Organic Chemistry I Lecture 8 PDF

Organic Chemistry I By: Dr. Haider Sultani Martin-Luther-University Halle- Wittenberg (MLU) Saxony-Anhalt-Germany First stage, 2nd Semester 23.06.2024 Lecture 8 Dr. Haider Sultani  CHAPTER 4: Organic Halogen Compounds I....

Organic Chemistry I By: Dr. Haider Sultani Martin-Luther-University Halle- Wittenberg (MLU) Saxony-Anhalt-Germany First stage, 2nd Semester 23.06.2024 Lecture 8 Dr. Haider Sultani  CHAPTER 4: Organic Halogen Compounds I. Nucleophilic Substitution  In reactions of this type, one covalent bond is broken, and a new covalent bond is formed:  Alkyl halides undergo nucleophilic substitution reactions, in which a nucleophile displaces the halide leaving group from the alkyl halide substrate.  In this example, the carbon–bromine bond is broken and the carbon–oxygen bond is formed. The leaving group (bromide) takes with it both of the electrons from the carbon– bromine bond, and the nucleophile (hydroxide ion) supplies both electrons for the new carbon–oxygen bond. 22 June 2024 https://albayan.edu.iq/en/ Slide 5 CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions  nucleophilic substitution reaction: 22 June 2024 https://albayan.edu.iq/en/ Slide 6 CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions  The most common nucleophiles are oxygen, nitrogen, sulfur, halogen, and carbon nucleophiles. CH3CH2OCH3 CH3CH2OH+HBr 22 June 2024 https://albayan.edu.iq/en/ Slide 7 CHAPTER 4: Organic Halogen Compounds Oxidation‫كجس‬ ‫اذا قل او زاد ابالو ني او اهلاديروجني‬  Examples of Nucleophilic Substitutions  The most common nucleophiles are oxygen, nitrogen, sulfur, halogen, and carbon nucleophiles. 22 June 2024 https://albayan.edu.iq/en/ Slide 8  CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions  The most common nucleophiles are oxygen, nitrogen, sulfur, halogen, and carbon nucleophiles. 22 June 2024 https://albayan.edu.iq/en/ Slide 9  CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions 1. Reaction of sodium ethoxide with bromoethane  Notice that the counterion of the nucleophile, Na+, is merely a spectator during the reaction. It is present at the beginning and end of the 2. Synthesis of propyl cyanide reaction.  Sodium cyanide or potassium cyanide can be used to supply the nucleophile 22 June 2024 https://albayan.edu.iq/en/ Slide 10  CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions 3. Show how 1-butyne could be converted to 3-hexyne Strong ‫يحتاج‬ Weak  Remember that acetylides react with alkyl halides to give acetylenes. We therefore need to convert 1-butyne to an acetylide. 22 June 2024 https://albayan.edu.iq/en/ Slide 11  CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions-limitations  The substitution reactions have some limitations with respect to the structure of the R group in the alkyl halide. For example, these are reactions ‫افتلاعل متيم هنايئا‬ of alkyl halides (halogen bonded to sp3-hybridized carbon). Aryl halides and vinyl halides, in which the halogen is bonded to sp2-hybridized carbon, do not undergo this type of nucleophilic substitution reaction. Another important limitation often occurs when the nucleophile is an anion or a base or both. 22 June 2024 https://albayan.edu.iq/en/ Slide 12  CHAPTER 4: Organic Halogen Compounds  Examples of Nucleophilic Substitutions-limitations H2o Weak ‫ما اضيفه للتفاعل‬  To understand these differences, we must consider the mechanisms by which the substitutions in take place. 22 June 2024 https://albayan.edu.iq/en/ Slide 13  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms  There are two main nucleophilic substitution mechanisms. These are described by the symbols SN2 and SN1, respectively. The SN part of each symbol stands for “substitution, nucleophilic.” A. The SN2 Mechanism  The SN2 mechanism is a one-step process in which the bond to the leaving group begins to break as the bond to the nucleophile begins to form.  The number 2 is used in describing this mechanism because the reaction is bimolecular. That is, two molecules—the nucleophile and the substrate—are involved in the key step (the only step) in the reaction mechanism. 22 June 2024 https://albayan.edu.iq/en/ Slide 14  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms I. The rate of the reaction depends on both the nucleophile and the substrate concentrations. II. Every SN2 displacement occurs with inversion of configuration. For example, if we treat (R)-2- bromobutane with sodium hydroxide, we obtain (S)-2-butanol. 22 June 2024 https://albayan.edu.iq/en/ Slide 15  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms III. The reaction is fastest when the alkyl group of the substrate is methyl or primary and slowest when it is tertiary. Secondary alkyl halides react at an intermediate rate.  To summarize, the SN2 mechanism is a one-step process favored for methyl and primary halides. It occurs more slowly with secondary halides and usually not at all with tertiary halides. An SN2 reaction occurs with inversion of configuration, and its rate depends on the concentration of both the nucleophile and the substrate (the alkyl halide). cis-4-methylcyclohexyl bromide trans-4-Methylcyclohexane-1-carbonitrile 22 June 2024 https://albayan.edu.iq/en/ Slide 16  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  The SN1 mechanism is a two-step process. In the first step, which is slow, the bond between the carbon and the leaving group breaks as the substrate dissociates (ionizes). The electrons of the C-L bond go with the leaving group, and a carbocation is formed.  In the second step, which is fast, the carbocation combines with the nucleophile to give the product. 22 June 2024 https://albayan.edu.iq/en/ Slide 17  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  When the nucleophile is a neutral molecule, such as water or an alcohol, loss of a proton from the nucleophilic oxygen, in a third step, gives the final product. 22 June 2024 https://albayan.edu.iq/en/ Slide 18  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  How can we recognize when a particular nucleophile and substrate react by the SN1 mechanism? Here are the signs 1. The rate of the reaction does not depend on the concentration of the nucleophile. The first step is rate- determining, and the nucleophile is not involved in this step. 2. If the carbon bearing the leaving group is stereogenic, the reaction occurs mainly with loss of optical activity (that is, with racemization).  In carbocations, only three groups are attached to the positively charged carbon. Therefore, the positively charged carbon is sp2-hybridized and planar the nucleophile can react at either “face” of the carbocation to give a 50:50 mixture of two enantiomers, a racemic mixture, an example is shown in next slide. 22 June 2024 https://albayan.edu.iq/en/ Slide 19  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  (R)-3-bromo-3-methylhexane with water gives the racemic alcohol. 3. The reaction is fastest when the alkyl group of the substrate is tertiary and slowest when it is primary. The reason is that SN1 reactions proceed via carbocations, so the reactivity order corresponds to that of carbocation stability (3° > 2° > 1°). 22 June 2024 https://albayan.edu.iq/en/ Slide 20  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  That is, the easier it is to form the carbocation, the faster the reaction will proceed. For this reason, SN1 reactivity is also favored for resonance-stabilized carbocations, such as allylic carbocations. Likewise, SN1 reactivity is disfavored for aryl and vinyl halides because aryl and vinyl carbocations are unstable and not easily formed (see next slide).  To summarize, the SN1 mechanism is a two-step process and is favored when the alkyl halide is tertiary. Primary halides normally do not react by this mechanism. The SN1 process occurs with racemization, and its rate is independent of the nucleophile’s concentration. 22 June 2024 https://albayan.edu.iq/en/ Slide 21  CHAPTER 4: Organic Halogen Compounds  Nucleophilic Substitution Mechanisms B. The SN1 Mechanism  Likewise, SN1 reactivity is disfavored for aryl and vinyl halides because aryl and vinyl carbocations are unstable and not easily formed. 22 June 2024 https://albayan.edu.iq/en/ Slide 22 CHAPTER 4: Organic Halogen Compounds The SN1 and SN2 Mechanisms Compared 22 June 2024 https://albayan.edu.iq/en/ Slide 23 CHAPTER 4: Organic Halogen Compounds The SN1 and SN2 Mechanisms Compared  Primary halides almost always react by the SN2 mechanism, whereas tertiary halides react by the SN1 mechanism. Only with secondary halides are we likely to encounter both possibilities.  One experimental variable that we can use to help control the mechanism is the solvent polarity. Water and alcohols are polar protic solvents (protic because of the proton-donating ability of the hydroxyl groups).  The first step of the SN1 mechanism involves the formation of ions. Since polar solvents can solvate ions, the rate of SN1 processes is enhanced by polar solvents. On the other hand, solvation of nucleophiles ties up their unshared electron pairs. Therefore, SN2 reactions, whose rates depend on nucleophile effectiveness, are usually retarded by polar protic solvents. Polar but aprotic solvents [examples are acetone, dimethyl sulfoxide, (CH3)2S=O, or dimethylformamide, (CH3)2NCHO] solvate cations preferentially. These solvents accelerate SN2 reactions because, by solvating the cation (say, K+ in K+ -CN), they leave the anion more “naked” or unsolvated, thus improving its nucleophilicity. 22 June 2024 https://albayan.edu.iq/en/ Slide 24  CHAPTER 4: Organic Halogen Compounds Electro positive Nuclephile  The rate of an SN2 reaction (but not an SN1 reaction) depends on the nucleophile. If the nucleophile is strong, the SN2 mechanism will be favored. How can we tell whether a nucleophile is strong or weak, or whether one nucleophile is stronger than another? Here are a few useful generalizations. 1. Negative ions are more nucleophilic, or better electron suppliers, than the corresponding neutral molecules. Thus, 2. Elements low in the periodic table tend to be more nucleophilic than elements above them in the same column. Thus 3. Across a row in the periodic table, more electronegative elements (that is, the more tightly an element holds electrons to itself) tend to be less nucleophilic. Thus 22 June 2024 https://albayan.edu.iq/en/ Slide 25 CHAPTER 4: Organic Halogen Compounds 22 June 2024 https://albayan.edu.iq/en/ Slide 26 CHAPTER 4: Organic Halogen Compounds Substitution and Elimination in Competition  Now we can consider how substitution and elimination reactions compete with one another. Let us consider the options for each class of alkyl halide: i. Tertiary Halides  Substitution can only occur by the SN1 mechanism, but elimination can occur by either the E1 (weak base/weak nucleophile) or the E2 (with strong base) mechanism. With weak nucleophiles and polar solvents, the SN1 and E1 mechanisms compete with each other. For example; 22 June 2024 https://albayan.edu.iq/en/ Slide 30 CHAPTER 4: Organic Halogen Compounds Substitution and Elimination in Competition i. Tertiary Halides  If we use a strong nucleophile (which can act as a base) instead of a weak one, and if we use a less polar solvent, we favor elimination by the E2 mechanism. Thus, with OH− or CN− as nucleophiles, only elimination occurs, and the exclusive product is the alkene  Because the tertiary carbon is too hindered sterically for SN2 attack, substitution does not compete with elimination. 22 June 2024 https://albayan.edu.iq/en/ Slide 31 CHAPTER 4: Organic Halogen Compounds Substitution and Elimination in Competition iii. Secondary Halides 22 June 2024 https://albayan.edu.iq/en/ Slide 34 CHAPTER 4: Organic Halogen Compounds Examples  Predict the product of the reaction of 1-bromo-1-methylcyclohexane with the following conditions: a. sodium ethoxide in ethanol. b. refluxing ethanol a. The first set of conditions favors the E2 process, because sodium ethoxide is a strong base, two elimination products are possible, depending on whether the base attacks a hydrogen on an adjacent CH2 or CH3 group 22 June 2024 https://albayan.edu.iq/en/ Slide 35 CHAPTER 4: Organic Halogen Compounds Examples  Predict the product of the reaction of 1-bromo-1-methylcyclohexane with the following conditions: a. sodium ethoxide in ethanol. b. refluxing ethanol b. This set of conditions favors ionization, because the ethanol is neutral (hence a weak nucleophile) and, as a solvent, fairly polar. The SN1 process predominates, and the main product is the ether.  Some of the above alkenes will also be formed by the E1 mechanism 22 June 2024 https://albayan.edu.iq/en/ Slide 36