Vollhardt Capítulo 8 (Álcoois)
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o h o l s CHEMICAL HIGHLIGHT 8-3 Transition Metal-Catalyzed Cross-Coupling Reactions The general coupling reaction of a haloalkane, containing a positively polarized carbon, with an alkylmetal, containing a negatively polarized carbon, is quite exothermic. \ufffd \ufffdR \ufffd\ufffd M \ufffd\ufffd R\ufffd \ufffd\ufffd X \ufffd\ufffd O O R MXR\ufffdO Yet, in the case of Li and Mg, such couplings are either too slow at room temperature or lead to product mixtures on heating. As this process constitutes one of the most fundamental C \u2013 C bond-forming reactions, it is not surpris- ing that synthetic chemists have devoted considerable effort to the solution of the problem, an effort that is ongoing. An early solution was provided by copper salts as catalysts. Catalysts enable reactions to proceed faster, through lower-energy transition states and mechanisms (Section 3-3). The method has been applied on an industrial scale in the manufacture of muscalure, the sex attractant of the housefl y. In conjunction with a toxic ingredient, it is \ufffd CH3(CH2)5CH2MgCl CH3(CH2)8OCH2CH3O Br 5% CuI \ufffd MgBrCl 82% \ufffd H H CuI \ufffd MgBr2 CH3(CH2)7 CH3(CH2)3CH2MgBr(CH2)7CH2Br H H CH3(CH2)7 (CH2)12CH3 Muscalure 80% used for pest control, particularly in poultry, swine, beef and dairy cattle facilities, and stables (see also Section 12-17). The mechanism of these reactions proceeds through organo- copper species, also called cuprates (see Section 18-10), which can be generated and used stoichiometrically, for example, from alkyllithium reagents. Fatal attraction to muscalure spells doom to the common house\ufb02 y. Let us begin with a few examples in which we predict reactivity on mechanistic grounds. Then we shall turn to synthesis \u2014 the making of molecules. How do chemists develop new synthetic methods, and how can we make a \u201ctarget\u201d molecule as effi ciently as possible? The two topics are closely related. The second, known as total synthesis, usually requires a series of reactions. In studying these tasks, therefore, we will also be reviewing much of the reaction chemistry that we have considered so far. Mechanisms help in predicting the outcome of a reaction First, recall how we predict the outcome of a reaction. What are the factors that let a par- ticular mechanism go forward? Here are three examples. How to Predict the Outcome of a Reaction on Mechanistic Grounds Example 1. What happens when you add I2 to FCH2CH2CH2Br? ICH2CH2CH2Br Not formed FCH2CH2CH2Br FCH2CH2CH2I I\ufffd I\ufffd Explanation. Bromide is a better leaving group than fl uoride. tarik Highlight C h a p t e r 8 311 Example 2. How does a Grignard reagent add to a carbonyl group? A A CH3CMgBr CH3MgBr\ufffdC OOCH3 H A A CH3CCH3 OMgBr \ufffd\ufffd H Not formed (CH3CH2)2O H3C H (CH3CH2)2OB HE \ufffd\ufffd \ufffd\ufffd\ufffd\ufffd \ufffd\ufffd Explanation. The positively polarized carbonyl carbon forms a bond to the negatively polarized alkyl group of the organometallic reagent. Example 3. What is the product of the radical bromination of methylcyclohexane? \ufffd Not formed Br2, hv CH3 H3CCH3 CH2Br Br Br2, hv Br \ufffdOther bromides More recently, a number of variations on this theme have been explored, employing M 5 Zn, Sn, Al, and others, in the presence of catalysts based on Ni, Pd, Fe, and Rh, just to name a few. The aim is to improve not only effi ciency, but also functional group tolerance. For example, unlike alkyllithium and Grignard reagents, the corresponding Zn compounds do not attack carbonyl functions. \ufffd O Ni catalyst 52% O I ZnI \ufffd Ni catalyst 62% O O O OI BrZn 2 CH3CH2CH2CH2Li 1 CuI ¡ (CH3CH2CH2CH2)2CuLi 1 LiI Lithium dibutylcuprate \ufffd 3 (CH3CH2CH2CH2)2CuLiCH3S O O CH3OCH2CH2O CH3O(CH2)5CH3 90% In these cases, the mechanism is not direct nucleophilic substitution, but rather assembly of the two fragments of R and R9 around the catalyst, as schematized in a simplifi ed manner below. R \ufffd Ni R\ufffdZnX \ufffd ZnX2 XO R Ni NiXO O R \ufffd Ni RO O R\ufffdR\ufffd O The development of transition metal \u2013 catalyzed C \u2013 C bond- forming reactions has seen an explosive growth during the past decade, and widely used methods employing metals in the coupling to alkenes and alkynes will be discussed in Chemical Highlights 12-4 and 13-1, and in Sections 13-9, 18-10, and 20-2. 8 - 9 S t r a t e g i e s t o C o m p l e x A l c o h o l s tarik Highlight 312 C h a p t e r 8 H y d r o x y F u n c t i o n a l G r o u p : A l c o h o l s Explanation. The tertiary C \u2013 H bond is weaker than a primary or secondary C \u2013 H bond, and Br2 is quite selective in radical halogenations. New reactions lead to new synthetic methods New reactions are found by design or by accident. For example, consider how two different students might discover the reactivity of a Grignard reagent with a ketone to give an alco- hol. The fi rst student, knowing about electronegativity and the electronic makeup of ketones, would predict that the nucleophilic alkyl group of the Grignard species should attach itself to the electrophilic carbonyl carbon. This student would be pleased by the successful out- come of the experiment, verifying chemical principles in practice. The second student, with less knowledge, might attempt to dilute a particularly concentrated solution of a Grignard reagent with what one might conceive to be a perfectly good polar solvent: acetone. A violent reaction would immediately reveal that this notion is incorrect, and further investi- gation would uncover the powerful potential of the reagent in alcohol synthesis. Exercise 8-17 Working with the Concepts: Using Mechanistic Knowledge to Predict the Outcome of a Reaction Predict and explain the outcome of the following reaction on mechanistic grounds. ClCH2CH2CH2C(CH3)2 CH2Cl NaOH H2O \ufffd A Strategy The fi rst step is to identify the functional sites in the two starting materials. Then you can list the possible modes of reactivity for these functional groups and sort out which ones best apply. Solution \u2022 The organic component is a dihaloalkane. Hence, it contains two reaction sites that might be subject to the chemistry described in Chapters 6 and 7: SN2, SN1, E2, and E1. \u2022 The inorganic NaOH is a strong unhindered base and nucleophile. Inspection of Table 7-4 reveals that hydroxide attacks haloalkanes at primary centers to make alcohols by SN2, but forms alkenes at more hindered (to nucleophilic attack) positions by E2. \u2022 Turning to the haloalkane, one Cl resides at an unhindered primary center; it should be replaced by OH through SN2. The second Cl is also bound to a primary carbon; however, it is sterically hindered by b branching. Such steric hindrance retards nucleophilic attack, resulting in favorable E2, but only in cases in which a b hydrogen is available for deprotonation. In the present case, the carbon is neopentyl-like and E2 is not possible. Therefore, no reaction occurs at this center. Consequently, the product is HO Cl Exercise 8-18 Try It Yourself Predict and explain the outcome of the following reactions on mechanistic grounds. (a) ClCH2CH2CH2C(CH3)2 CH3CH2OH Br \ufffd A (b) HOCH2CH2CH2C(CH3)2 OH PCC, CH2Cl2A tarik Highlight C h a p t e r 8 313 When a reaction has been discovered, it is important to show its scope and its limita- tions. For this purpose, many different substrates are tested, side products (if any) noted, new functional groups subjected to the reaction conditions, and mechanistic studies carried out. Should these investigations prove the new reaction to be generally applicable, it is added as a new synthetic method to the organic chemist\u2019s arsenal. Because a reaction leads to a very specifi c change in a molecule, it is frequently useful to emphasize the general nature of this \u201cmolecular alteration.\u201d A simple example is the addi- tion of a Grignard or alkyllithium reagent to formaldehyde. What is the structural change in this transformation? A one-carbon unit is added to an alkyl group. The method is valuable because it allows a straightforward one-carbon extension, also called a homologation.