucleophile can attack the on carbocation carbon from either of the two directions. But the side of the leaving group is to some extent hindered because of the presence of halides ion, so attack from this side is less, Thus, the major attack from this side which is just opposite to the halide ion. Hence, partial racemization takes place in which inverted product is major and retention product is minor. 9.7 ADDITION REACTIONS Unsaturated compounds containing double and triple bond between the two C atoms i.e. alkenes and alkynes give addition reactions, Their addition reactions with halogens and halogen acids are given below: Addition of halogens Halogens such as chlorine and bromine readily add to alkenes to form 1, 2-dihaloalkanes, For example, fa) CH = CH, +Brn—“* 5 CH,-CH, Gihsiene Io Br Br 1,2-Dibromoethane Ethylene bromide) (b) CH,CH =CH, + Cl, =“ 5CH, CH-CH, | Peeve @ropyene) aq 12 Dieh @ropylene chloride) Chlorine and bromine readily add to alkynes first forming 1,2-dihaloalkenes and then 1, 1, 2, 2-tetrahaloalkanes. For example, a, # Brg, cl _ \ 7 @) HOSSCH—» ec ek Ethyne CCC HCC M b trans-1,2-Dichloroethene 1,1,2,2-Tetrachloroethene (Westron) B, 4H PP Br a Pr ©) HYC-CSSCH eee yee Propyne CCB H CCl, | Br Br trans-1,2-Dibromopropene _.,1,2,2-Tetrabromopropane During this reaction, the reddish brown colour of Bry is decolourised and hence this reaction is used as a test for unsaturation, i.e. for double bond and triple bond.389 ORGANIC REACTIONS AND. SYNTHESIS OF A DRUG MOLECULE Addition of halogen halides. Alkenes react with Hed halogen halides (HCI, HBr, HI) to form monohaloalkanes calle’ alkyl halides. For example 7 Tas (a) Ca +HX —— c—c’ addition = 7 I Alkene Alkyl halide (b) CH, = CH, + HBr —> CHy—CH,Br Ethene Bromoethane (Ethylene) (Ethyl! bromide) The order of reactivit order of reactivity can be ex halides; lower the bond diss. y of halogen halides in this reaction is : HI > HBr > HCl. This Plained on the basis of bond dissociation energies of the halogen ‘ociation energy, more reactive is the halogen halide. . HI (300 kJ mol!) > HBr (360 ky mol-!) > HCI (430 kJ mol!) The actual product formed, however, depends upon whether the alkene is symmetrical or unsymmetrical as discussed below : Addition to symmetrical alkenes, When the alkene is symmetrical onl 'Y one product is theoretically possible, For example, (2) CH, = CH, + HBr — cu, —CH,—Br ' Ethene Bronioethane ¢ (b) CH;CH = CHCH, + HCl —> CH; —CH—CH,CH, But-2-ene | ~ ca 0 2-Chlorobutane Mechanism: Like the addition of halogens, addition of halogen halides to alkenes is also an electrophilic addition reaction and occurs by the following steps: Ionization ur, jr ————> H+ Br + Slow + Step 1 H,C==CH, + H’ ——» H,C—CH, Ethene Ethyl carbocation ilic atta Car -ocleophiie tack Br—CH,—CH, Step 2. 7 z1 Ethyl carbocation Fast Bromoethaneen 390 CONCEPTUAL ENGINEERING | CHemistay 9.7.1 Electrophilic Addition Reactions Alkenes are characterized by the presence of a double bond which consists of a Stron, C—C, o-bond and a weak C—C, -bond, The 1-electrons form an electron cloud which lies above and below the plane of ¢ -bonded carbon atoms. These, m-electrons are, therefore, more exposed and hence are less tightly held between the two carbon atoms. Since the electrons are negatively charged particles, therefore, the electrons attract the electrophiles and repel nucleophiles. In other words, alkenes undergo electrophilic reactions. Thus, the typical reactions of alkenes are electrophilic addition reactions and not the electrophilic substitution reactions. Mechanism of Electrophilic Addition Reactions Let us illustrate the mechanism of electrophilic addition reactions by taking the example of addition of Br, to ethylene. The reaction occurs by a two-step ionic mechanism as discussed below: Step 1. Bromine molecule itself is non polar but when it comes close to an ethylene molecule, the 1-clectrons of the double bond begin to repel the electron pair holding the two bromine atoms together in the bromine molecule. As a result, bromine molecule gets polarized. The positive end of this bromine dipole behaves as an electrophile and is attracted by the -clectrons of the ethylene molecule to form a x -complex which subsequently gives the carbocation ! and the bromide ion. This step is slow and hence is the rate-determining step of the reaction. ' Ethylene ea Br-Br—Etvlene_, Br-Br Polarized bromine molecule This step can simply be represented as CN {t Slow Le=—ch Been Ethylene H,C——cH,—Br + Br7 Bromoethyl carbocation Step 2. The carbocation formed in step 1 being a reactive chemical species immediately undergoes nucleophilic attack by the bromide ion present in the solution forming the addition product. This step is fast and hence does not affect the rate of the reaction, Br E Nucleophilic attack | Br + mCi ae Br Br Bromoethyl carbocation 1,2-Dibromoethane Evidence in support of the above mechanism. If the carbocations are really the intermediates in the above mechanism, then they i should also react with other nucleophiles when added to the reaction mixture and hence @ i91 ORGANIC REACTIONS aND SYNTHESIS OF A DRUG MOLECULE : ethylene is bubl 2- dibromoeth; . Ie, when ts should be formed, This has indeed been found to be $0, For Eee i Bled into an aqueous solution of bromine containing sodium chloride, ‘ane, I-bromo~ 2-chloroethane and 2-bromoethanol arc also formed Br 2 H [——> Br—CH,—CH,—Br Br, 1, 2-dibromoethane HC = “ C=C; #CXcH,-pr | SC ClCH, — CH, —Br Ethylene = -Br Bromoethyl 1-bromo-2-chilorocthane carbocation 2 4 ho Br—CHy—CH)-H,0" > Br-CHy—CHy— Br Addition to unsymmetrical alkenes, ho addin ne alkene i unsymmetrical, two products are theoretically possible, For example, the addition of HBr to Propenc in the dark and in the absence of peroxides can, in principle, give ‘wo products, But xperimentally, it has been found that under these conditions, the major Product is 2-bromopropane and the minor product is 1-bromopropane. CH;CH= CH, +HBr. Dak -CH- CH, CH, - Br pik Wine at promi? CH fa CH; + CHC nea Br (minor product) 2-Beomtepropane (major product) Markovnikov’s rule, Markovnikov, a Russian chemist, studied a large number of such addition reactions and postulated an empirical rule in 1869 which is known after his name as Markovnikov’s rule. The rule states that, The addition of unsymmetrical reagents such as HX, H,0, HOX, etc. to unsymmetrical alkenes occurs in such a wa iy that the negative part of the addendum (i.e., adding molecule) goes to that carbon atom of the double bond which carvies lesser number of hydrogen atoms. CH, CH, a] Forexample, CH;-C=CH, +H*cr —M##® , cH. ¢ cH, ‘2-Methylpropene cd ‘2-Chloro-2-methylpropane Explanation of Markovnikov’s rule. The addition of halogen halides to alkenes is an electrophilic addition reaction. Thus, during the addition of HBr to Propene, the first step involves the addition of a proton. This addition, in principle, can occur in two ways. If the proton adds on the terminal carbon atom of the double bond, a 2° carbocation (I) is formed and if the addition occurs on the middle carbon atom, a 1° carbocation (II) is produced.| 7 392 CONCEPTUAL ENGINEERING CHEMistay | —_ :/—.O 0 Oe | Addit H’, Addition at C, | + H’, Addition at C, 2 1 , 1 + H,C—CH—CH, <——————_ ;C CH=CH, ——————> ,C—CH,—CH, 7° Cate a Slow Propene Slow 1° Carbocation (1) ° Car ation ‘abl (more stable) (Less stable) Fast | Br Fast | Br HyC—CH—CH. Hj;C—CH,—CH,Br am , 1-Bromopropane 7 (minor product) 2-Bromopropane (major product) Since, a 2° carbocation (I) is more stable than 1° carbocation (II), therefore, carbocation (1) is predominantly formed. This carbocation then rapidly undergoes nucleophilic attack by the Brion forming 2-bromopropane as the major product. Thus, Markovnikov's addition occurs through the more stable carbocation intermediate. Peroxide effect. It may be noted that Markovnikoy’s rule is not always followed. In presetice of peroxides such as benzoyl peroxide (CeHsCO-O-O-OOCgH,), the addition of HBr (but not of HCI or HI) to unsymmetrical alkenes takes place contrary to Markovnikov’s rule. This is known as Peroxide effect or Kharasch effect. Thus, : (t:C00),.0 Cis CH= Cliy+ HBr —STSEeOR? CH CHly~CH Be 1-Bromopropane Propylene) (a Propyl bromide) Mechanism. The addition of HBr to alkenes in presence of peroxides occurs by a free radical mechanism. It consists of the following three steps: (a) Initiation. f i (i) HgCg-C—4 ALS —C—CeHs ———__» 2 ¢gH,-C—6 Benzoyl peroxide Homolytic fission j Oo i yy 4 . (ii) HsCgyCY-O ——> Cys + CO, ; i) ga + 9A, —> CoH + Br (b) Propagation. It consists of two steps.ORGANI 3 IC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE = During the first Step, a Br adds to the double bond in such a way so as to give the more Stable free tadical, : In the second step, the free radical thus produced abstracts a H from HBr '© complete the addition, © 4G + Br ——>» Hc—CH—cH,Br Propene 2° radical (more stable) (i) C—Ch—cHar 4 Sb, —> 1yC—cH,—cH,Br + Br 1-Bromopropane (c) Termination, @) 2Br—B, (i) CH,~CH-CH,Br+ Br —s CH,-CHBr-CH,Br / 1—Bromopropane : c. 2 me BC. 2 3CH, (ii) Beco! tt? HC BrH,C CH,Br 1,4-Dibromo-2, 3-dimethylbutane Exceptional behaviour of HBr, To understand why peroxide effect is observed only with HBr and not with HF, HCI or HI, let us consider the AH of the'two propagation steps. From the AH, it is clear that only with HBr, both the steps are exothermic and hence the peroxide effect is observed. With HCI or HE, the peroxide effect is not observed because the second step involving the reaction of carbon radical with HCI or HF is endothermic. Further, the peroxide effect is also not observed with HI because the first step involving the addition of iodine radical to alkenes is endothermic. 9.7.2 Free-radical addition An example of free radicaladdition mechanism is addition of HBr to an unsymmetrical alkene in the presence of peroxide. This is an anti-Markonikoff addition, It involves the following steps: (i) Chain initiation step: The reaction is initiated by the alkoxy radicals produced by the hornolytic fission of peroxides, which abstracts an atom of hydrogen from HBr generating bromine free radicals (Br' nS —> 270° Perioxides Alkoxy radical R-O+H-Br —> R-OH + Br ‘ (Chain initiation)394 CONCEPTUAL ENGINEERING CHEMistRY if i i : 7 ks the propylene molecule to give (by (ii) Chain Propagation Step: The Br’ then attac! ; analogy with carbonium ions), a more stable secondary (as opposed to 1°) free radical CH, -CH = CH, + Br — CH, - CH-CH,Br + CH; ~ CH- CH, 2°free -radical | more Stable 1° free radical less stable The secondary radical then reacts with another H~Br molecule to yield the product at another Br which can further propagate the reaction. CH; - CH - CH,Br + H-Br — CH, - CH) - CH,Br + Br 9.7.3 Addition of Halogen acids to alkynes Halogen halides add to alkynes, their order of reactivity being HI > HBr > HCI > HF ; HF adds only one under pressure. The addition of halogen acids can take place in the dark but is catalysed by light or metallic halides. These additions occur in accordance with Markovnikov's rule to form first vinyl halides and then alkylidene halides. HC=CH—“ 5cu, =cHcI—#"\_, CH,- CHCL tyne V-Chooeiens ME ABO thane (vinyl chloride) (Ethylidene dichloride) However, when acetylene is passed through dil. HCI at 338 K in presence of Hg?* ions as catalyst, only vinyl chloride is formed. HC=CH+ HC—4_5 CH, -CHCI Acetylene He Vinyl chloride With hydrogen bromide, first a vinyl bromide and then an alkylidene dibromide is formed. For example, ; _ HBr _ HBr H= CHCl = CHBr— rig CH;~ CHB, ‘Vinyl bromide 1,1-Dibromoethane HBr HC. HBr ae Se=cz, CBr Mark. addn, Br Mark.addn, = HC“ Br 2-Bromopropene 2,2-Dibromopropane However, in presence of perioxides, anti-Markovnikov's addition of HBr occurs. For example, CHSC = CH CH, CH = CHBr— 3 CH, CH, CHB, >ropyne 1-Bromopropene 1-Dibromopropene Mechanism: It is an electrophilic addition reaction and occurs in two stages as discussed below:395 ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE Stage I. uomicy + Slow v q —} H,C—=th ——> H,C—=CHC! Ethyne Vinyl cation —-Fa8t_ 1. Chloroethene + Slow a StageM. H,€—cy,¢1 Hc==cxc + HS, cuca 1° Carbocation (11) 2° Carbocation (1) (less stable) 1-Chloroethene (more stable) Since carbocation (1) is stablized by +R-effect of the Cl atom while carbocation (II) is destabilized by Ic “ ffect of Cl, therefore, reaction occurs through the more stable carbocation ( forming 1,2-dichlorocthane cl it + Fast 7 I oe AO oe mech (Stabilized by + effect een 1,1-Dichloroethane 9.7.4 Nucleophilic addition reaction Aldehydes and ketones have a carbonyl group (>C=0) which is polar C'—O-, so as that the carbon atom is clectron-deficient and the oxygen atom is relatively -electron rich. in Hany Teactions of carbonyl compounds, a new bond is set up between the carbonyl carbon and electron-rich species (nucleophile). Such reactions are called nucleophilic additions. An example of this types of reactions is illustrated by the base ~catalysed addition of HCN to acetaldehyde giving ig acetaldehyde cyanohydrin Mechanism of Nucleophilic Addition: Chemical reactions of carbonyl compounds are due to the presence of carbonylic group. This group: (i) provides site for nucleophilic addition and (ii) inceases the acidity of a -hydrogen, Both these effects are due to the ability of oxygen to accommodate a negative charge because there carbond-oxygen double bond and motile -electrons are pulled strongly towards oxygen. So carbonylic oxygen is electron rich and carbonylic carbon is electron deficient. A nucleophile can attack on carbonylic carbon and aldehydes or ketones undergo nucleophilic addition reactions Nu Zz RA stow | a | HO ® | | c=0 ——> R- — RF aa | RL. a! \p INo t OH n Reactant Transition state Product (Trigonal) (Tetrahedral) (Tetrahedral)= CONCEPTUAL ENGINEERING CHEMIstay 396 In this reaction, rate-determining step is the attack of nucleophile on carbonylic Carbon, So greater the clectron deficiency on carbonylic: carbon, more easy will a attack of nucleophile. Moreover, in reactant carbon is sp” hybridized, ic. trigonal in pea u in transition, state and in product carbon is tetrahedral in nature. So transition state is crowded, and there is steric hindrance in this reaction, i.e. larger group will tend to resist crowding more than smaller groups. Therefore, order of reactivity of carbonyl compounds depends upon the following factors: 1, Electronic effect: Alkyl groups have +I effect and being electron releasing they tend to destabilize the transition state. So greater the number of alkyl groups lesser will be the Teactivity and order of scactivity is K \ x c=0 > c=O > c=0 / i H H R’ 2. Steric effect: Ketones have two alkyl or aryl groups which are bulky and therefore nucleophile could approach to carbonylic carbon as casily as in case of aldehydes that have one alkyl or aryl groups. Ketones resist more strongly the crowding together in the transition state to make the ion of tetragonal transition state difficult. So ketones are less reactive than aldehydes. On the basis of these two factors order can be written as formati of reactivity of different carbonyl compounds HK R H5Cy R HC HsCy 8 f=0 > =0> c=0 > b=0 > ceo > cHo / / / / / H H # R H HC, Nucleophilic addition reactions of carbonyl compounds can be catalysed by the addition of acids. Acids protonates carbonylic oxygen forming a Conjugated acid of carbonyl compound, This acid is more prone to the attack by the nucleophile. joe + We Semin, \ Tp eon: Vf, Fag \, Nw Nu yl compounds are due to acidity of a -hydrogen, Due onylic group, a -hydrogen is acidic in nature. Basic hydrogen. Anion formed is resonance stabilized: tl 2 aie —H + 'OH —»R—C—c__ pal a ¢ R sy H —> R—C=C—H; Some of the properties of carbon to electron with drawing nature of carb: Teagents can easily remove thisORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE 397 9.8 ELIMINATION REACTIONS Reaction with alcoholic Potash—Dehydrohalogenation (formation of alkenes) When heated with concentrated alcoholii halogen acid to form alk halogen and th ic potassium hydroxide, alkyl halides eliminate enes. This reaction known as dehydrohalogenation involves the loss of © hydrogen atom from a car ‘bon adjacent to the one losing the halogen (B-elimination) H x fp a R—C—C—H + KOH —__ R—CH==CH, + KX + 1,0 | | (Alc.) HOW Saytzeff S rule: If the structure of an alkyl halide is such that it can undergo dehydrohalogenation in two different ways, the preferred product is the alkene that contains least number of hy 'ydrogen atoms on doubly bonded carbon atoms. The highly substituted alkene is the major product. This generalization is known as Saytzeff's rule, ¢.g, when heated with alcoholic potash, 2-bromobutane forms 2-butene as a major product. —> 4! mapensolpaaions HBr H OH an ew SU aN c bE | “ jn H—C—C—C—C—H + KOH —» H,C=CH—CH,—CH, + HyC—CH=CH—CH, | | | | (ls) 1-Butane 2-Butane eet HH HOH (Minor product 20%) (Major product 80%) “**® (Less substituted) ) Order of dehydrohalogenation of alkyl halides is 3° > 2° > 1°, 9.8.1 Mechanism of E, (Elimination bimolecular) Reactions The dehydrohalogenation of a majority of primary alkyl halides occurs by Ey mechanism. Kinetic studies of this reaction reveal so that the reaction follows second-order kinetics, ic. rate of dehydrogenation reaction ther is proportional to the concentration of both the alkyl halide and the base. Thus, Rate < [Alkyl halide] [Base] This means that E, reaction should be a one-step process and occurs through a transition state. As the hydroxide ion (hydrogen attached to carbon atom which is next to the carbon atom carrying the halogen atom), the carbon hydrogen bond begins to break. The ones carbon 1 bond starts forming and the leaving group (i.c. the halogen atom) starts leaving t < o, -carbon atom taking with it electron pair, breaking the carbon halogen bond. This is explaine below with the help of dehydrohalogenation of bromoethane.CONCEPTUAL ENGINEERING CHEMISTRY 398 ce Bromo ethane ; halide ion takes As elimination of a proton by a base and si yultancous ae ee place in one step, there is no opportunity of rearrangement. It is clear rhe Rie neree ae transition state has acquired some alkene character. This is explained by Transition stile HyC—CH,CH—CH, + KOH ———s H\(--Cl!,CH==CH + H,0 + KCI (Alc) In case of an alkyl halide having two different types of hydrogens, two alkenes can be obtained. It is, thus, clear that more substituted the alkene the more stable the transition state and hence more of this alkene would be formed. This explains the formation of 2-butene as the major product in the dehydrohalogenation of 2-bromobutane 9.8.2 Mechanism of E, (Elimination unimolecular) Reactions The rate of reaction in these reactions depends only on one reactant molecule. The E, reactions are shown by tertiary alkyl halides and in solution of low base concentration. The complete mechanism may be depicted as shown below. Step 1, Dissociation of halide to a carbonium ion by splitting a halogen anion. E, (Unimolecular elimination) x P| ~l 2 aa ies —> CC 4k ld lf (Carbonium) Step II. Splitting a proton in Presence of a base forming an alkene, slow) ° Cye-C—+B —> >C=C<+ H:B «.(Fast) | us Action of heat: Alkyl halides when heated above 573 K tend to lose a molecule of hydrogen halide fo alkenes C,HsBr—#4 cH, - CH, + HBr399 SRGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE 9.9 OXIDATION REACTION 5 clow: Most of the organic compounds undergo oxidation reactions as examplified b 1. Oxidation of alkanes i ; cidation (© Combustion: When burnt in excess of air or oxygen, alkanes undergo complete oxid: '0 produce carbon dioxide, water and large quantities of heat. For example, CH, +20, —> co, +2H,0; AH = -890 KJ -3110 KJ Due to the large quantities of heat produced during combustion of alkanes, this reaction has tremendous practical importance, Vast quantities of hydrocarbons obtained from Petroleum are used as fuels for the production of heat and power by combustion. Incomplete combustion of alkanes due to insufficient supply of air or oxygen results in the formation of soot or carbon black. This is used in the manufacture of Indian ink, Printer’s ink, black varnish and as a filler for rubbers. Cataly 2C2Hg + 70, —> 400, + 6H,0; 4H (ii) tic oxidation: When heated in a regulated supply of air or oxygen at high pressure and in the presence of suitable metallic catalysts, lower alkanes are oxidized to alcohols and aldehydes while higher homologues yield long-chain fatty acids. For example, when @ mixture of methane and oxygen, in suitable proportions compressed to 100 atm and Passed through copper tubes at 475 K, methane is oxidized to methanol. 2CH,+ 0, 8400.2" _, 29CH, OH CH,+0, Toa HCHO + H,0 ommaldehyde lation with Hot Alkaline KMnO, (Oxidative Cleavage of Alkenes) If an alkene is heated with concentrated solution of alkaline KMnO, at 373-383 K, cleavage of the C-bond takes place resulting in the formation of ketones and/or carboxylic acids and CO, depending upon nature of the alkene as shown below: (a) Terminal CH, is oxidized to CO}. 2. 0: (b) If there is any hydrogen attached to the double-bonded carbon atom, it is oxidized to COOH. (c) If there is no hydrogen attached to the doubly bonded carbon, it is oxidized to ketone For example, oO / i ) CHy— CH=CH, —O"*8H04 cH 6-011 +C0,+H0, Propylene thanoie set) oO jot int K l (ii) CH CH, ~ CH = CH, 27 SESH KOH, CH, ~CH,—C- OH +H,0+C0, rope wie ssid)—s CONCEPTUAL ENGINEERING CHEMg ray 400 HC. HC i nH OHS i oN (i) Hot KMnO,/KO! 'C=0 + CO, +H,0 A=, > He” BC ow ‘Acetone (Propanone) Thus, by identifying the products formed on oxidation a alkaline KM20,, itis possible to locate the positino of double bond in an unknown alkene 3. Oxidation of aromatic compounds Oxidation with hot alkaline KMnO, oxidizes side chain into acidic functional Stroup, Benzene ring is not oxidized under these conditions. Hy coon ° KMn0,/OH/ A =a Benzoic acid 8 COOH ow KMnO,/OH/A | = CH, ‘COOH Phthalic acid 4. Oxidation of Aldehydes Aldehydes can be easily oxidized to carboxy atoms. Ketones cannot be easily bond. Ketones are oxidized by conc. H,S0, +K, atoms lic acids having same number of carbon oxidized, as their oxidation involves the cleavage of C-c Strong oxidizing agents like acidified KMnO, or cone. HNO, or (C120, under strong conditions to carboxylic acids with less number of carbon Aldehydes can be oxidized by mild oxidizing agent 1 Fehling’s and Benedict's solution, ike Bry water, Tollen’s reagent, (i) Tollen’s reagent is ammonical AgNO3. When aldehydes are warmed with Tollen’s Teagent, a silver mirror is formed on the walls of container, i.e. Tollen’s reagent is reduced to metallic silver and aldehydes are oxidized to carboxylic acids. This test is also known as silver mirror test, AgNO; + NH,OH —> Agon + NH,NO, AgOH + 2NH,; —> [Ag(NH;),]OH Diamine silver hydroxide a) RCHO + 2[Ag(NH))]0H—> RCOO—NH, +2Ag) + 3NH; + H,0 Silver mirror Colourless solutionson ORGAN C REACTIONS AND SYNTHESIS OF A DRUG MOLECULE (ii) Fehling’s solution: Fehling’s solution i prepared by mixing equal volumes of Fehling’s Solution ‘A’, which 'S Copper sulphate solution containing few drops of conc. H,SO, and Fehling's solution “B",whichis alkaline solute, of Rochelle salt. Rochelle salt is sodium Potassium tartarate Aldehy des form 2+ carboxy) complex with Cu’ "ie acid and is reduced to red coloured Cuso, (from Fehling’s solution) and are oxidized to Cup *2NaOH —> 4 Cu(OH), + NaySO, ee een RCHO + 2cu0 — > cu,0) + RCOOH (Red ppt) Note: Aromatic aldehydes, however, do not reduce Fehling’s solution, 8.10 REDUCTION REACTIONS ; Most of the organic compounds undergo reduction to give different ee ee re varying reactions condition as illustrated by the following examples. 1. Reduction (Hydrogenation) of Alkenes Alkenes react with b , ydrogen in the presence of certain finely divided metal, such as nickel at 523-573 K (Sab; atier—Senderen’s reaction) or palladium or platinum at room temperature (298 K) to form alkanes NS Ni or Pd at 298K CSCO +H, ————-> \o_-” ZN or Niats23-573K ZT [\ Alkene pee Alkane. Examples: (i) HyC=CH,+H,—S*™! y4,¢-cH, Ethylene a Ethane (Ethene) (i) H,C-CH=CH,+ H, S274 4,C-CH,-CH, Propylene Propane (Propene) Hydrogenation of alkenes is an exothermic reaction. The heat evolved when 1 mole of unsaturated compound is hydrogenated, which is known as heat of hydrogenation, 2. Hydrogenation of Alkynes Depending on the conditions and the catalyst employed, one or two mol: lar equivalents of hydrogen will,to a carbon-carbon triple bond. ‘When a platinum catalyst is used, the alkyne generally reacts with two molar equivalents of hydrogen to given an alkane: CH,C = C -CH; + Hy —", CH,CH = CHCH, —!.”"_, CH,CH,CH,CH, Palladium or Raney nickel can also be used as catalystCONCEPTUAL ENGINEERING CHEMISTRY 402 3. Reduction of Aromatic Compound i i an easily obtain six- (a) By the catalytic reduction of benzene and its derivatives, we ci membered cyclo compounds. Ni 200°C + 3H, ———» oH Benzene oH Cyclohexane Ni, 200°C Zn dust + 3H, OO oP Phenol Cyclohexanol Cyclohexane rT (©) On reduction with hydroiodic acid at 520 K or hydrogen under pressure in the presence of finely divide nickel at 470 K, arenes form cycloalkanes. For example, toluene on reduction gives methylahydrocyclohexane CH, CH NYNI/A —_ Methyleydohexane ed by the activity of sodium and ethanol, ction is known as Metallic reciction. Thus, CHy C= N+ 4{H]—S¥cateot oy CH, -NH, Methyl cyanide (Ethanenitrile) (c) On reduction with Nascent hydrogen obtaing alkyl cyanides from primary amines. This rea Ethyl amine (Amino ethane) Reduction can also be achieved with H)/Ni o1 4. Reduction of Carboxylic Acids (i) Reduction to alcohol: C: initial products are alkoxi ir lithium-aluminium hydride (LiAIH,), arboxylic acids can be reduced to alcohol by LiAIH,. The de from which alcohol is liberated by hydrolysis, 4R- COOH + 2LiAIH, + 4H,+ UAIO,+(RCH, 0), AILi 54 RCH,OH Ui) Reduction to alkanes: Carboxylic acids ‘an be reduced to alkane with HI sence of red phosphorous at 430 K mprssenee SEIOR-CH,+ 2H,0+31, CH;COOH +6HI—BSP cy, CHy+2H,0+31,CESS EE TTS ORGAI NIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE 5. Reduction Of Acid Chloride (i) Reduction to al 403 duced ldehydes (Rosenmund’s reduction): Acid chlorides ea ect wan. the presence of finely divided palladium preiptated on BaSO, and S, iudehvdes. Sulphur is used to partially poison the catalyst to prevent further reduction to alcohol or alkane, Z Pd Ro +H, ——s eco + H,0 cl BaSO,/S Aldehydes (ii) Reduction to alcohols: Alcohols are formed from acid chlorides with sodium and aleohots or LiAIH, eo et ———> R-CH,0H + HCI 6. Reduction of Acid Amide Acid amides on reduction wit a ‘ith the same number of es with LiAIH, give primary amines wi R-CONH, Halls. p CH,NH+2H,0 Amine 9.11 CYCLISATION Cyelisation can be carried out by catalytic reforming, It involves reforming the petroleum. hydrocarbon molecules to enhance their octane number for gasoline blending, In this process, normally paraffin and naphthene (alicyclic hydrocarbon) molecules are reshaped into aromatics. For instance, n-heptane (C7H,,) is changed to toluene (CyHg), n-octane (CsHjg) to ortho- Xylene (CgHjo), cyclooctane (CyH,¢) to p- and m-xylenes. The process is carried out for the " manufacture of benzene, tolue and xylene ete The process is carried out at a temperature range of 250-S50°C in an adiabatic reactor ata pressure of 10 kg/em? in the presence of bimetallic catalysts platinum and rhenium, tin or germanium on a silica-alumina support 1. Cyclisation and Aromatisation (n-heptane is converted to toluene) CH; | oe CH; HC, CR CH; CH, cyclisation HC oH, aromatisation | | H, | k. 3H, HC. CH, a 3H, NA Nog ‘CH, 2 Toluene n-Heptane Methyl cyclohexaneCONCEPTUAL ENGINEERING CHEMISTRY 404 2, Dehydrocyclisation of alkanes 4H () HCO CH — CH, — CH, —— O +ah> n- hexane +4H, (i) HCH — oC, — CH, — cH, ——> 2 ne heptane Among these reactions, the first one takes place comparatively at a faster rate os it involves only dehydrogenation and other two involve isomerization and cyclisation is addition to dehydrogenation. 3. Reforming of n-octane n-octane under reaction conditions can undergo cyclisation at three positions namely 1,6; 2,7; or 3,8 giving rise to ethyl cyclohexane or 1,2-dimethyl cyclohexane, These two on aromatisation would yield ethyl benzene or 1,2~dimethylbenzene (o-xylene). 2 3 4 5 6 1 8 (CH, — CHC) — Cy CH — CH — CH 1 HC. n-octane under ideal laboratory conditions predominantly yield ethyl benzene and ortho xylene. Under actual commercial conditions isomerization and rearrangement leads to several other compounds such as benzene, toluene, meta xylene and para xylene. It can undergo cyclisation at 1,6 position to give 1,4-dimethyl cyclohexane or at 2,7 position to give 1,2-dimethyl cyclohexane.RY ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE = a i CH; CH; and cry 1,2-dimethyl cyclohexane 1.4-dimethyt eyctohexane The produ respectively, °*" Undergo dehydrogenation giving rise to p-xylene and o-xylene CHy cy CHy and cH, o-ylene p-xylene’ These products ‘may undergo isomerization to give other isomers namely m-xylene and ethyl benzene. 4. Preparation of Cyclo-alkanes by cyclisation reaction The following methods are commonly used for the Preparation of cycloalkanes, (i) Freund’s Method from ,-dihalides: Dichloro or dibromoalkanes having terminal halogen atoms, when treated with sodium or zinc, yield the corresponding cycloalkanes, For example, CH,Br CH Ethanol Ve HC + Na ———> mA + 2NaBr 4 \CH,Br ; CH, 1,3-dibromopropane cyclopropane H,C—CH,Br + Zn" + ZnBry H,C—CH,Br H,C—CH, cyclobutane 1 4-dibromobutane —CONCEPTUAL ENGINEERING CHEMISTRY 408 ‘The method is an extension of Wurtz reaction and may be regarded as = intemal Wartz reaction. The reaction is useful for the synthesis of three- to six-member foe on ay (ii) From barium or calcium salts of dibasic acids (Wislicenus met ae distillation of barium or calcium salts of dicarboxylic acids, a ayelokeios an which can be reduced to cycloalkane by Clemmenson’s reduction (Zn-Hg/HC!). H,C—CH,—CQO” H,C—CH, mp aL Reduce Nog teat CO + ZnC0y fs x / an-Hgticl | oY #,C—CH,—CO0 H,C—CA, Hy 2 Calcium adipate Cyclopentanone Cyclopentane This method is useful for the preparation of only, six- and seven-membered ring ketones, which can be further reduced to cycloalkanes. Gii) Condensation of a,«-dihalide with malonic ester (Perkin’s method): 01,00 - dihalide is condensed with malonic ester in the presence of NaOC,Hs. Alicyclic carboxylic ester thus obtained is hydrolysed and decarboxylated to yield cycloalkane. HC. C00C;H, CHBr FO0C Hs NA0C,H, _ + ae 7 0 a ~2HBr CH,Br COOC;Hs HC COOCzHs 1,4-dibromobutane Hydrolysis; -2C,H,OH HC, HAC, HAC. cooH \ a 4 \/ cH, <— CHCOOH <— c J -CO, J - CO, LN wae uf HC ‘COOH Cyclopropane Cyclopropane carboxylic acid In general, any other suitable 0,,0)-dihalide can be condensed with malonic ester in Presence of sodium ethoxide to get the desired cycloalkane (iv) From disodio acetoacetic ester and dihalogenated paraffins: Disodio derivative of aceto ester condenses with dihalogenated paraffin to form an ester which on hydrolysis and dec ylation gives cycloparaffins, Cyclobutane cannot be obtained by this methodORGANIC REACTIONS AND SYNTHESIS oF q DRUG MOLECULE CHy-CH,iBr Nat {HrCHaIBr NaS coon, c He CB ENG” \ coge , BN Disodicaceto acetic ester 407 CHe-CH,. « ,COCH, CH,-cH,” Ncooc,H, |p -C,H,OH Git Soda lime CHs-CH,./COCH, eee eats & 4, \cooH Hy-CH, Cyclopenty! COCH, ‘methyl ketone (*) Diels—Alder reaction [442] Cycloaddition: between a conjugated diene (4:n-electron system) Alder reaction. A in typi ical example is the addi 100°C to form tetrahydrobe aldehyde, : The [4+2] cycloaddition reaction to form an adduct is known as Diels— ition of 1,3-butadiene with acrolein at (CHO a CHCHO + Nori CH, 1,3-butadiene Actolein Similarly, 9 i C " ( > / S ‘CH, fi Butadiene O- Maleic anhydride 9.12 RING OPENING REACTION the addition of maleic anhydride to butadiene gives tetrahydrophthalic dride ‘Tetrahydrophthalic anhydride The following reactions of cycloalkanes are examples of ring ‘opening reactions: 1¢ follow! (i) Cyclopropane (bond angle 60°) is very reactive alkanes, and undergoes addition reactions likeCONCEPTUAL ENN ERING cg, nt Bit ccrcrey 1,3-dibromopropane HBr yet CH,CH,CHBr \ / Propyl bromide 2 cH 2 (@ Cone. H,SO, cyclopropane 2 CH3CH,CH,OH . (ii) HO Propanol-1 H,, Ni CH,CH,CH, 80°C: | Propane ° ly less reactive because of less ring strain and yelobutane (bond angle 90°) is generally 0 ” fects does not undergo addition reaction under normal conditions. - N,, Ni H,C—CH, ———— CH,CH2CH,CH, H,C—CH, 120°C n-Butane Cyclobutane (iii), Dicarboxylic acid formedwhen cycloalkanes are oxidized by alkaline alkaline potassium permanganate. CHCH,COOH CHjCH,COOH Adipic acid (i) Antipyreti i pyretics Gi) Analgestics (iii) Antiseptics and disinfectants (iv) Transquilisers, and a an (v) Antibiotics ‘We will not go ino the det: The most commonly usedORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE = Aspipin is obtained by the acetylation of Salicylic acid (o-hydroxy benzoic acid) with acetic anhydride or acetyl chloride inthe presence of little concentrated sulphuric acid or pyridine respectively. ‘On HOgs + y—OCOCH; om, {(C¥sC0}0 ——» © ° . cHyCOOH —cooH Salicylic acid Acetic Anlydride Aspirin HI Pyridine +CHyCocl ——__> COOH Salicylic acid Acetyl chloride Aspirin Requirements: Acetylation with acetic anhydride Acetylation with acetyl chloride a) Salicylic acid =5em a) Salicylic acid =5gm b) Acetic anhydride = 8 ml b) Pyridine =4ml ©) Conc. H,80, = 2-3 drops ©) Acetyl chloride = =4 ml Procedure: Step I. Acetylation with acetic anhydride i) Place Sgm of salicylic acid and 7 ml of acetic anhydride in a small absolutely dry conical flask. ii) Add 2-3 drops of conc. H,S0, and rotate the flask for thorough mixing, iti) Warm the conical flask on a water bath to about 50-60 °C, while shaking, for about 15 minutes. iv) Allow the mixture to cool and stir occasionally. vy) Add about 80 ml of water, stir well and filter at the pump. vi) Reorystallize the crude product from a mixture of equal volume of water and acetic acid. Step Il. Acetylation with acetyl chloride i) Dissolve Sgm of salicylic and in 4ml of dry pyridine contained in a small conical flask. ii) Then without delay run in Sm. of acetyl chloride, adding about Iml of chloride at a time. iii) Shake the content continuously during the addition, iv) Since the reaction is exothermic, maintain the temperature between 50°C and 60°C throughout the addition, cooling the flask occassionally in cold water, if necessary. v) Finally heat the mixture on a boiling water both for 5 minutes. Then cool in cold water and pour in a thin stream into about 200 ml of cold water, stirring the mixture vigorously. vi) The crude aspirin solidifies viata. CONCEPTUAL ENGINEERING CHEMISTRY viii) Filter the solid at pump and wash thoroughly with water. ; ix) Recrystallize from a mixture of equal volumes of water and acetic acid Precautions: i) The conical flask must be absolutely dry. Rinse it with alcohol and dry it an electric oven, ii) Coal the contents of the flask in water after addition of each small instalment of acetylating agent. iii) Use an air condenser while heating the reaction mixture on a water bath iv) Use minimum quantity of the solvent for recrystallisation. Solved Typical Problems §=_==== Problem 1. Free radicals are paramagnetic, but carbonium ions and carbanions are diamagnetic. Why. Solution. Free radicals posess odd electrons in them and are, therefore, paramagnetic in nature. While carbonium ion and carbanions have no unpaired electron in them and are, therefore, diamagnetic. Problem 2. What is the effect of increasing the number of carbon atoms on the acidic strength of carboxylic acid? Solution. Acidic strength of carboxylic acid decreases as the number of carbon atoms increases because of +I effect. The the carboxylate Ion show resonance as shown. o 4 wc’ — Ho—c \y Be The electron releasing group (+1 effect) will intensify the negative charge on the oxygen and destabilise the carboxylate ion. Greater the +1 effect of the group attached to the carboxyl group, weaker in the acid. H-COOH > CH,-COOH > H,C-CH,-COOH Problem 3. Arrange the following in increasing order of stability, HSC cH, CH; CeHs Hc \G HyC—C"; HC)-C" s HCy—C* ‘ont I | | 7 Lc CH; CHs HC HC “cH, Solution. In organic reactions the starting substance seldom change into products directly in one step. On the other hand, the reactants first change into the intermediate species, which ultimately yield the products. The reaction intermediates are generally short lived, and stable and reactive substance which cannot be even isolated. They are formed during the reactioner aGaNIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE ant or sehanism and immediately react to carry me the reaction further to completion. The usual reaction intermediates are free radicals, carbocations and carbanions. i The increasing order of stability of carbocation intermediates is as under Hy. CH, (Bs (oo) ie . me“E < Het Ny | \ ry As CRs Hs HC HC Neth This can be explained on the basis of inductive effect as well as hyperconjugation effect. Problem 4. Arrange the following according to decreasing stability: 2 ° (a) (CH;), CH (b) (CH,),€ Solution, Due to inductive effect, the methyl e Qe (0) Cy (4) CH, -CH, groups are electron releasing in nature. More the number of methyl groups attached to carbonium, more is the intensification of negative charge on carbon and lesser will be the stability Alkyl group (R) release electrons: intensifies charge, destablizes carbanion. Therefore, the greater the number of alky! group, the more unstable the carbanion. Tote te ad eta > 7 > Eat > RCH H H H R at r ¥ Problem 5, Explain why benzyl carbonium ion is more stable than ethyl carbonium ion. Solution, Because positive charge of benzyl carbonium ion is dispersed by resonance, cH ACH CH, CH, a C- or ae CT — \ . which ig more effective in charge dispersal than (#1) inductive effect of methyl group, in ethyl carbonium ion, e b > CH (effect) Problem 6, What are carbonium ions? Arrange the following according to increasin; stability r (@) CHCH,CH,CH, ——_(b) (CH)3C* (c) CH,CH,CHCH,CONCEPTUAL ENGINEERING CHEMistRy an Solution. Carbonium ions are the intermediates in which the positive charge is carried by the carbon atom with six electrons in the valence shell The order of increasing stability of given carbonium ions is : H CHy |. IL. + H,CH,CH,-C’ < HyCHs—¢ < H,C—C ik CH; CH; r 2° 2 The stability of primary, secondary and tertiary carbonium ions can be explained on the +1 effect (electron releasing effect) of the alkyl group. The electron releasing effect of alkyl groups disperse is the positive charge on the C atom of the carbanion which increases its stability. The greater the number of alkyl groups, the more will be dispersal of positive charge and higher would be the stability, Problem 7. (i) How would you decide whether the reaction : CH,Br + OH® = CH,OH + Br® proceeds by SN! or SN? mechanism ? (ii) Draw the energy profile diagram for the reaction : (CH,);CBr + OH- = (CO,);COH + Br® Indicate clearly thereants, transition states, activation energies and products of the reaction. Solution. (i) For deciding whether the reaction : CH;Br + OHO = CH,OH + BrO proceeds by SN! or SN? mechanism, we study the kinetics of the reactions. If it follows second order kinetics (i.e., if the rate depends on the concentration of both CH;Br and OH"), then it must be proceeding by Sy2 mechanism. Otherwise, if it follows first order kinetics then the reaction must be proceeding by Sy] mechanism. An increase or decrease in the [OH"] has no effect on the Sj! reaction. & (Transition state) Potential Energy > (ii) The energy profile diagram for the reaction : (CH;),CBr+ OH- = (CH,),COH+Br® is shown in the figure below: c toon 2 (Reactants) (CHy),C-OH-Br (Products) : Progress of reaction -> ‘The reaction proceeds through two step substitution mechanism. The order of the reaction being one, it is a case of SN! mechanism.3 GANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE a o problem 8. Write the chemical name and formula of Aspirin. solution. Aspirin is acetyl salicylic acid; while salicylic acid is o-hydroxy benzoic acid. So the formula.of aspirin may be written as 9° I O—C—cH, ‘COOH ~ Problem 9. Giving proper justification, categorise the following molecules/ ions as nucleophile or electrophil HS”, BF3, C]Hs0-, (CH3)3N: , Clt, H;C-Ct=0, N*O,, H,N-: Solution, (i) Nucleophile: » (CH),N! , HNE All the species have one or more lone pairs of electrons which it can easily donate to an electrophile and hence behaves as nucleophiles. Gi) Electrophiles: BF3, CI", H;C-C*=0, N*O, All the species (neutral or positively charged) have a sextet _of electrons around the positive charged atoms and hence can accept a pair of electrons and thus behaves as electrophiles. Similarly B in BF; has sextet of electron and acts as eletrophile, although it is neutral. Problem 10. Why are multiple bonds unlikely to undergo bond fission ? Solution. They are much stronger than single covalent bonds Problem 11. What is fission product of benzoyl peroxide ? Solution. Banzoyl peroxide free radicals. ° ° ° i il — il C. Hs— C-0- 0- C- C, Hs #52, Hs C-0 Problem 12. Why does benzene not undergo electrophic substitution reactions ? Solution, Benzene does not contain alteriiate single and double bonds, but possesses a delocalized ring of 6 electrons around the 6 C-atoms.\, Problem 13. Is the breaking of C-H bond in nucleophilic substitution homolytic or heterolytic ? Solution. Heterolytic. Problem 14. Which of the following is not a nucleophile : H,O, BF, NH3, OH ? Solution. BF; Problem 15: Why do aldehydes and ketones undergo nucleophilic addition reactions ? Solution. The carbonyl group (> C = 0) in these compounds gets polarized to > C** =O, due to higher electonegativity of O-atom than C-atom. Nucleophile (an electron-pair donor) is then attracted to the carbon-atom of the carbonyl group and reaction occurs as follows416 CONCEPTUAL ENGINEERING CHEMISTRY Problem 30, Arrange HCHO, CHjCHO, C,HsCOCH , C,HsCOC;Hg in order of decreasing reactivity towards nucleophilic addition reactions. Solution. HCHO > CH,CHO > CH,COCH, > C,HsCOC,H, Reasons : (i) The alkyl group at the’carbonyl carbon in ketones reduces the positive charge over it, due to clectron-repelling inductive effect (+1), thereby the tendency of a nucleophilic attack is reduced. Hence, ketones are less reactive than aldchydes towards nucleophilic addition reactions Problem 31. Arrange C,HsCHO, C6H,COCH , CcH,COC,Hs in decreasing order of reactivity towards nucleop! addition reactions. Solution. CcHsCHO > C6HsCOCH, > CcH,COC gH, Reasons : (i) Benzene ring causes the electron-donating resonance effect (+ M effect) ; while the alkyl group causes the clectron-donating inductive effect (+ 1). So both these groups increases the electron-density on the carbonyl carbon and, therefore, reduces the positive charge on the carbonyl carbon, thereby tendency of nucleophilic attack is reduced. Hence, CgHsCHO is more reactive towards nucleophiles than C,HsCOCH; and CgHsCOCgH,. Gi) The +1 effect of alkyl group is weaker than + M effect of benzene ring. In other words, ~CH, group reduces the positive charge on the carbonyl caused by -CcH group. Hence, CgH,COCH; is more reactite towards nucleophiles than CgHsCOCgHs. Problem 32. Arrange the following in the order of their increasing reactivity in nucleophilic substitution reactions : CH3F, CH;1, CHBr, CH,Cl. Solution. CH] < CH3Cl < CH3Br < CHI. Reason : The bond dissociation energies of : C-F > C-Cl > C-Br > C-I. Thus, C-I bond is most readily cleavaged; while the C-F bond is cleaved with most difficulty. Now lesser the bond dissociation energy, more is the reactivity of the haloalkane. This explains the above order of reactivity. Problem 33. The treatment of alkyl chloride with aqueous KOH leads to the formation of alcohols, whereas the presence of ale. KOH, alkenes are formed as the major products. Explain. Solution. Aqueous KOH contains only OH" ions, which act as nucleophile and these brings about hydrolysis of alkyl chloride to the corresponding alcohol RC + OH (ag) = 48, ROH C(aq) (Only nucleophile present) On the other hand, alcoholic KOH, cortains etlzoxide ions (C,H,0°), which are more than OH" ions. Consequently, ethoxide ions preferentially bring about dehydrohalogenation to form alkenes, ¢.g., H,C—CH, + KOH (ale) —» 1,0=CH, 41,0 + KBr er)ORGANIC REACTIONS AND SYNTHESIS OF A DRUG MOLECULE. = Problem 34. Why are haloalkanes more reactive than haloarenes ? Solution. Resonance structure of haloalkane (e.g. chlorobenzene) is : 5 - ° 3 ie “a: ei: 2Cli 6: oO = o a O = o- O 3 o ay am ayy) ™ Chlorobenzene is resonance hybrid of five structures; while haloalkane (e.g., chloromethane) is not idoilance stabilized. As a result of contribution of structures III, IV and V, the CCl bond in chlorobenzene acquires a partial double bond character. Consequently, the C-Cl bond in chlorobenzene is shortened (from 1.82 in CH,CI to 1.69 A in CgH5Cl) and is more stable. Therefore, chlorobenzene is more stable than chloromethane. In words, chlorobenzene is less reactive than chloromethane. Problem 35. Why are haloarenes more stable than haloalkanes and undergo electrophilic substitution at orthoL mrpara pos ion ? Solution. Unlike haloalkanes, haloarenes exhibit resonance : bobbed Ortho Para Ortho amy “W) ay) Resonance in haloarenes Due to resonance effect, haloarenes are more stable than haloalkanes (which do not undergo any resonance). Moreover, due to the resonance effect (of structures III, IV and V), the negative charge is localised at ortho and para positions only. Consequently, haloarenes undergo electrophilic substitution at ortho and para positions. Problem 36. Haloalkanes undergo nucleophilic substitution, whereas haloarenes undergo electrophilic substitutions. Account for it. Solution. Due to high electronegativity of the halogen aom, the C-X bond in haloalkanes (alkyl halides) is slightly polar, thereby the C-atom acquires a slightpositive charge (= c+S— x-5) Hence, C-atom is a good target for attack by nucleophiles (electron rich species). Therefore, the X-atom of the haloalkane is replaced by a nucleophile casily. Nu:+R*0—X-§ —9R-Nu +X"— : CONCEPTUAL ENGINEERING. CHEMISTR v On the other hand, in haloarenes (Ar-X), the halogen atom releases electron tot benzene nucleus through resonance, thereby making ortho and para positions of benzene bucleus relatively electron-rich w.r.t. halogen atom. As a result, the electrophile attacks at ortho or Para position. Hence, haloarenes undergo electrophilic substitution reactions. Note ; Haloarenes can also undergo nucleophilic substitution reactions, but under drastic conditions. Problem 37. What do you mean by acetylation? Solution. It is the process of replacement of an H-atom of the hydroxyl (—OH) or the amino 0 I group (—NH;) group by an acyl group |-O-C-CHy Problem 38. Name two acylating agents and give their structures. 0 Il Solution, (i) Acetyl chloride {H,C-C-C1} in the presence of pyridine. 0 0 ll I (ii) Acetic anhydride lac-teo-d- en in the presence of conc. H,SO, Problem 39, Name the raw materials for preparing aspirin giving their structures. OH COOH Solution. (i) Salicylic acid (O-Hydroxy benzoic acid), 0 Oo Il Il (ii) Acetic anhydride | H, C-C-O-C-CH, Problem 40. Give an important use of aspirin. Solution, Aspirin is an important anti-pyretic and is used as a medicine for lowering the temperature of the body and relieving head-ache etc (ae Revision Questions 1. Discuss the mechanism of the following types of reactions: ( _Electrophilic addition reaction i) Nucleophilic addition reaction 2 Whatis Markownikof's rule? Give an example and explain its mechanism. 3. What is peroxide effect? Explain it by example and discuss its mechanism. ewe