Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020) Preview Organic Chemistry Reaction Mechanisms Coursebook by Youcef Abdessalem Hammou (2020)
Copyright © 2020 by Youcef Abdessalem Hammou All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, without written permission from the author youcefjosefred@hotmail.com giuseppeyoucef15@gmail.com Content I Solvents I Definition I Solvent Classification I Apolar Solvents I 2 Polar Solvents Protic Solvents Aprotic Solvents I II Solubility Reactants 10 II Substrate 10 II 1 Carbocation 11 Definition and Structure 11 Stability 11 II Carbanion 15 Definition and Structure 15 Stability 16 II Free-radical Carbon 18 Definition and Structure 18 Stability 19 II Carbene 20 Definition and Structure 20 Singlet Carbenes 20 Triplet Carbene 21 Stability 22 II Leaving Groups 24 II Nucleofuges 24 II 2 Electrofuges 26 II Nucleophiles 27 II Types of Nucleophiles 27 Neutral Nucleophiles 27 Charged Nucleophiles 27 II II III Nucleophilicity 28 Electrophiles 29 Reaction Mechanisms 30 III Substitution Reactions 30 III 1 Free-radical Substitution Reactions 30 Alkanes Halogenation 30 Allylic and Benzylic Halogenation 38 III Nucleophilic Substitution Reactions 43 Nucleophilic Aliphatic Substitution Reactions 43 Nucleophilic Aromatic Substitution Reactions 63 Nucleophilic Substitution of Carboxylic acids and their Derivatives 71 III Electrophilic Substitution Reactions 78 Electrophilic Aromatic Substitution Reactions SEAr 78 III Elimination Reactions 100 III α Elimination Reactions 100 Formation of Carbenes 100 III 2 β Elimination Reactions 101 Regiochemistry and Stereochemistry 105 Regiochemistry and Stereochemistry 112 III γ Elimination Reactions 116 Freund Reaction 116 III Competition between SN1, SN2, E1, and E2 117 III Addition Reactions 121 III Nucleophilic Addition Reactions 121 Nucleophilic Addition Reactions to Aldehydes and Ketones 121 III Electrophilic Addition Reactions 129 General mechanisms 129 Regeochemistry and Stereochemistry 129 Dihalogenation Reaction 129 Halogenation Reaction 135 Hypohalogenation Reaction 139 Hydrohalogenation Reaction 143 Acid Catalyzed Hydration 156 Oxymercuration-Demercuration Hydration 165 Hydroboration Oxidation 169 III Concerted Addition Reactions 174 Addition of Carbenes 174 Epoxidation 177 Hydrogenations Reaction 179 III 4 III Free-radical Addition Reaction 186 Oxidation Reactions 191 III Alkenes 191 Ozonolysis 191 Oxidation with Osmium tetroxide 192 Oxidation with Potassium Permanganate 194 Acid Catalyzed Oxidation of Peroxides 197 III Alcohols 199 Jones Oxidation 199 With K2Cr2O7 (Na2Cr2O7) ; H2SO4 201 Oxidation with Chromium-Based Reagents 202 Oxidation with Sodium Hypochlorite NaOCl 203 Swern Oxidation 208 III Reduction Reactions 210 III Reduction of Alkenes and Alkynes 210 III Reduction of Benzene 210 Catalytic Hydrogenation 210 Birch Reduction 211 III Reduction of Carbonyl Compounds 217 With NaBH4 and LiBH4 217 With LiAlH4 219 With DIBAL 223 Clemmensen Reduction (Aldehydes and Ketones) 224 Wolff–Kishner Reduction (Aldehydes and Ketones) 225 Rosenmund Reduction 227 Mozingo Reduction 227 Luche Reduction 228 IV Selection of Named Reactions 230 IV Grignard Reaction 230 IV Aldol Reaction 233 IV Michael Reaction 236 IV Knoevenagel Reaction 239 IV Claisen Reaction 242 IV Robinson Annulation 245 IV Diels-Alder Reaction 247 IV Beckmann Rearrangement 252 IV Wurtz Reaction 254 IV 10 Witting Reaction 256 I Solvents I Definition By definition, a solvent is a chemical substance that can be solid, liquid, or gas in which reactants “solutes” dissolve resulting in a miscible mixture known as “solution” Furthermore, the amount of a solute that can be dissolved in a specific volume of a solvent is subjected to several factor including temperature, pressure, and stirring As a result, we can distinguish four types of solutions: Diluted solutions that contain very low amount of solute Concentrated solutions that contain the maximum amount of solute that can be dissolved at standard conditions Saturated solutions contain more than the maximum amount of solute In this case, the solution is exposed to high temperature in order to dissolve more molecules of the solute Supersaturated solution, which contain more dissolved solute than required for a saturated solution This type of solutions can be prepared by heating a saturated solution while adding more solute, then cooling it gently I Solvent Classification In chemistry, solvents can be classified in several categories depending upon their chemical and physical properties For instance, they are divided into two classes “polar solvents, and apolar solvents” based on their polarity I Apolar Solvents The vast majority of organic solvents are considered apolar solvents; they have either a frail dipole-dipole moments “polarizable inert solvents”, or not at all “inert solvents” These solvents are mostly used when dissolving non-polar species I 2 Polar Solvents Polar solvents are chemical substances that exhibit dipole-dipole moments, in other word, they have a positive side, which represents the least electronegative atom(s), and a negative side where there is the most electronegative atom or group of at oms Moreover, polar solvent s are further subdivided into two sub -classes “protic, and aprotic” based on whether they can form intermolecular hydrogen bonds among themselves or not Protic Solvents Protic solvents are characterized by their ability to form intermolecular hydrogen bonds among themselves These solvents should therefore possess certain functional group such as OH, SH, or NH2 Protic solvents are also referred to as amphiprotic solvents due to their ability to donate or accept hydrogen prot on depending upon the medium in which they are The term amphoteric is derived from the Greek word ἀμφότεροι [amphoteroi], which means "both" while protic refers to protons H+ Aprotic Solvents Aprotic solvents, on the other hand, cannot fo rm intermolecular hydrogen bonds among themselves ; however, they can be hydrogen -bonds acceptors HBA , also known as protophilic solvents, such as THF, and DMF, or hydrogen-bonds donors HBD “protogenic” such as acetone I Solubility As the famous aphorism says “likes dissolve likes”, substances tend to dissolve in solvents that have similar polarity with them As a result, polar solutes d issolve in polar solvents whereas apolar solutes dissolve in non -polar solvents This phenomenon is called solvation and it can be explained through the intermolecular forces between solvent -solute molec ules and the change of entropy For polar compounds, dipole-dipole and ion -dipole forces and in case of protic solvent, hydrogen bonds facilitate the solvation of solute in the solvent Dissolution of polar solutes in polar solvents On the other hand, apolar compounds dissolve in apolar solvents due to the entropy change since these substances have only frail London forces, which are too weak to form a solution alone Dissolution of apolar solutes in apolar solvents II Nucleophilicity The term nucleophilicity describes the strength of a nucleophile The more available the elec trons, the stronger the nucleophilic In general, nucleophilicity depends upon four factors: Charge Anionic nucleophiles are always stronger than their neutral forms H2O < HO H3N < H2N MeSH < MeS Electronegativity If the nucleophiles belong to the same row of the periodic table, n decreases with the electronegativity of the nucleophilic atom ucleophilicity F < HO < H2N < H3C Cl < HS < H2P Solvent The strength of nucleophiles varies depending upon the solvent in which they are In a protic solvent, nucleophilicity increases with basicity The stronger the congregate base, the stronger the nucleophile F < Cl < Br< I On the other hand, in aprotic solvents, nucleophilicity increases with electronegativity of the nucleophilic atom I < Br < Cl< F Steric hindrance Nucleophilicity decreases with the steric hindrance 28 II Electrophiles Electrophiles are chemical species with a vacant orbital; this property make them susceptible of accepting an electron pair from another species with high electron density and form a covalent bond with them Since they are electron acceptors, electrophiles are considered to be Lewis acids where most of them are positively charged Nu : Nucleophile E : Electrophile LG : Leaving Group, nucleofuge 29 III Reaction Mechanisms III Substitution Reactions In organic chemistry, substitution reactions are reactions where substituents get replaced by other species These re actions are categorized into three main classes depending upon the reaction conditions and reagents involved Free-radical substitution reactions Nucleophilic substitution reactions Electrophilic substitution reactions III 1 Free-radical Substitution Reactions Free radical substitution is a chemical reaction that involves free radical species in which one or more hydrogen atoms of an organic compound are re placed by another species This reaction occurs under the influence of UV light, significant amount of heat energy, or radical initiators Halogenation of hydrocarbons is one of the most important reactions in organic chemistry, it is performed via free radical substitution and it is characterized by three steps; initiation, propagation, and termination Alkanes Halogenation Alkanes are saturated hydrocarbons that contain only carbon and hydrogen atoms connected together with single covalent bonds In general, these compounds are considered unreactive since they lack reactive functional groups or unsaturation Nevertheless, alkanes can undergo some reactions such as combustion "destruction of alkanes”, pyrolysis “cracking”, reactions with magic acids such as HF-SbF5 and FSO3H-SbF5, and free radical halogenation This latter is the most commonly used reaction and it consists in transforming the unreactive alkane into a more reactive substance “alkyl halides, alkyl dihalides, alkyl trihalides, and alkyl tetrahalides Mechanism Free radical halogenation of alkanes is a chain reaction that passes through three stages Initiation The first step of halogenation requires UV li ght or sufficient heat energy in order to generate free radical halogens from dihalogen molecules However, once free radicals are formed, the reaction is self -sustaining and UV light or heat are no longer necessary For example, when UV light radiation penetrates dichlorine molecule, the covalent bond connecting the two chlorine atoms breaks in such a 30 way where each chlorine atom would carry away one unshared electron This process creates, as a result, two free radicals of chlorine Propagation The next step is called propagation where free radical halogens formed in the first step react with the substrate “methane” At this point, two types of reactions might occur; the first one is the reaction of chlorine free radical with methane in which chlorine grabs one hydrogen atom from methane resulting in the formation of two new species; hydrogen chloride and methyl free radical The second reaction proceeds in a similar way but in this case with the methyl free radical and another molecule of dichlorine, which produces a chloromethane molecule and a new chlorine free radical Termination In the final step, free radicals combine and form new molecules In this case, either two chlorine free radicals combine to give dichlorine, a chlorine free radical combines with alkyl radical, or two alkyl radicals combine to form a higher alkane 31 Control of Free Radical Halogenation Free radical halogenation of alkanes does not usually stop at one substitution If it is not controlled, a mixture of all potential products would be obtained For example, chloromethane can undergo further subs titution reaction and produces dichloromethane Similarly, dichloromethane can also reacts with other dichlorine molecules and form chloroform then carbon tetrachloride Moreover, free radical carbon species can also react with one another to form new CC covalent bonds This phenomenon happens because as more methane molecules turn into methyl chloride, the concentration of methane decreases and as a result, methyl chloride molecules produced would compete with the remaining methane molecules In this case, chlorine free radicals are more likely to react with methyl chloride and form dichloromethane than to react with methane The diagram below demonstrate how the concentration of methane affects the probability of further halogenations 32 Note: T his diagram is only to visualize the probability of dichlorination of methane in 1:1 ratio In order to maximize the amount of the desired product, specific procedure can be applied, which restrict further halogenation For example, using excess amount of methane at the course of the reaction would increase methyl chloride yielding as the probability of further chlorination of methyl chloride gets low er In addition, since haloalkanes have different physical properties than alkanes, it may bepossible to separate the products fr om th e reaction medium through distillation or other separation methods Relative Reactivity and Selectivity of Halogens Although both of bromine and chlorine undergo free radical halogenation, they not behave in the sa me way and give different yields f or the same products This differentiation is related to the relative selectivity of each hal ogen For instance, methane reacts with bromine in a similar way to chlorine and produces bromomethane, methylene bromide, bromoform, and carbon tetrabromide 33 However, in contrast to chlorination, bromination is a slower reaction due to stability of free radical bromine, which is maintained bythe bromine polarizability As a result , more energy mu st be provided to bromine in order to surpass the activation energy barrier and generate bromine free radicals The diagrams below illustrates the difference between chlorination and bromination of methane The activation energy of chlorination is smaller than the activation energy of bromination In addition, chlorinat ion of alkanes is an exothermic reaction where the products are more stable than the starting material In contrast, bromination is an endothermic reaction that requires more energy in order to proceed 34 Unlike bromine and chlorine, fluorine reacts vigorously with methane that even in the dark and at room temperature, fluorination must be carefully controlled Th e reason behind this is that fluorine has a higher reactivity than all the other halogens due to its higher electronegativity and small size Iodine, on the other hand, does not react with methane because of its higher stability Selectivity F Cl Br I Reactivity When performing a halogenation reaction, different products may be obtained with different yields This depends upon the selectivity of the halogen involved and the number of available hydrogen atomsthat can be replaced Reactivity and selectivity are inversely proportional, the more reactive a reagent, the less selective Bromine has a higher selectivity than chlorine As result, it tends to add to the most substituted carbon atom In contrast, chlorine is less selective that all potential products are produced with significant amount In theory, it is possible to predict the yield of all possible isomers using the following formula: Pi % = 100 n Hi R i ∑i n Hi R i Pi: Yield of product i Nhi: Number of hydrogen atoms of type i Ri: Reactivity factor for type i i: Sum of all types Table : Reactivity factors for chlorine and bromine Hydrogen Primary H Secondary H Tertiary H Cl 3.9 5.2 Br 82 1640 35 Example Comparison between dimethylcyclopentane monochlorination and monobromination of Dimethylcyclopentane is a symmetrical molecule that contains6 primary hydrogen atoms, secondary hydrogen atoms, and tertiary hydrogen atoms At the propagation step, a hydrogen atom would be abstracted from the substrate, which leads to the formation of a radical carbon intermediate In this case, there would be three potential radical carbon intermediate where the most stable is the one formed when abstracting a tertiary hydrogen atom On the other hand, primary radical carbon intermedia te are the least stable and ther efore, the probability of chlorine to add on this carbon is the lowest For primary hydrogens Pi % = 100 61 = 3.35% 61 + 63.9 + 25.2 For secondary hydrogens Pi % = 100 63.9 = 41.34 % 61 + 63.9 + 25.2 For tertiary hydrogens Pi % = 100 25.2 = 55.12 % 61 + 63.9 + 25.2 36 Products 1-(chloromethyl)-3-methylcyclopentane Yield: 3.35 % 2-chloro-1,3dimethylcyclopentane (1R)-1-chloro-2,4dimethylcyclopentane (1S)-1-chloro-2,4dimethylcyclopentane Yield: 41.34 % (1S)-1-chloro-1,3dimethylcyclopentane (1R)-1-chloro-1,3dimethylcyclopentane Yield: 55.12 % Notice that both stereoisomers form when the halogen adds to a chiral carbon The reason behind this is that free radical carbons have a planar geometry, which permits the addition of halogens on either sides and therefore, both stereoisomers may form In case of monobromination, -bromo-1,3-dimethylcyclopentane would predominate over the other isomers (95.21%) since bromine preferentially adds to the most substituted free radical carbon The other products might be observed but they would have an insignificant yields “0.019% and 4.46%.” 37 Products 1-(bromomethyl)-3-methylcyclopentane Yield: 0.019 % 2-bromo-1,3dimethylcyclopentane (1R)-1-bromo-2,4dimethylcyclopentane (1S)-1-bromo-2,4dimethylcyclopentane Yield: 4.76 % (1S)-1-bromo-1,3dimethylcyclopentane (1R)-1-bromo-1,3dimethylcyclopentane Yield: 95.21 % Allylic and Benzylic Halogenation Unlike saturated hydrocarbons, allylic compounds may follow different pathways depending upon reaction conditions At high concentration of halogens, allylic compounds undergo electrophilic addition (page 132) rather than free radical substitution reaction However, when the concentration of halogens is controlled and kept low, free radical s ubstitution reaction takes place whereby the allylic hydrogen atom gets replaced by the halogen 38 Allylic positions Benzylic position N-halosuccinimides are halogen source reagents typically used in allylic and benzylic halogenation reactions in order to avoid electrophilic addition to the double bond In this reaction, a stoichiometric amount of N-halosuccinimide is required along with a small amount of the corresponding hydrogen halide to produce a low concentration of the corresponding dihalide making free radical substitution reaction possible 39 NCS N-Chlorosuccinimide NBS N-Bromosuccinimide NIS N-Iodosuccinimide Mechanism Allylic bromination reaction is also known as Wohl-Ziegler reaction, which consists in converting olefins into olefin bromide s The reac tion mechanism is similar to regular alkanes halogenation except that Wohl-Ziegler reaction requires NBS to keep bromine concentration adequate for allylic substitution Production of dibromine This is a reversible reaction where NBS reacts with HBr to produce dibromine and succinimide This process is repeated whenever new HBr is available Initiation Under UV light or at high temperature, the dibromine formed would bromine free radicals upon homolytic fission of the covalent bond give two 40 Propagation and Termination When free radical carbon forms on the allylic position, resonance becomes possible and as a result, bromine can add on either radical allylic carbon atoms Moreover, although this reaction may produce four compounds , only one product would be predominant over the others because bromine preferentially adds to the most substituted allylic radical 41 Under UV radiation, at high temperature, or with radical initiators, benzylic compounds undergo free radical substitution reactions on the benzylic position when they are treated with NCS and HCl in CCl4 Nevertheless, this reaction is also possible with Cl2 and UV light 42 ... Leaving Group, nucleofuge 29 III Reaction Mechanisms III Substitution Reactions In organic chemistry, substitution reactions are reactions where substituents get replaced by other species These re actions... 2 β Elimination Reactions 101 Regiochemistry and Stereochemistry 105 Regiochemistry and Stereochemistry 112 III γ Elimination Reactions 116 Freund Reaction 116... Selection of Named Reactions 230 IV Grignard Reaction 230 IV Aldol Reaction 233 IV Michael Reaction 236 IV Knoevenagel Reaction 239 IV Claisen Reaction