CHEM 352 concepts - test one

carbonyl groups

aldehydes, ketones, acid halides, esters, amides, carboxylic acids; contains electron deficient (electrophilic) carbon and easily broken pi bond; uncrowded sp2 carbon

aldehyde and ketone reactivity

aldehydes more reactive than ketones because they are less sterically hindered and doesn’t have R’ to stabilize through hyperconjugation and induction

• in protic solution (H2O or ROH)

carbonyls with leaving groups reactivity

a more reactive RCOZ has a better leaving group (weaker base, strong conjugate acid) and more EN atoms draw e- away from the carbonyl and enhance the partial positive at C

• weak leaving groups can be used if nucleophile is more basic than the leaving group

oxidation

increase in C-Z bonds or decrease in C-H bonds

reduction

decrease in C-Z bonds or increase in C-H bonds

reduction of aldehydes and ketones

LiAlH4: stronger because its bonds are more polar, giving H a greater partial negative charge; reacts with ALL bonds (nonselective); reacted in anhydrous solution, add water after reduction

NaBH4: weaker, selectively reduces aldehydes and ketones, reacted in CH3OH

• both form racemic mixtures because new stereocenter is formed

H2: nonpolar bonds only

chiral reducing agent

S-CBS and H2O

because the chiral reducing agent introduces an additional stereocenter, the transition states are diastereomers with different properties and unequal energies. product with the transition state lower in energy happens faster and has a greater abundance.

achiral reducing agent

products are enantiomers with same energies (in transition state), physical properties and form in a 1:1, racemic, mixture

reduction of acid chlorides and esters

reduced to aldehydes (DIBAL-H or LiAlH[OC(CH3)3]3 or alcohols (LiAlH4)

• DIBAL-H and LiAlH[OC(CH3)3]3 are more reactive than NaBH4 but less than LiAlH4 due to steric hindrance and the dispersion of partial negatives onto EN atoms. Reaction must be kept at -78 C to stop reaction at aldehyde by preventing the formation of the tetrahedral intermediate (aldehyde more reactive than the product), then the aldehyde is removed. otherwise the reaction would form 1:1 of the primary alcohol and the starting material

reduction of carboxylic acids and amides

reduced by LiAlH4 only (acts as a base), is too strong to stop at the aldehyde product but milder reagents can’t initiate; forms alcohols and amines

• amide → imine → amine (OAlH3 less electronegative because NH has negative charge in tetrahedral intermediate, so is the best LG, forming amine)

oxidation of aldehydes

most commonly oxidized to carboxylic acids

• CrO3; anything can be oxidized

• AgO, NH4OH; only aldehyde is oxidized and silver color change occurs

NADH and NADPH

coenzyme, only works in the active site of an enzyme (h-bonding keeps carbonyl in place, comes from the top face of the ketone)

add hydride to aldehyde/ketone to form alcohol OR substitutes hydride for acyl phosphate to form aldehyde

organometallic reagents

carbon atom bonded to metal (Li, Mg, Cu) giving carbon partial negative charge; regents acts as bases + nucleophiles to form hydrocarbons

• Li strongest, then Mg, then Cu

preparing organometallic reagents

lithium: halogen and metal “exchange” R group

magnesium: metal inserts into C-X bond, stabilized by diethyl ether

acetylide anions

acid-base reaction of alkyne with a base, want to use as nucleophile with no acidic H

organolithium, grignard, and acetylide anions

add one new alkyl group to carbonyl carbon, form new C-C bond, react with H2O so reaction must be under anhydrous conditions with water added after, racemic mixture

retrosynthetic analysis of Grignard products

1. find carbon bonded to OH group in product

   1. break molecule into alkyl bonded to OH from the organometallic reagent - rest is from carbonyl component. technically has no preference and could be any alkyl group

protecting group

TBDMS removed by Bu4N+ F-

prevents acid-base reactions from occurring in molecules with both carbonyl and N-H or O-H groups by converting N-H/O-H to a non-interfering functional group

grignard reactants are strong bases and proton transfer happens quicker than nucleophilic addition

chiral organometallics

like Grignard but is chiral to form diastereomers with varying reaction pathways, NOT racemic

esters and acid chlorides

form 3° alcohols when treated with two equivalents of Grignard or organolithium regents, two new C-C bonds formed

nucleophilic substitution to form ketone, nucleophilic addition to form 3° alcohols; forms two identical R groups

acid chlorides

organo cuprates undergo nucleophilic substitution to form ketones

carbon dioxide

grignard reactants give carboxylic acids after protonation; carboxylation forms carboxylic acid with one more carbon than grignard reagent; uses acid not H2O because -OH is a stronger base and takes back H from carboxylic acid

epoxides

organometallic reagents open epoxide rings to form alcohols; nucleophilic attack from backside of epoxide followed by protonation of alkoxide

α-β unsaturated carbonyl compounds

conjugated bonds spread electron density four atoms over, allowing compounds to react with nucleophiles at two different sites

1,2 addition: organolithium + grignard

1,4 addition: organocuprate (also known as conjugate addition)

aldehyde and ketone stability

decreased reactivity with more alkyl groups due to increased stabilization through induction, hyperconjugation, increased sterics, and minimized partial charge

ketone nomenclature

1. longest chain with carbonyl group and change suffix to -one

2. number carbon chain to give carbonyl group the lowest number, apply usual nomenclature rules

common name: alphabetically list alkyl names and add “ketone”

• alkyl groups 4 or less

aldehyde nomenclature

chain: find longest chain and change suffix to -al

ring: name ring and add suffix -carbaldehyde (aldehyde gets priority at C1)

RCO- substituents

acyl groups (take IUPAC or common name and add -yl or -oyl)

enal: C=C + aldehyde

enones: C=C + ketones

ketone/aldehyde physical properties

dipole-dipole, no H bonding, soluble in organic solvents, soluble in water when it has less than five carbons; strong IMF have higher melting and boiling points

preparation of aldehydes

first degree alcohols (PCC), esters (DIBAL-H), acid chlorides (LiAlH[OC(CH3)3]3), alkynes (R2BH4, H2O2, -OH), and alkenes (O3, Zn/H2O OR S(CH3)2)

preparation of ketones

second degree alcohols (CrO3, Na2Cr2O7, or PCC), acid chlorides (R2CuLi, H2O), alkynes (H2O, H2SO4, HgSO4), and alkenes (O3, Zn/H2O OR S(CH3)2)

nucleophilic addition to aldehydes/ketones

negatively charged nucleophilic attack followed by protonation

new stereocenter: if formed from existing chiral molecule diastereomers form, not racemic, what is less sterically hindered in the reactant?

acid catalyzed nucleophilic addition

3 step mechanism catalyzed with strong acid

protonation of carbonyl oxygen is resonance stabilized and makes it more electrophilic and more susceptible to nucleophilic attack

nucleophilic addition of H- and R-

H-: nucleophilic attack followed by protonation yields 1° or 2° alcohols

R-: organometallics source nucleophile, forms 1°, 2° or 3° alcohols with new C-C bond, racemic mixture formed

nucleophilic addition of CN-

excess NaCN and HCl; -CN protanated by HCl to form weak acid used later for protonation

reversed by treating with base

hydrolysis of CN

replaces 3 C-N with 3 C-O bonds to form carboxylic acid; either done with acid or base, and heat

wittig reactant

P is a 3rd row element and can hold more than 8 e-, no net charge but resonance has negative on carbon making it nucleophilic; since P is larger, e- are further away and more likely to be given up

ylide: 2 oppositely charged atoms next to each other, both atoms have octets

typically synthesized with CH3X and 1° alkyl halides bc SN2

wittig reaction

P-O bond strong and longer (because of P size), reducing typical ring strain

mixture of alkene stereoisomers forms, single constitutional

• Z: lacks e- withdrawing groups

• E: has e- withdrawing groups

retrosynthesis: two possibilities, choose one that is most sterically unhindered on PPh3