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W i s e b r i d g e L ear ning Syst ems Organic Chemistry Rea ct i o n M e c h a n i s m s Po c ke t -Book WLS www.wisebridgelearning.com © 2006 J S We tzel LEARNING STRATEGIES ● The key to building intuition is to develop the habit of asking how each particular mechanism reflects general principles. Look for the concepts behind the chemistry to make organic chemistry more coherent and rewarding. ● Exothermic reactions tend to follow pathways where like charges can separate or where unlike charges can come together. When reading organic chemistry mechanisms, keep the electronegativities of the elements and their valence electron configurations always in your mind. Try to nterpret electron movement in terms of energy to make the reactions easier to understand and remember. ● For MCAT preparation, pay special attention to reactions where the product hinges on regioand stereo-selectivity and reactions involving resonant intermediates, which are special favorites of the test-writers. ALYL HALIDES SN2 Mechanism with Alkyl Halides . . . . . . . . . . . . . . 21 SN1 Mechanism with Alkyl Halides . . . . . . . . . . . . . . 22 E2 Mechanism with Alkyl Halides . . . . . . . . . . . . . . . 23 E1 Mechanism with Alkyl Halides . . . . . . . . . . . . . . . 24 ALLYLIC AND CONJUGATED STRUCTURES SN1 Mechanism with Allylic Cation Intermediate. . . 25 1,2 and 1,4 Addition to Conjugated Diene . . . . . . . . . 27 Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . 29 AROMATIC COMPOUNDS Electrophilic Aromatic Substitution with Halogen . . 31 Electrophilic Aromatic Substitution - Nitration. . . . . 33 Electrophilic Aromatic Substitution - Sulfonation . . 35 Friedel-Crafts Alkylation . . . . . . . . . . . . . . . . . . . . . . 37 Friedel-Crafts Acylation . . . . . . . . . . . . . . . . . . . . . . . 39 Alkylbenzene Oxidation . . . . . . . . . . . . . . . . . . . . . . . 43 Alkylbenzene Halogenation . . . . . . . . . . . . . . . . . . . . 44 Nucleophilic Aromatic Substitution . . . . . . . . . . . . . . 41 ALCOHOLS AND ETHERS Dehydration of Alcohols . . . . . . . . . . . . . . . . . . . . . . . 45 Reaction of Alcohols with HX – Dehydrohalogenation. . 47 Reaction of Alcohols with Thionyl Chloride . . . . . . . 48 Reaction of Alcohols with Phosphorus Tribromide . . . 49 Oxidation of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . 50 Alkoxide Ion Formation from Alcohols . . . . . . . . . . . 50 Reaction of Alcohols to form Ethers. . . . . . . . . . . . . . 51 Williamson Ether Synthesis . . . . . . . . . . . . . . . . . . . . 52 Acid Cleavage of Ethers . . . . . . . . . . . . . . . . . . . . . . . 53 Epoxidation of Halohydrins . . . . . . . . . . . . . . . . . . . . 54 Acid Epoxide Ring Opening . . . . . . . . . . . . . . . . . . . . 55 CONTENTS ALKANES Thermal Cracking - Pyrolysis . . . . . . . . . . . . . . . . . . . . 1 Combustion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Free Radical Halogenation. . . . . . . . . . . . . . . . . . . . . . 2 ALKENES Electrophilic Addition of HX to Alkenes . . . . . . . . . . . 3 Acid Catalyzed Hydration of Alkenes . . . . . . . . . . . . . . 4 Electrophilic Addition of Halogens to Alkenes . . . . . . 5 Halohydrin Formation . . . . . . . . . . . . . . . . . . . . . . . . . 6 Free Radical Addition of HX to Alkenes . . . . . . . . . . . 7 Catalytic Hydrogenation of Alkenes . . . . . . . . . . . . . . . 8 Oxidation of Alkenes to Vicinal Diols. . . . . . . . . . . . . . 9 Oxidative Cleavage of Alkenes . . . . . . . . . . . . . . . . . . 10 Ozonolysis of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . 10 Allylic Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Oxymercuration-Demercuration . . . . . . . . . . . . . . . . 13 Hydroboration of Alkenes . . . . . . . . . . . . . . . . . . . . . . 14 ALKYNES Electrophilic Addition of HX to Alkynes . . . . . . . . . . 15 Hydration of Alkynes. . . . . . . . . . . . . . . . . . . . . . . . . . 15 Free Radical Addition of HX to Alkynes . . . . . . . . . . 16 Electrophilic Halogenation of Alkynes. . . . . . . . . . . . 16 Hydroboration of Alkynes . . . . . . . . . . . . . . . . . . . . . . 17 Catalytic Hydrogenation of Alkynes . . . . . . . . . . . . . . 17 Reduction of Alkynes with Alkali Metal/Ammonia . . 18 Formation and Use of Acetylide Anion Nucleophiles . 19 Coupling of Alkyl Halides with Gilman Reagents . . . 20 ALDEHYDES AND KETONES Reduction of Ketones and Aldehydes . . . . . . . . . . . . . 57 Reduction of Aryl Alkyl Ketones . . . . . . . . . . . . . . . . 58 Oxidation of Aldehydes and Ketones . . . . . . . . . . . . . 59 Reaction with Grignard Reagents. . . . . . . . . . . . . . . . 60 The Wittig Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Acetal Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 The Wolff-Kishner Reaction . . . . . . . . . . . . . . . . . . . . 65 Reductive Amination . . . . . . . . . . . . . . . . . . . . . . . . . . 67 The Cannizzaro Reaction . . . . . . . . . . . . . . . . . . . . . . 69 Acid or Base Catalyzed Enolization . . . . . . . . . . . . . . 71 Alpha Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Haloform Reaction of Methyl Ketones . . . . . . . . . . . . 75 Aldol Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Claisen Condensation . . . . . . . . . . . . . . . . . . . . . . . . . 79 Conjugate Nucleophilic Addition . . . . . . . . . . . . . . . . 81 Conjugate Addition of Gilman Reagents . . . . . . . . . . 83 CARBOXYLIC ACIDS AND DERIVATIVES Acid Halide Formation . . . . . . . . . . . . . . . . . . . . . . . . 85 Fischer Esterification . . . . . . . . . . . . . . . . . . . . . . . . . 86 Use of Carboxylate Anion Nucleophile to form Esters . 87 Hydrolysis of Acid Halides . . . . . . . . . . . . . . . . . . . . . 88 Reaction of Acyl Halide with Ammonia or Amine . . . 89 Esterification of Acid Halides . . . . . . . . . . . . . . . . . . . 90 Esterification of Acid Anhydrides . . . . . . . . . . . . . . . . 91 Saponification of Esters . . . . . . . . . . . . . . . . . . . . . . . 92 Nitrile Hydrolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Nitrile Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Hofmann Rearrangement . . . . . . . . . . . . . . . . . . . . . . 95 Thermal Cracking - Pyrolysis Alkanes heat CH3(CH2)xCH3 CH3CH3 + CH4 + H 2C CH2 + etc Lower carbon number cleavage product mixture High carbon number petroleum distillate A process carried out on petroleum distillates at high temperature and pressure, thermal cracking yields lower carbon number product, probably by means of a radical (homeolytic) mechanism. The thermodynamics are dominated by the entropy change rather than the enthalpy change, especially if the volume is kept constant. Combustion Alkanes CnH2n + 2 + (3n + 1)/2 O2 nCO2 Oxygen Carbon dioxide Hydrocarbon + (n + 1) H2O Water Many organic molecules can undergo combustion, forming carbon dioxide and water in an exothermic reaction. The heat released in the combustion reaction (the enthalpy change) can be used as an indicator of the relative stability of isomers. Combustion is more exothermic for unbranched alkanes, for example, than for their branched isomers, and we can infer that the branched isomer is the more stable. Such comparisons are often used in organic chemistry. For example, ketones are pointed out as more stable than their aldehyde isomers. The more stable the isomer, the lower the heat of combustion. 1 Free Radical Halogenation Alkanes RCH3 + Alkane Initiation X2 hv X2 X. 2 X. Halide radical + Halide radical X2 + Halogen Termination X. HX Hydrogen halide Alkyl halide Halogen Propagation + RCH2X Halogen RCH2. RCH3 Alkane RCH2. RCH2X Alkyl radical + X. + Alkyl halide RCH2. X. RCH2. + + HX Alkyl radical + X. Halide radical RCH2X X2 RCH2. RCH2CH2R Because of the relative stability of alkyl radical intermediates, selectivity in free radical halogenation favors tertiary over secondary over primary carbon radicals. Bromination, though, is more selective than chlorination, because the proton extraction step is more endothermic in bromination than chlorination. This follows from Hammond’s postulate, which governs the correlation between proximity in energy and proximity in structure among transition states and intermediates. Halogenation is the classic illustration of Hammond’s postulate. Because the activated complex prior to formation of the alkyl radical intermediate must have more radical character for bromination compared to chlorination, the effect of substitution in stabilizing radicals plays a greater roll with bromination leading to a higher degree of regioselectivity. 2 Electrophilic Addition of HX to Alkenes Alkenes X R H C C Alkene H H R + HX Hydrogen halide C C C H H Alkene + R H C δ+ R H C C Br H Carbocation Intermediate δ- H H Br H H R Br- + H H Alkyl halide + HBr Hydrogen halide C C H H R H H C H C H H Alkyl halide H Because tertiary and secondary carbocations are more stable than primary carbocations, Markovnikov addition is observed in the electrophilic addition of HX to alkenes, so the product formed is the one with the halogen substituent upon the more highly substituted carbon. Also, rearrangement (hydride or methyl shift to form a more stable carbocation) might occur, typical of reactions that have a carbocation intermediate. Remember that electrophilic addition will not be observed in the presence of peroxides. Peroxides initiate anti-Markovnikov addition via free-radical addition. An interesting fact about electrophilic addition of HX to alkenes, is that the more acidic the hydrogen halide, the more electrophilic it will be. HF, for example, only a weak acid, does not react. 3 Acid Catalyzed Hydration of Alkenes Alkenes H R H C H20, H+ H H C Alkene R Aqueous Sulfuric acid C H H R H C C H2 H H R H δ+ C C Alcohol O H 0, H+ H O H H δ+ H H + R C H C H Carbocation H intermediate H H C Alkene H R H O+ C H C H H H Oxonium ion H R H O H H O C + C H H Alcohol H + H+ Markovnikov’s rule is followed in hydration of alkenes. Therefore, in the alcohol product, the hydroxyl group is located upon the more highly substituted carbon. Watch for rearrangement of the carbocation intermediate, if methyl or hydride shift is probable. Note that this reaction is the reverse of acid catalyzed dehydration of alcohols. 4 Electrophilic Addition of Halogens to Alkenes R H C H H C Alkene Halogen molecule C H H C + Br2 R H δ+ C H X R + X2 C C H H X Vicinal dihalide Br R H Alkenes Br δ- Br + R C H C H H C H Br- + H Alkene + Br C δ+ C H H H Cyclic halonium ion intermediate R Br- + R Br C R C H H H Br H Br C C Br H H Vicinal dihalide δ- In analysis of the addition of halogen to an alkene, the anti stereospecificity of the dihalide product serves as evidence that the mechanism occurs via a cyclic halonium ion intermediate. For problem solving, this anti stereospecificity is especially pertinent in the cases of addition to cyclic alkenes or where the product carbons are chiral. 5 Halohydrin Formation R H Alkenes C H H C Alkene R X2 H2O C H H C + Br2 R H Halogen δ+ C C C H OH Halogen in aqueous conditions H + HX Halohydrin Br R H X H Br δ- Br + R C H C H H C H Br- + H Alkene + Br C + H H H Cyclic halonium ion intermediate R R R H C C H H Br- H R H O H C Br- Br C Br H +O H Br- + C H C OH R H Br H C C +O H H H H H Br- Br C H H + HBr Halohydrin In aqueous solution, electrophilic addition of halogen results in the formation of halohydrin. Water performs the ring opening instead of halide ion, which opens the ring in non aqueous halogenation. Water addition is preferential for the more highly substituted carbon, which receives a bit more of the distributed positive charge in the halonium ion than the other carbon. 6 Free Radical Addition of HX to Alkenes H H C Alkene R O Alkyl radical peroxide aqueous conditions are sufficient to supply peroxide hv 2R H H + Br H Alkyl halide Halide radical O ROH H Br Hydrogen halide H H C C C Alkoxy radical C C Alkene Br R H R H + H Br Hydrogen halide H + Br Halide radical H C C H H C R H Br hv HBr R + + Br Br + O O Peroxide initiator Alkoxy R radical Halide radical Hydrogen halide R H C Alkenes Br R H Alkyl radical R H C C H H Alkyl halide H + Br Halide radical In the presence of a peroxide initiator, hydrogen halide adds to alkene via an anti-Markovnikov, free-radical mechanism. The carbanion radical product of the first propagation step will be more stable if the carbon with the lone electron, the radical carbon, is highly substituted. For this reason, the halogen atom binds to the less substituted carbon, in other words, anti-Markovnikov addition. 7 Catalytic Hydrogenation of Alkenes RCH CH2 + H Alkenes H R H C H C H catalyst H H catalyst H Hydrogen Alkene H R C C H RCH2CH3 Alkane H H catalyst catalyst + R H C H H C H H Hydrogenation of alkenes occurs in the presence of a metal catalyst, a syn addition process. The two hydrogen atoms add to the same face of the double bond. Furthermore, if one side is more hindered than the other, addition is stereoselective for the less hindered side. Hydrogenation is exothermic, and relative heats of hydrogenation can be used to infer the relative stability of double bonds in different contexts. The more stable the double bond, the lower the heat of hydrogenation will be. 8 Oxidation of Alkenes to Vicinal Diols Alkenes O O Mn Potassium permanganate in basic solution KMnO4 O R C C C H C C OH H H H Vicinal diol H Cyclic manganate or osmate intermediate H H C OH R H 2O O H R H - Alkene O OsO4 Osmium tetroxide O Os O R O C C H OH R NaHSO3 H 2O C OH H H H Vicinal diol H H C Both of the above oxidation mechanisms proceed by syn addition. To accomplish anti hydroxylation of alkenes, the method to employ is hydrolysis of epoxides. As shown above, in basic conditions, oxidation of alkene with potassium permanganate results in formation of vicinal diol, but with acidic or neutral conditions, complete cleavage occurs to produce carboxylic acids or ketones (or carbon dioxide). 9 Oxidative Cleavage of Alkenes R H C Alkenes Alkene O KMnO4 H H C R C OH H 2O Potassium permanganate in acid or neutral solution + CO2 Carboxylic acids (CO2 from terminal alkene carbon) In basic conditions, treatment of alkene with potassium permanganate forms a vicinal diol. Oxidative cleavage by permanganate in neutral or acidic conditions, however, leads to cleavage to form carbonyl compounds by means of the same cyclic manganate ester intermediate. Where ozonolysis, another method of oxidative cleavage of alkenes, produces an aldehyde or formaldehyde, cleavage with permanganate produces a carboxylic acid or carbon dioxide respectively. Ozonolysis of Alkenes R H C Alkenes O C O O3 H H CH2Cl2 Alkene Ozone R H O O C C O Ozonide H H R O C H C H H Zn CH3COOH Reducing agent Molozonide O O RCH + HCH Aldehyde mixture If aldehyde product is desired over carboxylic acid, ozonolysis is preferred in cleavage of alkenes over potassium permanganate cleavage. Also, with terminal alkenes, the end carbon leads to formaldehyde molecule. Cleavage of such alkenes by potassium permanganate forms carbon dioxide. 10 Allylic Halogenation H 3C H C H C C Alkene C H C C H H3C HC C C H H CC C C H C H3C H C H 3C H hv H3C H C H H C H C Br H3C CH or H3C H H C C H H3C H C H3C H H H H C H Br Br C C H H C H H H H C Br Resonance stabilized allylic radical H H H H C C CCC H H H Br Br or H C H3C H H H C H H C Br H C C H H 3C H C C H continued Br H C C C C H Allyl halide mixture C C C H Br H3C H or H H Br Br H C Br Br + H3C H H H C Br Br2 H H C C H3C H H H H H C H H C Br H 3C H Halide radical 2 Br C C Br Br H C H H C Halogen H hv C Halide radical C H3C H H3C H hv H + HBr Br2 H 3C H H H H3C H C Br2 2 Br Alkene H 3C H H H hv Br2 Halogen H3C H Alkenes 11 + Br + Br H C H H C H H Br C C H Br or H H3C H C C H C H H Allyl halide mixture At high temperatures chlorine and bromine react with alkenes larger than ethylene by free-radical substitution. (At low temperatures, electrophilic addition to produce vicinal dihalides occurs). Halogenation is selective for two particular carbons due to the resonance stabilization that can occur with an allylic radical intermediate. 12 Oxymercuration-Demercuration Alkenes OH R H C H H C R 1. Hg(OAc)2 in THF, H2O C 2. NaBH4, OH- C H H H Alcohol + Hg(O2CCH3)2 H O C O O -OC CH + H H + R C 3 H R H O + C O C H H O R H C H 3 C H H H C O C H HgOCCH3 C H HgOCCH3 H - H3CC O H O HgOCCH3 Mercuric acetate H carbocation Intermediate H R Mercuric acetate Alkene + H R C C H H C O C O H R H g O C C H 3 O Alkene H R H O+ O HgOCCH3 C C H H H Oxonium Intermediate H O H HgOCCH3 O + C H NaBH4, OH- HOCCH3 H R H O C C H H H Alcohol Hydroxyalkyl mercuric acetate Oxymercuration-demercuration is usually preferred over acidic hydration to form Markovnikov alcohols from alkenes. The reaction begins with electrophilic approach onto the alkene by mercuric acetate to form a mercuric acetate carbocation derivative, which can rearrange. Hydration then occurs followed by a demercuration step with sodium borohydride. 13 Hydroboration of Alkenes H R C C Alkene Alkenes -OH H2O2 BH3 THF H H H H H R C C BH3 THF H H Alkene H R C δ+ B C δ- H OH H C R C Alcohol H H H H H H H H B H C R C H H -OH H2O2 Alkylborane -OH H2O2 H H C OH C H H R Alcohol Hydroboration-oxidation of an alkene forms an alcohol by means of a mechanism leading to anti-Markovnikov regioselectivity. Furthermore, the geometry of the activated complex produces a syn addition product. Note as a point of general interest that borane derives its electrophilicity from a vacant p orbital. 14 Electrophilic Addition of HX to Alkynes R C CH Alkyne HX no peroxides Alkynes R X H C CH Vinyl halide Hydrogen halide HX no peroxides R Hydrogen halide X H C CH X H Geminal dihalide Electrophilic addition to alkynes is very similar to the analogous reactions upon alkenes, although two additions occur. Markovnikov addition is observed. Due to the greater instability of vinylic carbocations, however, alkynes are somewhat less reactive than alkenes. Hydration of Alkynes C R Alkynes CH Alkyne H2O, H2SO4 HgSO4 OH H C R O CH Enol Aqueous sulfuric acid with mercuric sulfate catalyst C R Ketone H CH H The vinylic alcohol, or enol, intermediate forms when an alkyne is hydrated which immediately rearranges to form a ketone. This process of rearrangement is called keto-enol tautomerism. Due to decreased reactivity of alkynes for electrophilic addition compared to alkenes, acid catalyzed hydration of alkynes requires a mercuric sulfate catalyst. 15 Free Radical Addition of HX to Alkynes R C HX CH Alkyne peroxides Alkynes R H X C CH Vinyl halide Hydrogen halide with peroxides HX peroxides R Hydrogen halide with peroxides H X C CH H X Geminal dihalide As with alkenes, free radical addition occurs when hydrogen halide reacts with alkynes in the presence of peroxides. Two anti-Markovnikov additions occur leading to a geminal dihalide product. Electrophilic Halogenation of Alkynes R C C Alkyne R' X2 CCl4 Halogen molecule Alkynes R X C C Vicinal vinylic dihalide X R' X2 CCl4 X X C R R' C X X Tetrahaloalkane Bromine and chlorine add with trans stereochemistry to an alkyne. The process may be concluded at the trans vinylic dihalide, or if excess halogen is employed, addition can be made to occur a second time. 16 Hydroboration of Alkynes R C Alkynes -OH BH3 THF CH Alkyne R H 2O 2 H OH C CH R Alkyne Borane in tetrahydrofuran solution followed by aqueous hydrogen peroxide in basic solution H O C CH H Aldehyde Due to its anti-Markovnikov selectivity, hydroboration-oxidation of a terminal alkyne leads to an enol which rearranges to form a terminal aldehyde. The alternative method, hydration (either acidic hydration or oxymercuration-demercuration) applied to such an alkyne would result in a ketone. Catalytic Hydrogenation of Alkynes RC H + CR' Alkyne Alkynes catalyst H C H R' C C C H R H C R' H C Cis alkene R' R R H Hydrogen H + R H catalyst catalyst catalyst C C R' H Catalytic hydrogenation occurs by syn addition resulting in the formation of a cis alkene. Metal-ammonia reduction, an alternative hydrogenation method, yields trans alkenes. 17 Reduction of Alkynes with Alkali Metal/Ammonia R C 1. Na, NH3 2. H2O R' C Alkyne R C C Alkyne C R' C Alkenyl radical R - C Alkenyl anion C R H Sodium or Lithium in Ammonia R C C R' Alkenyl anion radical R Alkynes H R' H R' + + Na Sodium R Na Sodium H NH2 Ammonia H R' C Trans alkene - + C C R' Alkenyl anion radical + Na Sodium ion H C C R' Alkenyl radical R H NH2 Ammonia + C R - C C Alkenyl anion R H C H R' C Trans alkene H R' + - NH2 Amide ion + + Na Sodium ion + - NH2 Amide ion Of two alternative means of carrying out the hydrogenation of an alkyne, catalytic hydrogenation yields a cis alkene, while metal-ammonium reduction yields a trans alkene. The latter occurs due to the trans stereochemistry of the alkenyl anion radical intermediate in metal/ammonia reduction.. 18 Formation and Use of Acetylide Anion Nucleophiles H H R C C CH3CH2 + H Alkyne Alkynes C NH2Na Br R Sodium amide C C CH2CH3 C Alkylated alkyne H H Primary alkyl halide R C C + NH2Na + H Alkyne Na R C - C C Na + + Acetylide anion Sodium amide + C R H H - CH3CH2 Acetylide anion NH3 Ammonia C R Br C C C H H Primary alkyl halide CH2CH3 + NaBr Alkylated alkyne An acetylide anion is formed by reaction of a terminal alkyne with sodium amide, which is a very strong base. The acetylide anion can then perform nucleophilic substitution upon methyl and primary alkyl halides. (Being a strong base, acetylide anion would react by elimination with secondary and tertiary alkyl halides, rather than by nucleophilic substitution). 19 Coupling of Alkyl Halides with Gilman Reagents H CH3CH2 CH3 C R C + Br CH3 H3C R Alkyl halide R 2 Li + X R R 2 R Li H - + Cu Li CH3CH2 Li + LiBr + CH3 C C R CH3 H3C Gilman reagent (Lithium dialkylcuprate) - + Cu Li CuI + Alkyl Halides Alkyl substituted product Formation of Gilman reagent (Lithium dialkylcuprate) LiI R R CH3CH2 C H3C H CH3 R C + Br CH3 R Alkyl halide H CH3CH2 C H3C - + Cu Li Gilman reagent CH3 CH3CH2 C H3C CH3 Cu - R Br Li CH3 C + H Mechanism isn’t fully understood C R CH3 Alkyl substituted product Lithium dialkylcuprates react with alkyl halides via a substitution mechanism which is not well understood. It appears that nucleophilic attack by the negatively charged copper atom leads to an intermediate which fragments to produce the alkane product. Reactions such as this which form new carbon-carbon bonds are extremely useful in organic synthesis. 20 SN2 Mechanism with Alkyl Halides Alkyl Halides H H3C C H - Nu Br Nu H H Alkyl halide H3C H C C Substitution product - H3C Nu Br CH3 - Nu H H H C Br Nu H C H CH3 Nucleophilic bimolecular substitution (SN2) occurs mainly with primary and sometimes secondary alkyl halides. Because of the geometry of the bimolecular mechanism, the reaction always takes place with inversion of configuration. A polar aprotic solvent like DMSO is used, because a protic solvent like water will over-stabilize the nucleophile through solvation and promote E1 elimination instead, or the SN1 mechanism. Both E2 and SN2 prefer polar aprotic solvents. With primary alkyl halides, however, regardless of solvent, the SN2 mechanism almost always predominates. This occurs even if the nucleophile is a strong Bronsted base. With primary alkyl halides, only strong, bulky (hindered) base like tert-butoxide can cause elimination (E2) to occur rather than SN2 substitution. The SN2 mechanism is more difficult to achieve with secondary alkyl halides than with primary. Instead of substitution, strong bases react by elimination (E2) with secondary alkyl halides. SN2 substitution is possible with secondary alkyl halides if the solvent is polar and aprotic and the nucleophile is a weak base, like cyanide ion or alcohol. SN2 substitution does not occur with tertiary alkyl halides, which are too hindered for nucleophilic attack, and it does not occur with vinylic or aryl halides. 21 SN1 Mechanism with Alkyl Halides H 3C H 3C C H 3C H3C H3C C H3C Alkyl Halides H 3C H 3C C - Nu Br H 3C Alkyl halide H3C H3C C - Nu Br Nu H3C + C CH3 CH3 attack from either side Attack from either side + C CH3 CH3 Carbocation intermediate H3C Br H3C Alkyl halide - Nu Substitution product H3C H3C C Nu H3C Substitution product With secondary and tertiary alkyl halides, SN1 and E1 occur in protic solvents with weakly basic nucleophiles. The reactions occur more easily with tertiary alkyl halides, if the nucleophile is not a strong base. The SN1 mechanism is always in competition with E1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide is secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination is favored, not SN1 or E1 (with both secondary and tertiary alkyl halides). The SN1 mechanism, because it proceeds through a trigonal planar carbocation intermediate, will not lead to a product that is composed of pure enantiomer, as would happen if only SN2 occurred. Although the nucleophile prefers the side of the carbocation opposite the leaving group, attack can occur onto either face of the carbocation, and also rearrangement can occur in the carbocation intermediate. 22 E2 Mechanism with Alkyl Halides H H3C H3CH2C H C Alkyl Halides - CH3 C H3C H3CH2C Base Br C C Alkene H CH3 Alkyl halide - H H3C H3CH2C H C C Base Base CH3 H H3C H3CH2C Br H C C CH3 H3C H3CH2C C C H CH3 Br anti periplanar transition state Strong bases react with secondary and tertiary alkyl halides by the E2 (bimolecular elimination) mechanism. As with SN2, the best solvent for E2 is polar and aprotic. While SN2 predominates with primary alkyl halides even if the nucleophile is a strong base, E2 will always predominate with a strong base on secondary and tertiary alkyl halides (if weak base is used with such alkyl halides, in protic solvent, E1 and SN1 will be favored.) Bimolecular elimination obeys Zaitsev’s rule, i.e. forming as highly substituted an alkene as possible. Also, in the activated complex of the E2 mechanism, the proton abstracted by the base is anti-periplanar to the leaving group. Such stereochemistry, in some instances, will determine whether product will be cis or trans, and with ring alkyl halides, the anti-periplanar geometry of the transition state will determine the conformation of alkene ring product. On rings, both the proton and leaving group must be axial to be also anti-periplanar. 23 E1 Mechanism with Alkyl Halides H3C H3C C Alkyl halide H3C H3C C Alkyl halide H3C Alkyl Halides - H C H Base Br H3C H3C H3C C - Base Br C Alkene H3C Br CH3 CH3 + C CH3 CH3 Carbocation H 3C - Base H H C H + C CH3 CH3 CH H C C CH3 H 3 Alkene With secondary and tertiary alkyl halides, the E1 and SN1 mechanisms occur in protic solvents with weakly basic nucleophiles. The reactions occur more easily with tertiary alkyl halides if the nucleophile is not a strong base. The E1 mechanism is always in competition with SN1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide is secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination, not E1 or SN1, is favored with both secondary and tertiary alkyl halides. E1 product is most often obtained in mixture with SN1, and with a very weak base. With a moderately vigorous nucleophile (like ethanol), SN1 will predominate. 24 SN1 Mechanism with Allylic Cation Intermediate H 3C H C C Alkene with allylic leaving group H3C H C H C C H 3C H C C H H3C H H3C H C C C H 3C H HBr H3C H C H3C H H3C H C C OH H H C OH H 3C H C H C C C H C H H +C H H H Br C H3C H H H C C C + H HH3C HH H C + OC H Br H H C H H H H C + H3COHC HH C C H H Br H H C Allylic carbocation intermediate continued 25 - H + O+ H H H3C H H H C C + C Br H H H C Br C C H + H C C OH Br H H H Alkene mixture + H3C C H H C H C H + H C H Br C H 3C H C C Br H + H H + HBr O+ H H H C H C C H H3C H HBr H H C H H3C OH C C H HH +C H C C Br H HHC H3C H C OH H H C Oxonium C ion C H3C H HBr H Alkene with allylic leaving group H3C H H H C Allylic and Conjugated Structures H3C H C C H C H H C H + HH3C C H H C H3C H + C C H C H H C H H H O+ H - Br H3C H C C H C H Br + H H3C H C C Br H C H H Alkene mixture The departure of an allylic leaving group is eased by resonance stabilization within the allylic carbocation intermediate. Allyl halides, for example, are candidates for SN1 substitution, even if the carbon is primary. 26 1,2 and 1,4 Addition to Conjugated Diene Allylic and Conjugated Structures H 2C H 2C CH Br2 CH2 CH Conjugated diene CH Br Br CH CH2 + Br H 2C CH Br CH CH2 CH + Conjugated diene H2C Br2 H 2C H 2C CH CH2 CH H2C CH + CH CH2 Br CH Br CH Br Br CH2 H 2C Br CH Halogen Br2 1,4 product CH2 CH Br H2C 1,2 product CH2 CH + + H2C BrBr CH CH Allylic carbocation intermediate CH CH CH CH2 2 + Br - continued Br H2C H2C CH CH CH2 CH + CH + Br2 Br Br H2C CH CH CH2 H2C CH + CH CH2 H2C CH CH + CH Br Br CH CH2 1,2 product CH2 Br or H2C + CH H2C + H2C CH2 CH CH H2C + CH H2C CH2 CH CH2 Br CH CH CH2 + Br - Br CH CH2 Br Br + Br Br Br or CHBr 2 CH CH + H2C Br 27 Br Br Br Br H2C Br CH CH CH2 1,4 product Instead of forming the triangular halonium ion typical of electrophilic addition of halogen to alkene, halogen adds to a conjugated diene to form a resonance stabilized allylic carbocation intermediate. The two resonance forms of the resonancestabilized allylic carbocation lead respectively to two different possible products, the 1,2 and 1,4 products of addition. A very interesting and significant discussion arises from the fact that while the pathway to the 1,4 product occurs with greatest free energy decrease, the pathway to the 1,2 product is achieved with less activation energy. This means that formation of 1,4 product is favored thermodynamically, but 1,2 product is favored kinetically. Higher temperatures, ‘thermodynamic conditions’, promote the formation of 1,4 product, because if a larger fraction of the molecules possess activation energy for either pathway, as would occur at higher temperature, a large portion of diene concentration continuously moves down the 1,4 pathway and forms the more stable 1,4 product. Lower temperatures, however, are ‘kinetic conditions’. At lower temperatures, fewer reagent diene particles have enough energy to get over the activated complex energy hump to form the 1,4 product, so 1,2 addition predominates. 28 Diels-Alder Reaction H H Allylic and Conjugated Structures C C H CH2 + CH2 H3C Conjugated diene C C C H N H H3C Dienophile C N H Diels-Alder adduct H H C C H CH2 + CH2 H3C H H3C C C C C H N H H3C C N H N H 29 A conjugated diene, such as 1,4 butadiene, combines with an alkene in the Diels-Alder reaction. Especially favored are those alkenes which are dienophiles (having electron withdrawing substituents). The Diels-Alder reaction is a pericyclic process. In other words, it occurs by means of a particular type of transition state in which electrons simultaneously redistribute in a cyclic manner. The process starts with the bonding overlap of the terminal π lobes of the conjugated diene with those of the alkene. The stereochemistry of the Diels-Alder reaction is informed by concerns particular to pericyclic reactions. The overlap occurs between the HOMO of one of the species (Highest Occupied Molecular Orbital) and the LUMO of the other (lowest unoccupied molecular orbital). Cycloaddition reactions can be antarafacial or, suprafacial, which means that the reagents must rotate for orbital overlap or not, respectively. Diels-Alder is of the suprafacial type, so it takes place more easily, i.e. at lower temperatures. Note that if the alkene reagent is trans, the derived ring substituents will also be trans. 30 Electrophilic Aromatic Substitution with Halogen Aromatic Compounds Br + FeBr3 Br2 Ferric bromide catalyst Halogen Aromatic ring Halogenated aromatic ring Br + Aromatic ring Br Br2 Halogen Br FeBr3 Ferric bromide catalyst Br H H + Br H Br + Resonance stabilized carbocation intermediate - + Br H Br - Br + + HBr Halogenated aromatic ring 31 Electrophilic aromatic substitution of bromine is assisted by a ferric bromide catalyst, ferric chloride for chlorination. Unlike electrophilic addition to alkenes, a catalyst is necessary to enhance the electrophilicity of the halogen to react with an aromatic ring because aromatic π electrons are more stable than vinylic π electrons, Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para relative to the halide substituent. After this addition, a proton departs, completing the overall substitution with aromaticity restored. Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original halogen substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Being electronegative, halide substituents are ring deactivating by induction. However, nonbonded pairs of electrons are present on the halide substituent which can donate by resonance. Because of these combined effects, a halide substituent, already present on the ring, is a ring deactivating, ortho-para director for further electrophilic aromatic substitution. 32 Electrophilic Aromatic Substitution - Nitration Aromatic Compounds NO2 HNO3 H2SO4 Aromatic ring Nitric acid/ sulfuric acid mixture Nitrated ring + + NO2 Nitronium ion + HNO3 H2SO4 Sulfuric acid Nitric acid - HSO4 + H2O + NO2 + + NO2 Nitronium ion Aromatic ring NO2 H NO2 H + NO2 H + Resonance stabilized carbocation intermediate + H NO2 H O NO2 H + + + H3O Nitrated ring 33 2+ The electrophile for the nitration reaction, the nitronium cation (NO ), is generated by reaction of nitric acid (HNO3) with sulfuric acid (H2SO4). Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored. Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original nitro substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Nitro is such a substituent. Containing only electronegative atoms, nitro is electron-withdrawing by induction. Furthermore, the nitrogen atom in nitro also has no electron pairs capable of donating into the ring by resonance. A nitro group, already present on the ring, is a ring deactivating, meta director for further electrophilic aromatic substitution. (Some substituents, such as halogen or hydroxide, even though being electronegative (electron withdrawing inductively), will donate electron pairs to the ring by resonance and are still ortho para directing, though deactivating by induction.) 34 Electrophilic Aromatic Substitution - Sulfonation Aromatic Compounds SO3H SO3 H2SO4 Aromatic ring Fuming sulfuric acid Sulfonated ring O S H2SO4 SO3 Sulfur trioxide + OH + O Aromatic ring SO3H H + SO3H H Resonance stabilized carbocation intermediate + SO3H H + H SO3H H O H SO3H + + + H3O Sulfonated ring 35 Sulfur trioxide, the electrophile in sulfonation of benzene, is present in small amounts in normal sulfuric acid and sulfonation of benzene will occur with sulfuric acid. Frequently, though, a solution of sulfur trioxide and sulfuric acid is used (called oleum or fuming sulfuric acid). Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored. Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original sulfonate substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Sulfonate is such an electron withdrawing substituent. Containing only electronegative atoms, sulfonate is electron-withdrawing by induction. Furthermore, the sulfur atom has no lone electron pairs to donate into the ring in resonance. A sulfonate group, already present on the ring, is a ring deactivating, meta director for further electrophilic aromatic substitution. 36 Friedel-Crafts Alkylation Aromatic Compounds + Cl H3C Alkyl halide AlCl3 Cl Aluminum trichloride H 3C Aromatic ring H3C H C CH(CH3)2 H 3C H C Alkylated ring Alkyl halide AlCl3 H Aluminum trichloride C + CH3 CH3 - AlCl4 Carbocation H + Aromatic ring H C + C + CH3 CH3 CH3 CH3 Carbocation CH(CH3)2 H + Resonance stabilized carbocation intermediate CH(CH3)2 H + CH(CH3)2 H + CH(CH3)2 H Cl CH(CH3)2 + + HCl Alkylated ring 37 The aluminum chloride catalyst in Friedel-Crafts alkylation facilitates carbocation formation from an alkyl halide, preparing the species as an alkyl electrophile for electrophilic aromatic substitution. Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored. Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original alkyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Alkyl groups are electron-donating by induction. Because carbon is only moderately electronegative, alkyl groups have negative charge to share with the positive carbon in the orthopara resonance form. An alkyl group, already present in the ring, is ring activating and ortho-para directing. 38 Friedel-Crafts Acylation Aromatic Compounds R O + R C AlCl3 Cl Aluminum trichloride Acyl halide Aromatic ring O C Acylated ring O R C Cl Acylated ring AlCl3 + C R Aluminum trichloride R O Carbocation + O C + - AlCl4 Acyl cation R + O C + R C O Acyl cation + Aromatic ring R O C R H + + Resonance stabilized carbocation intermediate R R + H O C H + O C O C H - R O C Cl + HCl Acylated ring 39 The same aluminum chloride catalyst used in Friedel-Crafts alkylation is also used for Friedel-Crafts acylation. In this context, aluminum chloride assists in the formation of an acyl cation from acid halide to serve as an electrophile for aromatic substitution. Unlike alkyl cation, acyl cation has the advantage of not rearranging. Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. Finally, the proton departs and substitution at the carbon is complete with aromaticity restored. Acylation is frequently followed by Clemmensen reduction in synthesis, which will transform the acylbenzene into an alkylbenzene. Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original acyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Acyl group is electron withdrawing due to the electronegativity of the oxygen atom, which draws electron density toward itself and leaves the carbon electron poor. Acyl is a ring deactivating, meta director for further electrophilic aromatic substitution. 40 Nucleophilic Aromatic Substitution Aromatic Compounds Br Br or Aryl halide with electron withdrawing substituent ortho or para Ortho or Product with nucleophile substituted for halogen NO2 Aryl halide with ortho electron-withdrawing substituent - Br Nu NO2 Resonance stabilized carbanion intermediate - Nu Br Nu O N+ Br NO2 - Nu or NO2 Ortho Product with nucleophile substituted for halogen Para Ortho O NO2 Br Br - Nu - Nu - Nu - Nu 41 - Br Nu Br Nu O N+ NO2 O Br Nu NO2 Br Nu - - -O N + O Br Br NO2 - NO2 - NO2 - Nu - Nu Br - Nu NO2 Br Nu NO2 Br Nu Br Nu Br Nu - Resonance stabilized carbanion intermediate Br Nu NO2 NO2 Meta continued NO2 NO2 NO2 Nu Para Nu NO2 NO2 Br Br Nu Br Nu Aryl halide with para electron-withdrawing substituent or Br NO2 Nu Br Nu Nu - NO2 Para NO2 -- NO2 - Nu Br - Nu NO2 Ortho NO2 NO2 Para Br Br Nu Nu - Nu NO2 NO2 NO2 -O N + O NO2 - Nu Product with nucleophile substituted for halogen NO2 Br Meta Aryl halide with meta electron-withdrawing substituent - Nu NO2 Nucleophilic aromatic substitution (also called addition-elimination), requires an electron withdrawing substituent to be present on the ring ortho or para to the halide being substituted. The reaction is difficult to achieve with aryl halides for which halogen is the lone ring substituent. If a strongly electron-withdrawing substituent is present, however, ortho or para to the halogen, the carbanion intermediate will be more stable. A substituent such as nitro, while deactivating electrophilic aromatic substitution (which forms a carbocation intermediate), activates ortho and para positions, if they contain halogen, for nucleophilic aromatic substitution. Basicity of the nucleophile also facilitates the reaction. 42 Alkylbenzene Oxidation Aromatic Compounds H C H O KMnO4 COH CH3 Benzoic acid Aromatic ring with alkyl substituent Potassium permanganate or chromic acid oxidize an alkyl side chain on an aromatic ring to form a carboxyl group. If the alkyl group has more than one carbon, cleavage occurs at the benzylic position. 43 Alkylbenzene Halogenation Aromatic Compounds H C H CH3 Br2 C H Halogen Aromatic ring with alkyl substituent hv Halogen Br Br2 hv + CH3 Br Halide radical Haloalkylbenzene (Halogen at the alkyl position) 2 Br Halide radical H C CH3 H Aromatic ring with alkyl substituent H + C Br Halide radical H Br C CH3 H Br CH3 Br C CH3 H Benzyl radical Br C Haloalkylbenzene H CH3 + Br Halide radical Free-radical halogenation of alkylbenzene is selective for benzylic carbons because the benzylic radical is stabilized by resonance (like the allylic). Otherwise, the mechanism is completely analogous to the free-radical halogenation of alkanes. 44 Dehydration of Alcohols H3C CH3CH2 C Alcohols and Ethers OH C CH3CH Acid catalysis H3C CH2 CH3 + H major product C CH3 CH3 Alcohol Alkene mixture H3C CH3CH2 C H3C CH3CH2 + OH + + O H H3C CH3CH2 C H H Alcohol H3C H3C H CH3CH2 CH3CH C2 COH+O H3C + H H3C H C CH CH3CH + 2 3CH C O H H3C OH + H + O H H H3C H H3C CH3 + CH3 CH2 H3C CH3 CH CH+ CH 3 C 2 2 Carbocation C H3C CH3 Alkyloxonium ion H2O H3C CH3CH2 C H H H C H CH C C + H OH continued CH3 C H3C CH3 CH3CH2 C OH + 45 CH3CH 3 H C H + + H H O H H H2O H H H3C H3C H H H C H H3C H CH C C ++ CH3CH32 C O H H C H H3C H H H + O H3C H CH3CH2 CH3CH2 + C O H3C CH2 C CH3CH2 CH3 H3C + C H3C H H2O H H H C H CH C C + CH3 CH3CH 3 H C CH3 H C H H Alkene mixture H H H C H C+ CH3C H H C H H CH2 H2O CH3CH2 C CH3 Protonation in acidic conditions of the hydroxyl group of secondary and tertiary alcohols converts the hydroxyl group into a leaving group, which departs as water. The carbocation intermediate, which can rearrange, will then be deprotonated in an E1 elimination mechanism. This reaction is the reverse of acid-catalyzed hydration of alkenes. 46 Reaction of Alcohols with HX – Dehydrohalogenation H3C CH3CH2 C + OH H3C CH3CH2 C HX Hydrogen halide H3C Alcohol H3C CH3CH2 C HX Hydrogen halide H3C OH + H CH3CH2 H3C H3C CH3CH2 C Cl H3C + C + O H H H3C Alkyloxonium ion + H2O + Cl- CH3CH2 Halide anion H3C Carbocation H H3C CH3CH2 C H H3C + O H3C H2O Alkyl halide OH + H3C CH3CH2 C + X H3C Alcohol H3C CH3CH2 C Alcohols and Ethers H3C + C Cl - H3C Cl Alkyl halide Dehydrohalogenation only takes place with secondary and tertiary alcohols. The reaction begins with protonation in acidic conditions of a hydroxyl group. The hydroxyl group is converted into a leaving group and it departs as water. The carbocation intermediate formed attracts a nucleophile, in this case a halide ion, completing the SN1 substitution. This reaction competes with acid-catalyzed dehydration (E1 elimination). 47 Reaction of Alcohols with Thionyl Chloride Alcohols and Ethers H SOCl2 RCH2OH Cl Thionyl chloride Alcohol C R H Alkyl halide O RCH2OH Alcohol SOCl2 RCH2 O S Cl Alkylsulfonyl chloride Thionyl chloride H Cl C R + SO2 + + HCl Hydrochloric acid - Cl R O H C O S Cl H HCl H Alkyl halide Reaction of alcohols with thionyl chloride followed by hydrochloric acid results in the replacement of the hydroxyl group of the alcohol with a chloride substituent, forming an alkyl chloride product. This mechanism does not, like dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement cannot occur in reaction with thionyl chloride. Note that thionyl chloride can also convert a carboxylic acid into an acid chloride. 48 Reaction of Alcohols with Phosphorus Tribromide RCH2OH Alcohol RCH2OH Alcohol PBr3 C R Br Phosphorus tribromide O PBr2 Phosphobromide ether H Br H PBr3 RCH2 Phosphorus tribromide + Alcohols and Ethers C H + R Alkyl bromide R - HBr Br Hydrogen bromide H C O PBr2 H HOPBr2 H Alkyl bromide Analogous to their reaction with thionyl chloride, reaction of alcohols with phosphorus tribromide followed by hydrobromic acid results in the replacement of the hydroxyl group of the alcohol with bromine, forming the alkyl bromide product. This mechanism does not, like dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement cannot occur in this reaction. A carboxylic acids can be converted to an acyl bromide with this reaction. 49 Oxidation of Alcohols Alcohols and Ethers O R CH2 O H R C OH Carboxylic acid Primary alcohol O R CH2 O H R H R Secondary alcohol H H O O C R' C Aldehyde Primary alcohol R C R' Ketone Oxidation of a primary alcohol yields an aldehyde or, under the most strong, vigorous oxidizing conditions, a carboxylic acid. The stronger oxidizing agents KMnO4 and K2Cr2O7 both mainly transform primary alcohols into carboxylic acids, while Collin’s reagent, PCC and PDC form aldehydes. Oxidation of a secondary alcohol yields a ketone. Extreme conditions are necessary to oxidize a tertiary alcohol, producing cleavage mixtures. Alkoxide Ion Formation from Alcohols ROH Alcohol + NaH Sodium hydride Alcohols and Ethers RO- Na+ + H2 Alkoxide salt Alkoxide ions can be formed by a very strong base such as sodium hydride. (The alkoxide ion may be later used to serve as an SN2 nucleophile upon a primary alcohol to produce an ether.) 50 Reaction of Alcohols to form Ethers Alcohols and Ethers H2SO4 2 CH3CH2OH H2SO4 CH3CH2 Acid catalyst O H2 O Ether + H 2 CH3CH2OH 2 Alcohol + CH3CH2OCH2CH3 Acid catalyst 2 Alcohol H O+ H Oxonium ion + CH3CH2 H CH3CH2OH Alcohol CH3CH2OH + OH2 H H C C H H H H H C H C CH3CH2OCH2CH3 Ether H HOCH2CH3 + Ether oxonium ion CH3CH2OH H With primary alcohols, acidic conditions prepare hydroxyl to leave in an SN2 reaction in which another alcohol serves as the nucleophile. In this condensation reaction, the product formed is an ether. Two alcohols have combined releasing water. (Note that the conversion of hydroxyl group into a leaving group with secondary and tertiary alcohols leads to E1 and SN1). 51 Williamson Ether Synthesis Alcohols and Ethers RO- Na+ - + O Na Alkoxide ion R'I + Alkoxide ion ROR' Alkyl halide Ether H + CH3I Alkyl halide OCH3 + O - H C I H NaI Ether In the Williamson ether synthesis, alkoxide ion acts as an SN2 nucleophile upon a primary alkyl halide forming an ether. Williamson ether synthesis can be used to form asymmetrical ethers. The mechanism will not work upon secondary or tertiary alkyl halides because of competition from the E2 mechanism, which would form an alkene. 52 Acid Cleavage of Ethers Alcohols and Ethers Hydrogen halide Ether Alkyl halide Alcohol Hydrogen halide Ether Dialkyl oxonium ion Halide ion Alcohol Alkyl halide Ethers are generally unreactive to most species. With strong acid, however, ethers undergo a cleavage through a process begun by protonation of the ether oxygen. HI and HBr are often used. The products separate in either an SN1 or SN2 style process, determined by the shape of the ether, the halide anion serving as nucleophile. Some of E1’s alkene product, as always, will be mixed in if SN1 occurs. 53 Epoxidation of Halohydrins Alcohols and Ethers OH C C H3C H3C CH3 CH3 Br O NaOH H2O C H3C H3C Base Halohydrin C CH3 CH3 Epoxide H OH C C CH3 CH3 H3C Br H3C Halohydrin NaOH H2O Base - O C H3C H3C OH O C CH3 CH3 Br C H3C H3C C CH3 CH3 Br - CH3 O CH3 C C H3C Br H3C Halohydrin anion O C C H3C CH3 CH3 H 3C Epoxide Basic conditions activate a halohydrin to complete an intramolecular process to form an epoxide. The oxygen of the hydroxyl substituent displaces the halide through nucleophilic attack. This mechanism is essentially an intramolecular Williamson ether synthesis. The product formed is a triangular epoxide molecule. Epoxides are useful substances because of their own high reactivity toward nucleophiles in epoxide ring opening reactions. 54 Acid Epoxide Ring Opening Alcohols and Ethers O H C H+ C H H H - Nu C H H H O acid-induced with normal nucleophile H C C H H Alcohol with nucleophile as new substituent O H OH R Nu Epoxide C H C C H H - R Nu H C C Nu H H + O H+ Nu H OH R C H C - H H H H R C Nu Nu OH C H H Alcohol with nucleophile as new substituent O basic nucleophile H C H O C H H - Nu R C H C H R H Nu - OH C H H C Nu H 55 In epoxide ring opening reactions, the SN2 approach of a nucleophile on an epoxide results in cleavage of the epoxide. Nucleophilic attack occurs at the more highly substituted carbon in acidic conditions. In basic conditions, steric hindrance is the determining factor with nucleophilic attack occurring at the less substituted carbon. 56 Reduction of Ketones and Aldehydes Aldehydes and Ketones O R OH C R H Aldehyde Reducing agent C H OH O R C Primary alcohol H R R' Reducing agent Ketone C H Secondary alcohol R' NaBH4 and LiAlH4 are reducing agents commonly used for transforming an aldehyde or a ketone, respectively, into a primary or a secondary alcohol. Note that Wolff-Kishner and Clemmensen reduction reduce aldehydes and ketones further than NaBH4 and LiAlH4, all the way to alkanes. (Note the special case where catalytic hydrogenation may be used to reduce a benzylic carbonyl group to an alkane.) Remember of the sequence in oxidation states of carbon, from more reduced to more highly oxidized: alkyl, alcohol, aldehyde, ketone, carboxylic acid. 57 Reduction of Aryl Alkyl Ketones Aldehydes and Ketones O C CH2CH3 H2 catalyst CH2CH2CH3 Alkyl aromatic Aryl alkyl ketone O O CH2 C CH3 H2 catalystC OH CH2 CH2CH 3 H 23 CH catalyst C O CH2 C CH3 H2 catalyst CH2CH2CH3 OH CH2 C CH3 Reduction with hydrogen in the presence of a catalyst reduces a non-benzylic carbonyl group only to a hydroxyl group. A carbonyl carbon located at the benzylic position may be reduced to become an alkyl carbon. It is not necessary to employ Wolff-Kishner reduction or Clemmensen reduction, which reduce even nonbenzylic carbons to this point. For benzylic carbonyl groups, the process can be carried out by catalytic hydrogenation. (The reducing agents NaBH4 and LiAlH4 reduce aldehydes or ketones only to alcohols, even if the carbonyl is benzylic.) 58 Oxidation of Aldehydes and Ketones O R C O - 1. KMNO4, OH H R 2. H3O Aldehyde Aldehydes and Ketones C OH Carboxylic acid O O - 1. KMNO4, OH CH3 C CH2CH3 Ketone 2. H3O CH3 + O C OH + C CH3CH2 + OH CO2 Carboxylic acid cleavage mixture (CO2 if methyl ketone) Potassium permanganate (extreme conditions) Many of the stronger oxidizing agents such as KMnO4 will transform aldehydes into carboxylic acids. Tollens’ reagent (Ag2O) is frequently used. A shiny mirror of metallic silver is deposited through oxidation of aldehydes by Tollens’ reagent, so it is frequently used as a test for aldehydes. Aldehydes are themselves oxidation products of alcohols. A strong oxidizing agent like KMnO4 will oxidize a primary alcohol past the aldehyde all the way to the carboxylic acid oxidation state, while other, weaker oxidizing agents, like PCC, can be used to form aldehydes from alcohols, not oxidizing the aldehyde further. In general, normal ketones are not oxidized except under extreme conditions, with benzylic carbonyl group being an exception, which KMnO4 oxidizes easily. 59 Reaction of Grignard Reagents with Aldehydes and Ketones O C R' + R R'' + Mg Magnesium O C R'' R' Aldehyde or ketone + H3O + R' + 2. H3O Grignard reagent Aldehyde or ketone R Br Alkyl halide R' MgBr Aldehydes and Ketones R'' C R OH Alcohol Acid only for clean-up after the initial reaction. R MgBr Grignard reagent R MgBr Grignard reagent R'' C R' R O MgBr R' R'' C R OMgBr + H3O Alkoxymagnesium halide R'' C OH R Alcohol Grignard reagents, which are obtained by reaction of alkyl, aryl, acetylenic halides, are very important instruments of synthesis. A Grignard reagent provides a nucleophilic carbon which can be used for bonding to another carbon. (The carbon bonded to magnesium in the Grignard reagent is nucleophilic, being the more electronegative end of the bond with magnesium.) For example, Grignard reagent carbon reacts with electropositive carbonyl carbons. Grignard reagents also react to form new carbon-carbon bonds with esters, nitriles, epoxides, and carbon dioxide carbons. (Grignard reagents can’t be used in the presence of acidic protons. The acid in the mechanism above is only applied in the reaction’s last stage.) 60 The Wittig Reaction Aldehydes and Ketones H R O + Br C (C6H5)3P C R'' Triphenylphosphine R' H R (C6H5)3P Triphenylphosphine C Br + (CR6' HAlkyl 5)3P halide + H + (C6H5)3P C R' O C R R''' R'' + (C6H5)3P Aldehyde or ketone + (C6H5)3P C R' R R' + - (C6H5)R3P'' O C R''' + (C6H5)3P - O R''' C C - R Br R (C6H5)3P H C R' - R Br NaH BuLi - R + (C6H5)3P C R' or O C O C R R' R'' R''' R R' C C R'' R''' - R + (C6H5)3P C R' H R'' R O C R''' C Br C C continued R' R R' C - Br Triphenylphosphonium ylide + R (C6H5)3P C R' + NaH - (C6H5R)3''P C R' R or BuLi O C R''' + (C6H5)3P (C6H5)3P C R' R''' R - R + (C6H5)3P C R' + (C6H5)3P C R' R'' O C R''' R R' R'' R''' H C R'' - R + (C6H5)3P C R' Br Triphenylphosphonium (C H ) P 6 5 3 ylide +H C O O Br C R'' R''' C Alkene H R + R' C R'' R R' C R''' Aldehyde or ketone Alkyl halide Unstable betaine intermediate + C O C R R' R'' R''' - R + (C6H5)3P C R' '' R + R'' (C6H5)3P C R''' O C R''' R R' R'' R''' R R' C (C6H5)3P C R'' R''' (C6H5)3P C O C + (C6H5)3P 61 O R R' R'' R''' O Alkene Phosphorus ylides are used in the Wittig reaction to convert aldehydes and ketones to alkenes. In the process a new carbon-carbon bond is formed. To prepare the triphenylphosphonium ylide reagent, an SN2 reaction is utilized between triphenylphosphine and an alkyl halide (followed by deprotonation). The ylide (an ylide is a dipolar substance with adjacent opposite charges) is then made to undergo a reaction with an aldehyde or ketone that is somewhat analogous to the reaction of aldehydes or ketones with Grignard reagents. The ylide carbanion electrons lead to bond formation with the positive carbon pole of the carbonyl group. A betaine is formed, which is unstable (a betaine is a dipolar substance with nonadjacent opposite charges.) Electron pair movement continues as oxygen departs its bond with carbon to bond with phosphorus. The two carbons of interest now possess a double bond between them. (Carbon-carbon bond forming reactions are of particular importance for organic synthesis. Other important reactions that form carbon-carbon bonds include the use of acetylide anion as an SN2 nucleophile, Grignard reagents, Gilman reagents, and the aldol & Claisen condensations.) 62 Acetal Formation Aldehydes and Ketones O R' + R'' C 2 equiv. Alcohol Aldehyde or Ketone R' HCl 2ROH Acid + R' C O R'' Aldehyde or ' C RKetone ROH Alcohol + R'' + O R' O R R' O R' C R' Acid HCl R' C R' OH R' R'' C R'' O R + H H O C R'' H RO O R' C R'' HCl + OH H2 R' + O C R'' R'ROC '' C + RH O RO R' C + O R' R 63 C OHR'' R' C R'' O O R R +H H O R + H R' O R'' H O' OH O R R + H C R'' C Cl H H RO H H OR R' C + R'' OH2 RO R' R'' C + O R + O R'' O RO + OH2 R' RO continued R'' R RO C R' R + O OH ' '' '' R' R C C RR R'' RR O H O ' R '' C OH R R' O R + C H R'' Cl H H + OH2 Cl OH R' RO Hemiacetal + ROH R'' R' R'' C R'' C O R R H R R O R' C R'' C R'' RO OH C OR H H R'' R' + O O R + H OH C Cl R'' C R' R'' C Acetal O HCl 2ROH H R'' C RO H O OR R'' O R + H R' O C R' R'' O R + H O H H OR C RO R'' Acetal An aldehyde or a ketone reacts with alcohol in the presence of an acid catalyst to form a geminal diether product called an acetal. Acetal formation begins with protonation of the ketone or aldehyde carbonyl oxygen by an acid catalyst, increasing the attractiveness of the carbonyl group to the approaching alcohol nucleophile. A tetrahedral intermediate forms, which is typical of nucleophilic reactions with carbonyl compounds. After a subsequent protonation, the hydroxyl group leaves as water, forming a cation intermediate. This intermediate is approached by another alcohol nucleophile. One interesting use of acetal formation is to protect carbonyl groups from hostile reaction conditions. Ethylene glycol is often used in this way to form a cyclic acetal, which can be converted back into the aldehyde or ketone at a later stage. 64 The Wolff-Kishner Reaction - O R Aldehydes and Ketones C H N H + R' Hydrazine H OH H H N R C Aldehyde or Ketone H N H + O C R' R C Aldehyde or Ketone R' N H + Hydrazine N H R -C H H N R' N C R N H O H + HH N H C H N R' N+ H H N - + OHR OH - OH R N C R' N N H C ' N RH R H HC R' N H + H N HN H N C R H R' - + OH R C CH R' R ' R OH - OH H O HH N - H N R C H R' R C R' - + OH H R N C O NH N H N R H R' N H H - - O N N + H - C H N OH H C R' R' R Hydrazone anion + H2O R C - R R' - + OH N N N R' H H - R continued 65 C H N H N + N N+ + HH 2O 2O C R' R R' OH - + OH N C R' + H2O N H - C H R - O R C R' + +H H2O C N H R' R H Hydrazone H N H N R OH H H N H N H N N + R C H C R' R R' - OH + N H H - H H H HN N H H N N ++ R' C C OH' H R N RH H H N + H N N H H C R' R - O O N H N H H R' - H R' R' O C C C R' + N HN + H O +H N 2 N H Tetrahedral H intermediate H N H H R HR H OH R C R' + N H H R OH H N H - O R H - O R H H + H2O N N Alkane O O R + H R' C O H H N N - R' H N N R + C OH H - R H R H H - C R' R C H R' R' O N N OH H R H C H R' Alkane + - C H + + H2O R' Carbanion - OH A ketone or an aldehyde is reacted with hydrazine in Wolff-Kishner reduction. The reaction begins with nucleophilic attack of hydrazine upon the carbonyl carbon. This is one of the more challenging mechanisms. Conceptual framing is helpful to learning. Wolff-Kishner belongs to the group of reactions that are possible between ketones/aldehydes and amines and amine derivatives. In these reactions, if the nucleophile is a primary amine, having two hydrogens to lose, reaction with a ketone or an aldehyde will produce an imine form, in which the carbon originally double bonded to oxygen will be double bonded to nitrogen. If the amine is secondary, the product is an enamine, in which the carbon-nitrogen bond is single, but the carbon is double bonded. In Wolff-Kishner, the tetrahedral intermediate formed by the nucleophilic attack, resolves itself by losing the original carbonyl oxygen as hydroxide, forming eventually a hydrazone, the structure of which is of the imine type (not enamine). Deprotonating with a strong base puts electrons on the move within the hydrazone in a manner similar to an elimination mechanism, except that here we have electrons moving into nitrogen-nitrogen bonds, not carbon-carbon, with resonance stability also. Two deprotonations occur moving two electron pairs between the nitrogens, displacing electrons onto the original carbonyl carbon, eventually turning the alkyl portion of the molecule into an E2 style leaving group, which, after departing, is protonated to form the alkane product. 66 Reductive Amination Aldehydes and Ketones O R R' C Aldehyde or ketone H R 1. NH3 2. H2 R' C N Ammonia then Hydrogen H H Amine O O R + R' C Aldehyde or ketone R NH3 Ammonia R -C C R' N+ H H R' 1. NH3 2. H2 R R' C Tetrahedra intermediate R' H H H O R R' C N H H H H C N OH N H H R R' C N+ H NH3 O RO C - O R R' H H Carbinolamine H N + + NH+ 3 C R' R C R' O R H R H2 H - OH - O H H C NR' + R R C NH3 OH R' O R - continued NH + C R' R C R' N+ H H H - H2O H2 67 H C OR' R ' N C R H HH N + H H R OH R R' C N C N H H O H R' H H H N + R C R' Conjugate acid of imine H2 R + - H OH R OH H N + C NH R' R C R' Imine + H2O H2 H C N H R' H Amine Reductive amination is a means of converting an aldehyde or a ketone into an amine. The reaction begins with nucleophilic addition of ammonia or an amine to the carbonyl group of an aldehyde or a ketone. The imine or enamine derivative formed is subsequently reduced by hydrogen to form the amine product. If the nucleophile is ammonia, a primary amine will be formed in reductive amination. If the nucleophile is a primary amine, the product will be a secondary amine. With a secondary amine nucleophile, a tertiary amine product will be obtained. Recall that the nucleophilic addition of ammonia or primary amine results in imine formation and addition of a secondary amine to an aldehyde or ketone results in enamine formation. Both are ultimately reduced to form amines in reductive amination. 68 The Cannizzaro Reaction O H3C C H3C C 2 2 O H3C C OH C H3C H3C H C Aldehyde 3 H3C C C OH O O H3C C H3C H3C CC C HH H3C H3C H3C - 1. OH H 2. H3O + - --H O H3C C H3C C H3C H + H H3C H3C OH H3C + + - O OH HH3C HOH 3C Tetrahedral C C intermediate H H3C H C - H Hydride ion continued - H -H O H3C C OH C H3C O H-3C H3C H3C OC C H3C H C C H3C H H H3C OH + + H3O 69 - H H3C H3C Aldehyde H3C H3C C - O H3C C H3C C - OH H3C Carboxylic acid H3C H3C C OH + H3C H3C C H3C O O H3C C C HC3C H H H Alcohol O H3C C OH H3C C H OH C H3C O H H3C C OH H-3C C O H3C - OH H H33C C C OC H3C H C C H3C HH H3C OH + H3O H3C C H3C + H3O + H3C O H3C C C H3C - H3C H3C C H3C 2. H3O + OH H3C H3C C Carboxylic acid H3C 2 O H3C C OH H3C C - 1. OH H H3C Two equivalents aldehyde 2 Aldehydes and Ketones H -H H3C H3C C - O C H + H3O H3C H New tetrahedral intermediate OH C H H The Cannizzaro reaction resembles the acyl exchange reactions among carboxylic acid derivatives, although it occurs with aldehyde. With aldehyes (or ketones) tetrahedral intermediate formation is not typically followed by the departure of an acyl type leaving group. Reactions of nucleophiles with aldehydes and ketones differ in this respect from reactions of carboxylic acids. Although sometimes the original carbonyl oxygen will depart (as in acetal or imine/enamine formation) the reaction of a nucleophile with an aldehydes most commonly results in a tetrahedral product) In the Cannizzaro reaction, a strong base reacts with an aldehyde having no α-hydrogens. The hydroxyl adds to the aldehyde to produce a typical tetrahedral intermediate, except that this intermediate resolves itself with hydride (hydride!) departing as an ‘acyl type’ leaving group, forming a carboxylic acid. The freshly departed hydride then acts as a nucleophile upon another aldehyde, producing a new tetrahedral intermediate, which, after protonation, becomes an alcohol. One equivalent of aldehyde becomes carboxylic acid and the other leads to the alcohol form. 70 Acid or Base Catalyzed Enolization H 3C O H + H 3O CH3 C C Aldehydes and Ketones or C H 3C H 1. OH CH3 CH3 H H O 2. H2O Aldehyde or Ketone C H H + H3O CH3 C C C H CH3 - H3C O CH3 + CH3 + C H O C C 3 CH 3 C HC CH 3 CH3 CH3 H2O HO 3C H C H H3C C O H H + O CH3 CH3 OH C C C C C CH3 CH3 CH3 H CH3 H H CO 3 H H C H H3O H H3C C C H O - CH3 O CH3 H3C + C C C H3C C C C CH3 HH CH3CH3 CH3 H2O H 3C HH 2O C H O -O CH OH3 C H3C C C CHC 3 H CH3 O C - CH3 Base CH3 - CH3 CH3 CH3 Enol CH3 CH3 C H H H3C H C H HO O CH3 O CH CC 3 CH H CHC 3C H2O H3C H C C C CH3 CH3 H CH3 C CH3 CH3 3 - O C CH3 C CH3 CH3 O CH3 71 O CH3 O CH3 C C C CH3 C C CH CH33 CH3 H H -O continued 3 H3C C H CH3 CH3 Resonant Enolate anion intermediate C C C - H3CH3C H H C C Aldehyde or Ketone H3C H CH3 C CHC3 O H CH3 CH3 CH3 CH3 HH OO CH 3 + 3C HH 3C C C C C C C CH CH3 3 CH3 HH CH H H C H HO H Base Catalyzed CH3 CH3 O H CH3 + H3C C C C H 3O CH3 CH3 Acid HH O CH CH H CH3 3 3 O Aldehyde or or H 3C H C C C C C Ketone H3 CH H 1. OH + O H CH3 H HCHO CH3 3 H3C + H3C 2. H2O C C C C C C CH3 CH3 H CH3 H CH3 Resonant cation intermediate H H +O H H H H3C H 3C O H C Enol Either Acidic or Basic conditions H +O Acid Catalyzed CH3 C O H3C H C C Enol CH3 C CH3 CH3 Keto-enol tautomerism is one of the most important aspects of the reactivity of aldehydes or ketones. The movement from an aldehyde or ketone to its enol isomer involves proton exchange between an α-carbon and the carbonyl oxygen of an aldehyde or ketone. Although continuous interchange between the carbonyl compound and its enol does exist normally in neutral conditions, keto-enol tautomerism can be catalyzed by the addition of either acid or base. The particular events differ between the cases, but the same net intramolecular process occurs with either acid or base catalyzed enol formation, the transfer of a proton from the α-carbon to the carbonyl oxygen, accompanied by the shifting of electron pairs up toward oxygen, forming the vinylic alcohol known as an enol. α halogenation, the haloform reaction, and aldol condensation, among other reactions, involve the reactivity of the enol form, which, in these processes, is approached by an electrophile at the α-carbon. In another instance, the presence of enolate anion intermediate contributes to the special reactivity of α-β unsaturated carbonyl compounds to nucleophiles at the β carbon. 72 Alpha Halogenation Aldehydes and Ketones O H H3C CH3 C C Br2, HBr C CH3 C C CH3 CH3 H O H H3C C CH3 CH3 Br Aldehyde or Ketone H H3C O H CH3 C C H C + O H H 3C C H3CC C C C CH3 CH3 H Br32, CH O C CH 3 H 3 CH H CH3 C C H CH3+ H O H H3C CH3 H CH3 Aldehyde or Ketone Br HBr H H CH H3C3 C CC C CH3 Resonant cation H CH3 intermediate H O + O C C CH3 CH3 CH3 CH3 Br H3C O H C C HCH3 H O Br Br + CH3CC CH3 + O H CH3 + CHH 3 H3C - H3C CH3 C CH3 CH3 - C Br Br C C + O continued CH3 CH3 H H O H CH3 CH3 H H3C + O H CH3 C C , C C C C Br H3C 2 CH3 CH+3 C C Br CH3 CH3C Br CH3 H CH3 H OH H H3C H3C H C O C C Br 3 C CH3 CH3 C CH3 C CH CH33 CH3 + 73 HBr Br H O C C CH3 C C CH CH3 CH 3 3 H Br H +H O H CH O H CH3 3 H3C H3C + C C C C C C CH CH3 3 H Br CHCH3 H3C H H3C C H O H C H 3 CCHC CH3 H O Br H CH3 CH3 H C CH3 C - Br C C H3C H H O H Br2, C H H3C CH3 CH3 CH3 H3C C CH3 CH3 H C Br C Br H3C H + O C H C H H CH3 H3C C CH3 CH3 Resonant cation H C O C Br + CH3 C CH3 CH3 intermediate Br CH3 C + O CH3 CH3 H3C H C Br O C CH3 C CH3 CH3 + HBr α-halo derivative The process of acid catalyzed keto-enol tautomerism allows aldehydes and ketones with α-hydrogens to react with electrophiles. α-halogenation is a typical reaction of this type. In this reaction, the π electrons between the vinylic carbons of an enol form of the aldehyde or ketone are subject to electrophilic attack, leading to a new bond between the α−carbon and halogen. 74 Haloform Reaction of Methyl Ketones H O H H CH3 C C Aldehydes and Ketones O Br2 C CH3 CH3 OH - Halogen with base Methyl ketone CH3 C HO C CH3 CH3 Carboxylic acid H H H H C H O C CH3 OH C O CH CH 3 3 CH3 C MethylC ketoneC H H - - Br2 H H C OH CH3 C C CH3 CH3 H O CH3 H C C C HC CH3 Br CH Br 3 - - - C OH CH3 CH3 Br2 OH - Br2 OH - Br2 OH O - CH 3 -Above mechanism Br C C twice repeated CH3 CH3 O Br CH3 - C O C CH3CH3 CH3 H Br C C C H CH3 O H CH 3 Br Br C Br Br O C C H H Br Br C Br O O C H - O CH3 CH3 - CH3 C CH3 CH3 + - Br continued O CH3 O CH3 Br C C C Br2 H CH3 C C H C CH3 CH3 Br CH3 Br Br HC H Br C O O C C O -Br O O Br C C CH3 CH C 3 C CH3 CHCH 3 3 H CH3 O CH3CH3 + C CH3CH3 CH3CH3 CC Br Br Br C Br -O O - Carboxylate anion - 75 + - Br - HCBr OH 3 CH3 C C O H O C OH - Br H H Br2 C -Br CH3 CH3 C CH3 CH3 CH3 O H CHO CH3 3 H + C C C C C CH3 CH3 CH3 BrCH3 CH3 C Br - C CH3 C - O - Br CH3 O C Above C mechanism C CH3 repeated twice Br O CH3 H Br C H CH3 O H H C CH3 O CH3 H H C Enolate anion HO OH CH3 C - HO HO Br2 H H C C C + H Base CH3 CH3 O O H H CH3 CH3 Tetrahedral intermediate CH3 C CH3 CH3 + HCBr3 Haloform The haloform reaction is a variation of α-halogenation. Under basic conditions for enolate formation of a methyl ketone, halogenation of the α-carbon continues until its supply of hydrogens is exhausted. The resulting trihalo-derivative is unstable, undergoing an acyl type substitution resulting in formation of carboxylate and haloform. The iodoform version of this reaction is used as a qualitative test for methyl ketones. Yellow iodoform precipitate convincingly indicates upon reaction with iodine the presence of a methyl ketone. 76 Aldol Condensation Aldehydes and Ketones O H 2 H 3C C - CH3 C CH3 CH3 H C 2. H2O Aldehyde or Ketone O H OH C O CH3 CH3 H 2 H 3C C C C Aldehyde or Ketone H O H3C H H3C CH3 - H 3C C C -H HO 2. H2O C CH3 CH3 O - H3C H C OH CH3 C CH3 H 3C C H CH3 O C H3CH C3 C Aldol addition product C C CH3 CH3 H - CH3 C CH3 H CH 3 O H 1. OH CH3 CH3 C C - CH3 C H 3C CH3 2 H3C C C H CH3 C C H H C C CH 3 H CH 3 3 O C 1. OH C OH H H 3C C C CH3 CH3 CH3 CH3 Enolate anion H3C 2 H3C H C O H C C O CH H 3 C C 3 H3CCHC CH H3 H CH3 H3C C CH3 CH3OOH CH3 C H3C H C O C H C CH3 CH3 HO - - OH O H CH3 CH3 H3C H C C C C3 C H C C CH3 H2O H H C C CH CH + 3 H CH 3 3 3 O C H3C C H 3C CH 3 CH3 O H C C H H3C H H3C H2O H - C OH CH3 CH3 CH3 O CH3 O C 77 H2O CH3 C CH3 CH3 H O - CH3 C C C H H C C CH 3 H CH 3 3 O C C CH3 CH3 CH3 C C CH3 C H H C C CH 3 H CH 3 C 3 CH3 O C CH3 C CH3 H3C CH3 H3C C C - C continued - H3C C CH3 H2O CH3 Anion form of product OH CH3 C C C H H C C CH 3 H CH 3 3 O C H3C - H3C H O H C CH3 + - OH CH3 Aldol addition product Many of the reactions involving aldehydes or ketones fall into one of two categories. One set of reactions take place by means of nucleophilic attack upon the electropositive carbonyl carbon. The other set occurs by means of keto-enol tautomerism, a process that exposes an aldehyde or ketone to electrophilic attack at its α-carbon (as in α-halogenation). Aldol condensation, however, belongs to both categories. Aldol condensation occurs with bond formation between the carbonyl carbon of one equivalent of aldehyde or ketone and the α-carbon of another equivalent. Keto-enol tautomerism generates the enolate form from one molecule of the aldehyde or ketone, and the α-carbon of the enolate acts as a nucleophile, forming a bond with the carbonyl carbon of another aldehyde or ketone molecule. 78 Claisen Condensation H 2 Aldehydes and Ketones - O H C C H O Ester 2 O H H C C 2 O CH3 C C O O CH3 C CH2 C O - H H H H C C O + CH3 CH3OH Alcohol O H C C O CH3 H Base HO O - 1. OH - + O 2. H3O CH3 O Claisen condensation product - O H OH Ester H H 1. OH + 2. H3O CH3 CH3 C O + CH3 CH3OH O - H H C CH3 O CH2 C C O CH3 Enolate ester 2 H O C C CH3 O C HO -CH3 C H C C H H H O H O H H OH O - H CH3 H C C O H C H O OCHC 3 C H C H HO 79 CH3 O CH3 - - -O C O C H O CH C CH CO CH3 3 H H H O C H H O continued - O H O - +H C H3OH O O C CH3 CH3 C O CH2 C O + CH3 CH3OH O H CH3 O H C C O - O H CH3 H H O C C CH3 - C C H H O H O CH3 H C H O C Tetrahedral O intermediate CH3 H O H C H C - O H C H O C O CH3 + H3O O O CH3 C CH2 C O CH3 Claisen condensation product + CH3OH Alcohol CH3 Claisen condensation of esters is very similar to aldol condensation (which is why we have included this methanism in this section, even though esters are carboxylic acid derivatives). In Claisen condensation, the enolate form of one ester molecule carries out nucleophilic attack on the carbonyl carbon of another ester molecule. How Claisen condensation differs from aldol condensation illustrates a general difference in the reactivity of esters vs. aldehydes and ketones. In Claisen condensation, the enolate form of one ester molecule approaches another, similarly to aldol condensation, but, in this case, the tetrahedral intermediate resolves itself along an acyl substitution pathway. Both the aldol and Claisen condensations begin with an α-substitution, but in aldol condensation the overall pathway corresponds to nucleophilic addition, while Claisen condensation resolves itself in the manner of an acyl substitution reaction with sp2-hybridization returning with the departure of the leaving group. 80 Conjugate Nucleophilic Addition Aldehydes and Ketones O O CH3CH2 C - + CH2 CH CH3CH2 Nu α,β – unsaturated aldehyde or ketone CH3CH2 C C Nu H H Nucleophile Product with nucleophile having added at β position O O C H H C CH - + CH2 α,β – unsaturated aldehyde or ketone O CH3CH2 CH3CH2 Nu C CH O H - C Nu C CH3CH2 H C H H - H + H C C Nu H Resonance stabilized enolate ion O C C Nu - H H CH3CH2 C Nucleophile H H C H C Nu H Product with nucleophile added at β position 81 With α,β unsaturated carbonyl compounds (also called conjugated enones), some nucleophiles will approach and bond to the β-carbon, such as amines, cyanide, and Gilman reagents. Normally with aldehydes and ketones, a nucleophile will only approach and bond to the carbonyl carbon. Being in a polar bond with oxygen, carbonyl carbons are electropositive. However, with an α,β unsaturated carbonyl compound, the positive charge arising due to the polarity of the carbonyl group is shared between the carbonyl carbon and the β-carbon by means of allylic resonance. This is why the β-carbon of α,β unsaturated carbonyl compounds is attractive to nucleophiles. 82 Conjugate Addition of Gilman Reagents Aldehydes and Ketones O CH3CH2 O R C CH + CH2 Cu Li α,β-unsaturated aldehyde or ketone R 2 Li + X R R CH3CH2 + Li 2 R Li CH3CH2 C + CuI CH CH2 - R+ Cu Li + R R CH3CH2 CH CH2 α,β-unsaturated aldehyde or ketone O R + X 2 R Li CH3CH2 2 Li - C CuI CH3CH2 C Li R - + Cu Li + LiBr + CH3CH2 CH3CH2 C C - C R C H H R - + Cu Li continued H C R C 83 H H O CH3CH2 RH - + H C+ CCu RLi CR H H O H CH3CH2 C LiI O CH CH2 CH3CH2 H H C C H H R - C R O CH O H R + H CH3CH2 O R C Product with alkyl group added at β position O LiI - H + + Cu Li H C H Formation of Gilman reagent + + Cu Li Gilman reagent R C H LiBr R O R C C Gilman reagent (lithium dialkylcuprate) O R H H C O R C H H C Resonance stabilized enolate ion CH3CH2 C CH C H H R - + Cu Li R - H C C R H H + H O CH3CH2 C H H C R C H H Product with alkyl group added at β position Gilman reagents (lithium dialkylcuprates) can be used to carry out nucleophilic addition upon α,β unsaturated carbonyl compounds, adding an alkyl group to the β-carbon. This is a useful reaction for organic synthesis. 84 Acid Halide Formation Carboxylic Acids and Derivatives O CH3CH2 O C + OH SOCl2 Carboxylic acid CH3CH2 Thionyl chloride O CH3CH2 C O OH Carboxylic acid + SOCl2 Thionyl chloride O CH3CH2 O CH3CH2 - Cl CH3CH2 O C O Cl O C O S Chlorosulfite + Cl - O S - Cl O CH3CH2 O C C Acid halide HCl O C O Cl Tetrahedral intermediate S Cl O S Cl CH3CH2 C Cl Acid halide Cl + SO2 + - Cl Thionyl chloride can be used to convert a carboxylic acid into an acid chloride. (Phosphorus tribromide will accomplish an analogous reaction, converting carboxylic acids to acid bromides.) The mechanism is composed of two successive nucleophilic acyl substitutions, the first substitution converting the carboxylic acid into the reactive chlorosulfite form, which is then attacked by chlorine anion, resulting in the formation of the acid chloride product. 85 Fischer Esterification Carboxylic Acids and Derivatives O R C OH H O + R C OH Carboxylic acid R R'OH Alcohol C C + O C R OH R OH + O H + O R C OH OH C R O R' + H H + O OR' Cl OH R' OH O R' + H Tetrahedral intermediate R R OR' C Ester O HCl Acid R Acid Alcohol Carboxylic acid O HCl R'OH + R C H OH C H O+ R'O O R O OH H OH H O+ H H H O OR' C C R'O H H R C OR' Ester + + H3O Fischer esterification involves the formation of an ester from a carboxylic acid and an alcohol. The mechanism is an acid promoted acyl substitution, which results in the substitution of an alkoxy group for the hydroxyl portion of the carboxyl group. (An alternate method of ester formation involves the use of the carboxylate anion as an SN2 nucleophile upon a primary alkyl halide.) 86 Use of Carboxylate Anion Nucleophile to form Esters O O CH3CH2 Carboxylic Acids and Derivatives C 1. NaOH OH CH3CH2 2. CH3Br Carboxylic acid C O O + CH3CH2 C OH Carboxylic acid - + CH3CH2 C O Na Carboxylate anion NaOH Base O O - + O Na Carboxylate anion CH3CH2 OCH3 Ester Base then Alkyl halide + C CH3Br Alkyl halide CH3CH2 C O + - H H2O H C Br H O CH3CH2 C + OCH3 NaBr Ester Titrating carboxylic acid with a strong base forms a carboxylate salt. The carboxylate anion can then serve as a nucleophile in an SN2 reaction upon a primary or secondary alkyl halide to form an ester. (Fischer esterification is often the choice over this SN2 process to form esters from carboxylic acids, especially if the alkoxy portion is tertiary.) 87 Hydrolysis of Acid Halides Carboxylic Acids and Derivatives O R O H2O C Water Cl R C OH Carboxylic acid Acid halide O O R C R C R Cl O Cl H Acid halide R H O O C H Cl OH2 + R C OH2 + + - Cl O C O+ H Cl Tetrahedral intermediate - O R C + H O Cl H O R C OH Carboxylic acid A typical acyl substitution reaction is the hydrolysis of acyl halides to form carboxylic acids. The progression among acyl derivatives from highest to lowest enthalpy (toward greatest stability) is as follows: acid chloride, acid anhydride, ester, amide, and finally carboxylic acid. Therefore, thermodynamics favors the hydrolysis of an acid halide. 88 Reaction of Acyl Halide with Ammonia or Amine O R Carboxylic Acids and Derivatives O + C 2 NH3 Cl Amide Acid halide NH2 Ammonium salt O O R C + R NH3 Cl C Amine R Cl H H H R O O C Cl R C NH3 + O R + C NH2 Amide HCl Acid O Cl C Tetrahedral N+ H H H intermediate N Acid halide + NH4 Cl + C R 2 equiv. amine NH3 + - O - + Cl Cl C R N + H H H O NH3 R Ammonia C NH2 Amide + NH4 Cl Ammonium salt + Among acyl derivatives, amides are next in stability to carboxylic acids, and both are more stable than acid halides. Just as water will easily hydrolyze an acid halide to form a carboxylic acid, ammonia will aminolyze an acid halide to form an amide. These types of reactions are characterized by the pattern of the electropositive acyl carbon accepting a pair of electrons from the nucleophile while shifting a bond pair over to oxygen, forming the tetrahedral intermediate. The amide product is formed after departure of the halide leaving group. The conjugate acid of the amide has formed, which is a stronger acid than hydrogen halide, so proton transfer occurs onto the halide ion. The amide product will therefore be accompanied by hydrogen halide. Thus two equivalents of ammonia are consumed in the reaction, one consumed in neutralizing the acidic hydrogen halide. 89 Esterification of Acid Halides Carboxylic Acids and Derivatives O R O C R'OH + Cl R Alcohol Acid halide C Ester OR' O O R'OH Alcohol + R C Cl Acid halide R R O C O - C O R' + H Cl Tetrahedral intermediate O C O R Cl O H R' Cl R O R' + H R C R' O + H R' O + H C - + Cl C OR' Ester + O Cl R HCl Because of their relative thermodynamic instability, acyl halides are good starting points for the formation of the whole array of carboxylic acid derivatives (carboxylic acids, amides, esters, or acid anhydrides). An alcohol, like water or ammonia, begins the reaction by donating an electron pair to the acyl carbon. An ester is formed when an alcohol performs as the nucleophile in an acyl substitution reaction. 90 Esterification of Acid Anhydrides O O O R Carboxylic Acids and Derivatives C R'OH + R C O R Alcohol Acid anhydride O O O R C O C Acid anhydride R R R'OH + C O C R O O C C O + OR' C C R Tetrahedral intermediate + O R' C R H H O R' + H O O O R' + H + O R' C R R - C O O O O R O H R' R R O Alcohol - OR' C Ester Cl - HCl Ester Acid anhydrides are somewhat unstable carboxylic acid derivatives. Like acyl halides, which are also unstable, acid anhydrides may be hydrolyzed, aminolyzed, or esterified through acyl substitution. 91 Saponification of Esters Carboxylic Acids and Derivatives - O R O OH C OR' Base C R O - + Carboxylate anion Ester O - O R C Ester R OH - Base OR' R C R OR' R'OH Alcohol OH O C OH OR' Tetrahedral intermediate O O O OR' C R OH C OH Carboxylic acid + - OR' Alkoxide anion R C O OR' H H O R C O - Carboxylate anion + R'OH Alcohol Refer to the order of stability among carboxylic acid derivatives to predict the ease of carrying out a given acyl transfer reaction. Among common derivatives, the acyl chloride form is the most unstable, followed in order by acid anhydride, ester, amide, and lastly carboxylate (or carboxylic acid), the most stable (lowest free energy). Reaction equilibrium favors the more stable form. For this reason it is a simple process to carry out the saponification of an ester by a strong base and transform the relatively unstable ester molecule into a carboxylate anion. The most common use of this reaction is the saponification of triglyceride to make soap. 92 Nitrile Hydrolysis Carboxylic Acids and Derivatives - O 1. OH R N C Nitrile + 2. H3O R R H2O Base C O N C R O N C N - O H C R - H R H - OH OH C N Nitrile OH Carboxylic acid Base then Acid R C O 1. OH + H 2. H3O C O R H R C C R OH- NH2 Amide H2O N R O N R C C - - O + + H3O NH3 O C R R N R Carboxylate anion + + H3O Acid Ammonia Tetrahedral intermediate - O NH2 R O HC C R H C - OH R - OH R Carboxylic acid NH3 NH2 C - N NH2 continued 93 H O H O NH2 C OH O - N O OH - NH2 C NH2 C O C H N O OH O O - C R O H + OH O R OH C C R NH2 - NH2 OH N R C R R NH2 O H H OH O RO R OH - H C C R H N O O H C C R - O OH O O - H C R N + - O - NH2 R Amine ion C NH2 O H O C OH R Carboxylic acid The electropositive nitrile carbon is similar to a carbonyl carbon in that it can accept the approach of a nucleophile for addition, although the overall process is significantly different with nitriles. Nitrile hydrolysis begins with the nucleophilic addition of hydroxide anion to the nitrile. The first intermediate formed then takes a proton from water and subsequently undergoes an intramolecular rearrangement to form an amide. This amide is temporary, however, in a strong base environment, becoming transformed through the acyl substitution hydrolysis to form the carboxylate anion. Nitrile Reduction Carboxylic Acids and Derivatives R C Nitrile N LiAlH4 Reducing agent R CH2 NH2 Amine Nitrile is a highly oxidized form, and it will mine the reducing agent, LiAlH4, for its hydrides (H–). The reduction of a nitrile produces an amine. 94 Hofmann Rearrangement Carboxylic Acids and Derivatives O C R Amide O C R N -N C OH, Br2 - + Br N - - OH OH, Br2 R H2O O R C -N C R H2O N H Br - R N C - C Br+ H+ N O O H O R C N H N H O H H - N O R C - + H O H C N H Br O R - N Br R C - N R + H O+ CH2O N-Alkyl isocyanate N Br R + O H2O O C R - Br C R N HN H O N C + H O H Betaine intermediate O R N H O H N-Alkylcarbamic acid C RN N H continued - C O R 95 + - Br R N + H O H O O C O O C H O R - CO2 - Br R OH N O - C + H CO O H R NH Br O R N H -R CC N+ H O Br O H R H N H Amine C R OH O R - OH O O H H N R H O H H2O CO2 + H R N Br N-Bromo amide Br O C H H N + C H R N Conjugate base of amide C Conjugate base of N-Bromo amide O Carbon dioxide O - O H N H C R CO2 + O H H N H Br R C - H H ON R Amine O R Halogen in OAqueous Base C H H N Halogen in Aqueous Base OH, Br2 C R R H2O - H H Amide O - OH, Br2 H H N H O C N R H CO2 + Carbon dioxide Hofmann rearrangement converts an amide, with the loss of one carbon, into an amine. Beginning with the amide, strong base, and halogen, the strong base ionizes the amide to form an amide anion. Amide anions have certain characteristics in common with the enolate anions, and halogenation occurs in manner similar to the α-halogenation of aldehydes and ketones. Halogenation enhances the acidity of the remaining hydrogen, which the base removes easily. To assist the task of retaining in memory the formidable Hofmann rearrangement mechanism, imagine the point of view of nitrogen atom at this point. In the bromoamide anion, nitrogen has one bond to a carbonyl carbon, which has the strong electronegative pull of oxygen working across it, and another bond to bromine, which also pulls tenaciously on electrons. From the point of view of nitrogen, these are two greedy neighbors. Intramolecular electron pair migrations occur to stabilize the entire system as an alkyl shift occurs from the carbonyl carbon onto nitrogen and the departure of halide ion. Isocyanate results, which contains a very electropositive carbon that draws the approach of a nucleophilic water molecule. This leads to N-alkylcarbamic acid, which is still unstable. Decarboxylization occurs as the last major step, releasing carbon dioxide to leave the final amine, with a new carbon-nitrogen bond. 96