Chapter 12- Alcohols from Carbonyl Compounds, Redox Reactions and Organometallic Compounds

Carbonyl Compounds Carbonyl Compounds are a broad group of compounds that include aldehydes, ketones, carboxylic acids, and esters Examples We will cover each of this in more detail in later chapters Here, we will only be concerned with how they can be converted to alcohols.

Structure of the Carbonyl Group The carbon-oxygen double consists of a sigma bond and a pi bond. The strongly electronegative oxygen attracts the electrons of Both the bonds This causes both bonds to be polarized This leaves the carbon with a substantial partial positive charge and the oxygen with a substantial partial negative charge We can demonstrate this with resonance Structures

Structure of the Carbonyl Group This substantial partial positive charge leaves the carbon very electrophilic and susceptible to nucleophilic attack. When the nucleophile attacks the carbonyl carbon by attacking with its electrons, the double bond to the oxygen opens, transferring the pi electrons to the Oxygen When this happens, the carbonyl carbon is transformed from an sp 2, trigonal planar carbon, to an sp 3, tetrahedral carbon Example:

Important Nucleophiles Two important nucleophiles that add to carbonyls are: – Hydride ions: H -, typically from sodium borohydride or lithium aluminum hydride; and – Carbanion like reagents: from organolithium and grignard reagents

Oxidation-Reduction Reactions Another related set of reactions are reactions in which alcohols and carbonyls are oxidized or reduced. Example Reduction reaction: any reaction in which the number of C-O bonds is decreased and/or the number of C-H bonds is increased Oxidation reaction: any reaction in which the number of C-O bonds is increased and/or the number of C-H bonds is decreased

Reduction Examples [H] is a generic symbol for a reduction. It is used to write a general reaction without specifying what the reducing reagent is.

Oxidation Examples Basically the reverse of the reduction examples [O] is a generic symbol for an oxidation. It is used to write a general reaction without specifying what the oxidizing reagent is.

Synthesis of Alcohols by Reduction of Carbonyls Primary and Secondary alcohols can be synthesized by the reduction of a variety of compounds that contain carbonyls Carboxylic acids, esters, and aldehydes call all be reduced to a primary alcohol Ketones are reduced to a secondary alcohol

Synthesis of Alcohols by Reduction of Carbonyls Reductions of carboxylic acids are the most difficult, but they can be reduced with a very powerful reducing agent, Lithium Aluminum Hydride, LAH, LiAlH 4 When followed by acid and water, carboxylic acids are reduced to primary alcohols in excellent yields Example:

Synthesis of Alcohols by Reduction of Carbonyls Esters are also difficult and require LAH. Ex On an industrial scale, esters are reduced with hydrogen gas at very high pressure Ex

Synthesis of Alcohols by Reduction of Carbonyls Aldehydes and Ketones are much easier to reduce. They can be reduced by: – H 2 / M (Pt, Pd, Ni) – Na in alcohol – LAH The reagent most used, however, is Sodium Borohydride, NaBH 4 Ex.

Synthesis of Alcohols by Reduction of Carbonyls The key step in the reduction of a carbonyl compound by either LAH or NaBH 4 is the transfer of a hydride ion from the metal to the carbonyl carbon. Mechanism:

LAH vs NaBH 4 Sodium Borohydride is much less powerful as a reducing agent than LAH While LAH will reduce all carbonyl compounds, NaBH 4 will only reduce aldehydes and ketones. Ex.

Oxidation of Primary Alcohols Primary alcohols can be oxidized to both aldehydes and carboxylic acids Ex. The oxidation of the aldehyde to the carboxylic acid is actually easier, thus it is difficult to stop the oxidation at the aldehyde stage Special conditions must be used to prepare aldehydes from primary alcohols.

Oxidation of Primary Alcohols A variety of reagents are available for these oxidations One of the most used is pyridinium chlorochromate (PCC) It is prepared by mixing CrO 3 with HCl, then treating with pyridine

Oxidation of Primary Alcohols PCC when dissolved in methylene chloride, CH 2 Cl 2, will oxidize primary alcohols to an aldehyde and stop at that stage. Ex. PCC also does not attack carbon-carbon double bonds!

Oxidation of Primary Alcohols Primary alcohols are easily oxidized to carboxylic acids by potassium permanganate, (KMnO 4 ) The reaction is usually done in a basic, aqueous solution Ex. Note: 1) Count your carbons! 2) Watch out for reactions with other functionalities! (alkenes)

Summary To get an aldehyde from a primary alcohol, use PCC in methylene Chloride To get a carboxylic acid from a primary alcohol, use KMnO 4 with NaOH/water and heat, followed by dilute acid.

Oxidation of secondary alcohols to Ketones Secondary alcohols can be oxidized to ketones The reaction usually stops at the ketone because further oxidation would require the breaking of a C- C bond Example Various oxidizing agents based on Chromium IV have been used for this type of oxidation The most common used reagent is Chromic Acid, H 2 CrO 4

Oxidation of secondary alcohols to Ketones The oxidation of secondary alcohols are generally carried out in acetone or acetic acid Examples Note: Chromic acid also oxidizes primary alcohols to carboxylic acids.

Take Home Quiz Show how each of the following transformations could be accomplished.

Organometallic Compounds Compounds that contain carbon-metal bonds are called organometallic compounds The nature of the carbon-metal bond varies widely, ranging from bonds that are essentially ionic to those that are primarily covalent examples

Organometallic Compounds While the organic portion of the organometallic compound has some effect on the nature of the C-M bond, but the identity of the metal is of far greater importance! The reactivity of organometallic compounds increases with the percent ionic character of the carbon-metal bond

Organometallic Compounds Alkyl Sodium and alkyl potassium compounds are highly reactive and are among the most powerful bases They react explosively with water and burst into flames when exposed to air Organomercury and organolead compounds are much less reactive and more stable

Organometallic Compounds Organometallic compounds of lithium and magnesium are of great importance in organic synthesis They are relatively stable in ether solutions, but their carbon-metal bonds have considerable ionic character Due to this ionic character, the carbon atom that is bonded to the metal of an organolithium or organomagnesium compound is a strong base and powerful nucleophile

Preparation of organolithium and organomagnesium compounds Organolithiums are made by reacting alkyl halides with lithium metal. Ex Only ether or THF is used as a solvent and moisture must be avoided! Why?

Preparation of organolithium and organomagnesium compounds Order of reactivity: RI > RBr > RCl Flouride are not used. Examples:

Preparation of organolithium and organomagnesium compounds Organomagnesium halides are called Grignard reagents, after the man that discovered them They are made by mixing alkyl halides with magnesium in diethyl ether Example:

Preparation of organolithium and organomagnesium compounds Grignard reagents are rarely isolated. They are normally used in the same they are prepared in The ether solvent is very important in that it forms a diether complex with the grignard reagent that provides its solubility and stabilizes the reagent.

Reactions of alkyl lithiums and Grignard reagents A) Reactions with compounds that contain acidic hydrogens Alkyl lithiums and grignard reagents are very strong bases They will react with any compound that has a hydrogen attached to an electronegative atom such as oxygen, nitrogen, or sulfur examples

Reactions of alkyl lithiums and Grignard reagents Not only are these reagents strong bases, they are also very strong nucleophiles! This is very important because it can be used to make carbon-carbon bonds!

B) Reactions of Grignards with Oxiranes Grignard reagents attack epoxides at the less substituted carbon. – Attacks via base catalyzed mechanism After adding acid in a second step, we are left with an alcohol Ex. Mech.

C) Reactions of Grignard Reagents with Carbonyl Compounds From a synthetic point of view, the most important reactions of Grignard reagents and organolithium compounds are those in which these reagents act as nucleophiles and attack an unsaturated carbon, especially the carbon of a carbonyl We have seen that the carbon of a carbonyl group is electrophilic and very susceptible to nucleophilic attack. Reaction: Mech:

C) Reactions of Grignard Reagents with Carbonyl Compounds Grignard additions to carbonyl compounds are especially useful because they can be used to prepared primary, secondary, and tertiary alcohols. – Grignards + formaldehyde to get primary alcohols – Grignards + all other aldehydes to get secondary alcohols – Gignards + ketones to get tertiary alcohols. – Esters + 2 equivalents of Grignards to get tertiary alcohols

Planning a Grignard Synthesis By using the grignard synthesis skillfully, we can synthesize almost any alcohol we wish In planning a gridnard synthesis, we must simply choose the correct grignard reagent and the correct aldehyde, ketone, ester or epoxide. We do this by examing the alcohol we wish to prepare and by paying special attention to the groups attached to the carbon atom baring the –OH group

Planning a Grignard Synthesis Most of the time, there will be more than one way of carrying out the synthesis In those cases, our final choice will probably be dictated by the starting compounds available.

Planning a Grignard Synthesis Three step process: 1)Locate the carbon attached to the –OH group 2)Examine the other groups bonded to that carbon 3)Decide which bonds can be made Note: the C-OH bond used to be the C=O! Example: Show how to make 3-phenyl-3- pentanol using grignard reagents.

Use in a multi-step synthesis Problem: Using an alcohol of no more than 4 carbons as your only starting material outline a synthesis of:

Planning a Grignard synthesis Reminder: You can also make the bond two bonds away from the alcohol by using the appropriate epoxide! Example: Synthesis the following starting with bromobenzene.

Restrictions on the use of Grignard Reagents Although they are very versatile, they are not without limitations Most limitations arise from the fact that in addition to being a strong nucleophile, they are also a very strong base It is not possible to prepare a Grignard from an organic compound that contains an acidic hydrogen By acidic Hydrogen, we mean any hydrogen that is more acidic than the hydrogens on an alkane or alkene

Restrictions on the use of Grignard Reagents For example, we can not prepare a Grignard from a compound containing: -OH, -NH, -SH, -CO 2 H, -SO 3 H If we tried to do so, when the grignard formed, it would simply abstract the acidic hydrogens. Note: Remember that protecting groups are an option for –OH’s!!!

Restrictions on the use of Grignard Reagents Also, since the grignard is a powerful nucleophile, we cannot prepare them from a compound that contains a: Carbonyl, epoxide, nitro, or cyano If we were to try, the grignard would only react with itself! Ex.

Restrictions on the use of Grignard Reagents This means that when we prepare grignard reagents, we are effectively limited to alkyl halides or to analogous organic halides containing C-C double bonds, internal triple bonds, ether linkages, and –NR 2 groups And remember, when planning to use a grignard in synthesis, neither the grignard, nor the Carbonyl compound can have an acidic hydrogen!

Restrictions on the use of Grignard Reagents Acid/Base reactions will always happen faster than nucleophilic attack or any other type of reaction. Occasionally, there will be circumstances in which a chemist will knowingly ignore this rule and add multiple equivalents of the grignard reagent Example.

Restrictions on the use of Grignard Reagents This occurs when the grignard reagent is cheap and the electrophile is very expensive! This problem can also be overcome with the use of protecting groups! Example

The use of alkyl lithium reagents Organolithium reagents react with carbonyl compounds in the same way as grignard reagents This provides another method for preparing alcohols! Example: Organolithium reagents have the advantage of being somewhat more reactive than grignard reagents.

The Use of Sodium Alkynides Sodium alkynides are also considered organometallic compounds They also react with aldehydes and ketones to yield alcohols. Example:

Lithium Dialkylcuprates Lithium Dialkylcuprates are a specialty organometallic compound featured in the Corey- Posner-Whiteside-House synthesis The use of lithium dialkylcuprates are a highly versatile method for the direct synthesis of alkanes and other hydrocarbons from organic halides It does not create a new functional group for use in further reactions, other than radical halogenations, but it does provide a method for coupling the alkyl portions of alkyl halides

Lithium Dialkylcuprates Overall reaction: The first step in the process is the conversion of one of the alkyl halides into a lithium dialkylcuprate (R 2 CuLi) This conversion requires two steps: – Alkyl halide to alkyl lithium – Alkyl lithium to lithium dialkylcuprate

Lithium Dialkylcuprates Step 1- Alkyl halide to alkyl lithium – Use the same process we saw earlier – example Step 2- alkyl lithium to lithium dialkylcuprate – The alkyl lithium is treated with cuprous iodide (CuI) to form the lithium dialkylcuprate – example

Lithium Dialkylcuprates When the lithium dialkylcuprate complex is treated with a second alkyl halide, coupling takes place between one alkyl group of the dialkylcuprate and the alkyl group of the new alkyl halide Examples:

Lithium Dialkylcuprates For the coupling to give a good yield of alkane, the second alkyl halide added must be a methyl halide, a primary alkyl halide, or a secondary cycloalkyl halide The alkyl group on the lithium dialkylcuprate can be methyl, primary, secondary or tertiary.

Lithium Dialkylcuprates The two alkyl groups don’t have to be different The overall scheme for the alkane synthesis is: Examples