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  • 12.4: Preparation of Alcohols via Reduction

    • Oxidation states

      • a way of quantifying the number of electrons on an atom that treats all bonds as ionic and breaks them heterolytically→ electrons go to the more electronegatively atom in each case

      • using formal charges: a carbon atom on a methanol molecule has 0 charge because it has 4 electrons on the atom (which is the number of valence electrons it should have)

      • using oxidation: the same carbon atom has a state of -2 because it is counted as having six (2 more valence electrons)

      • a carbon with 4 bonds will always have a 0 formal charge, but can have anywhere from -4 to 4 in terms of oxidation state

      • oxidation reactions involve an increase in the oxidation state of an atom (i.e. converting methanol into formaldehyde)

      • a reduction is when the oxidation state is decreased

    • Reducing agents

      • reductions require a reducing agent that will get oxidized

      • common reducing agents used in converting ketones/aldehydes to an alcohol

        • similar to alkene hydrogenation in the presence of a metal catalyst, but occurring at higher temperatures and pressures

        • NaBH4 (sodium borohydride) paired with a solvent (serving as a H+ source).

          • sodium borohydride is a H- source.

          • Common solvents are methanol, ethanol, and water.

          • Occurs in 2 steps: 1) hydride transfer to the carbonyl group and 2) proton transfer

          • H- is nonpolarizable and thus a poor nucleophile so NaH can only act as a base. Since NaBH4 is a nucleophile, it can act as a delivery agent for a nucleophilic H-

          • the carbon atom of the carbonyl group is sp² and trig planar prior to attack. after it becomes sp³ and tetrahedral→ important to unsymmetrical ketones (2 different 3 groups) which form pairs of enantiomers

        • LiAlH4 (LAH or lithium aluminum hydride), similar to sodium borohydride

          • much stronger and reacts violently with protic solvents like water (acidic proton is added in a secondary reaction step)

          • unsymmetrical ketones also produce a pair of enantiomers

          • NaBH4 and LiAlH4 will reduce an alcohol over an alkene when one is present (H2 and metal catalyst will also convert the C=C)

          • LiAlH4 can reduce carboxylic acids and esters but NaBH4 can’t.

          • ester reduction involves the transfer of 2 hydrides→ after leaving group is lost, the carbonyl reforms which can be attacked a second time to form the alcohol group

  • 12.6: Preparation of Alcohols via Grignard Reagents

    • Grignard reagents are characterized by the C-Mg bond→ difference in electronegativity makes it functionally ionic

    • grignard reagents function as a carbon nucleophile that can attack ketones/aldehydes to form alcohols using a mechanism similar to reduction using hydride reagents

    • it’s also a reduction reaction that also adds a new R group

    • proton source is added in a separate step like with LiAlH4→ grignard’s will deprotonate acids since it is a strong base

    • when a chiral center is formed, racemic mixtures are formed

    • reacting with esters, grignard’s also produce alcohols but introduce 2 new R groups

    • grignard reagents are incompatible with a carboxylic acid since they contain a mildly acidic proton

  • 13.10: Ring Opening Reactions of Epoxides

    • Reactions of epoxides with strong nucleophiles

      • when undergoing strong nucleophilic attack, epoxide rings undergo ring opening

      • step one is an Sn2 reaction where an alkoxide acts as a leaving group

        • epoxide rings are high energy substrates but exhibit different characteristics of usual high energy substrates meaning they can undergo the reaction more readily then usual

        • regiochemistry: unsymmetrical epoxides will undergo attack at the less substituted position

        • stereochemistry: attack at a chiral center exhibits inversion of configuration

      • step two is a proton transfer

    • Acid-catalyzed ring opening

      • ring-opening reactions also happen under acidic conditions: i.e. ethylene oxide and and halogen hydride (HI, HBr, HCl)

      • two step reaction: proton transfer and nucleophilic attack

      • other possible reactants: water/alcohol in acidic conditions (i.e. H2SO4)

      • protonation as the final step removes the charge after attack by a neutral nucleophile.

      • regiochemistry: unsymmetrical epoxides are attacked at the least substituted position unless one of the sides is tertiary→ electronic effect causes partial positive charge that is more stable on the tertiary carbon

      • steric effect vs electronic effect; for tertiary carbons, electronic is dominant, for primary/secondary, steric is

      • stereochemistry: attack at a chiral center results in inversion of configuration (consistent with backside Sn2 attack)

  • 13.12: Synthesis Strategies Involving Epoxides

    • Installing two adjacent functional groups→ ring opening can create 1,2 disubstituted molecules

    • Grignard reagents: controlling the location of the resulting functional group

      • when reacting an epoxide with a Grignard reagent, an alcohol group adds differently then it would in the corresponding carboxylic acid/Grignard reaction

      • this is useful in retrosynthesis: the a-B position can be formed from multiple nucleophilic reactions involving aldehydes and Grignard reagents

      • epoxide/Grignard reagents result in a addition between the B-y positions

  • 12.10: Reactions of Alcohols: Oxidation

    • reverse of forming alcohols via reduction: forming a carbonyl via oxidation

    • outcome depends on substitution of the starting alcohol (1*, 2*, or 3*)

    • primary:

      • has two a protons→ can be oxidized twice

      • produces an aldehyde on first oxidation, a carboxylic acid on second

    • secondary:

      • has only one proton in the a-position

      • oxidizes once into a ketone

    • tertiary: don’t undergo oxidation as there are no alpha protons

    • most common oxidizing agent is H2CrO4→ mechanism proceeds in two stages

      • stage one: formation of a chromic ester

      • stage two: E2 forming a carbonyl bond

    • primary w/ H2CrO4

      • forms a carboxylic acid

      • aldehyde is difficult to control for

    • primary w/ PCC in Ch2Cl2

      • a more selective oxidant to form an aldehyde

      • only undergoes one oxidation

    • Chromium oxidants produce toxic byproducts and so other methods are more common

    • Swern oxidation: using DMSO (dimethyl sulfoxide) and COCl2 (oxalyl chloride)

      • base treatment as a second step after reaction

      • stage one of the mechanism: DMSO reacts with COCl2 and forms chlorodimethylsulfonium which acts as the oxidizing agent in stage two

      • stage 2: intramolecular elimination reaction to oxidize into a ketone

      • converts primary alcohols to aldehydes

    • Dess-Martin periodinane oxidation: using DMP and CH2Cl2

      • converts primary to aldehydes, secondary to ketones

      • doesn’t occur under acidic conditions unlike chromium-based oxidations

      • proceeds via a periodinane intermediate

    • Swern and DMP oxidations are cleaner but inefficient. Swern produces DMS, and DMP is explosive

  • 12.11 Biological Redox Reactions

    • reduction/oxidation reactions are common in labs, but also in natural processes→ much more selective and complex

    • bio processes are usually enantioselective (produces only one enantiomer)

    • NADH:

      • reactive center acts as a hydride delivery agent→ reduces ketones and aldehydes into alcohols

      • acting as a reducing agent, NADH is oxidized into NAD+

      • NAD+ can be reduced by an alcohol to form NADH again

      • one use is in the citric acid cycle where NAD+ is converted into NADH

      • in converting ADP to ATP, NADH is reduced to NAD+

      • the redox reactants mark the travel of energy from sun, to food, to movement

  • 12.13: Synthesis Strategies

    • when proposing a synthesis, consider:

      • changes in the carbon skeleton

      • changes to the functional group/s

    • Functional group interconversion

      • conversions between single, double, and triple bonds

      • ketones → 2* alcohol (i. LiAlH4 ii. H3O+) and 2* alcohol → ketones (Na2Cr2O7, H2SO4, H2O)

      • aldehydes → 1* alcohols (i. LAH ii. H3O+) and 1* alcohol → aldehyde (PCC, CH2Cl2)

      • conversions of functional groups are reduction/oxidation reactions

    • C-C bond formation:

      • forming new C-C bonds through reaction of a Grignard reagent and ketone/aldehyde

      • esters and Grignard reagents form an alcohol (2 new C-C bonds)

      • chaining reactions can help in converting between aldehydes and ketones

    • Functional group transformations and C-C bond formation

      • chaining reactions, retrosynthesis

  • 20.2: Nomenclature of Carboxylic Acids

    • Monocarboxylic acids

      • containing only one carboxylic acid group

      • named with -oic acid

      • the parent is the longest chain including the carbon atom of the CA group, also the first locant in the chain

      • carboxylic acid groups attached to a ring are named with a cycloalkane parent: cycloalkanecarboxylic acid

      • common names: formic acid, acetic acid, propionic acid, butyric acid, benzoic acid

    • Diacids

      • containing 2 CA groups, named with -dioic acid

      • common names: oxalic acid, malonic acid, succinic acid, glutaric acid

  • 20.8: Preparation and Reactions of Acid Chlorides:

    • Preparation of acid chlorides

      • formed by treating carboxylic acids with thionyl chloride (SOCl2)

      • mechanism:

        • Part 1: converting OH group into a living group by the pi bond of the carbonyl attacking the sulfur on SOCl2, and expelling the leaving group, then a proton transfer to resolve the charge

        • Part 2: nucleophilic attack on the carbonyl carbon that expells the sulfur leaving group and attaches a Cl atom

    • Hydrolysis of acid chlorides

      • in water, acid chlorides hydrolyze into carboxylic acids

      • mechanism:

        • nucleophilic attack of the carbonyl carbon

        • loss of leaving group

        • proton transfer

      • pyridine solvent reacts with HCl to neutralize it to any side reactions

    • alcoholysis of acid chlorides

      • in alcohol, acid chlorides react to become esters

      • mechanism: same as hydrolysis w/ pyridine base

    • Aminolysis of acid chlorides

      • treating with ammonia, acid chlorides yield amides

      • ammonia is sufficient to neutralize HCl→ i.e. 1:2 ratio of reactants in order for ammonia to act as solvent

    • Reduction of acid chlorides

      • LAH reduces them to alcohols

      • reactants added in steps: LAH first, and then a proton source (H3O+, etc)

      • first two steps proceed as expected: nucleophilic attack, loss of leaving group that reforms carbonyl→ produces aldehyde

      • aldehyde is then attacked to produce an alkoxide→ protonation yields the alcohol

      • other reagents: lithium t-butoxy aluminum hydride

    • Reactions between acid chlorides and organometallic reagents

      • treated with grignard reagents, yield alcohols with 2 new alkyl groups

      • must also add a second step of protonation

      • same mechanism as reduction

      • can’t yield a ketone→ needs a more selective nucleophile like a Gilman reagent

    • Summary of reactions of acid chlorides

      • form, carboxylic acids, alcohols, amides, esters, ketones, aldehydes, etc