Orgo 2 Exam 3 (Ch 20)

carboxylic acid derivatives

acid halide

anhydride

ester

amide

how does LG affect reactivity

acid halide > anhydride > ester > amide

• as list progresses:

  • LG becomes less e- neg

  • LG becomes a less likely LG

  • LG becomes less acidic

  • resonance increases, more stable, unlikely to react

LGs and their notes

• -X —> fast, even at room temp

• -OCOR —> slow at RT but still reacts with nucleophile

• -OR —> very slow, use catalyst or heat

• -NR2 —> not observed, unles use catalyst, heat, time

resonance with acid derivatives

• resonance with acid halide: (+) on X, (-) on O

  • minor resonance product, because (+) charge on a highly e- neg atom

• resonance with amide: (+) on NR2, (-) on O

  • important contributor because (+) is stable enough.

  • C=N double bond is shorter than C=X bond in above resonance.

  • NMR shows 2 isomer outcomes due to barrier rotation

where on carboxylic acid is acidic and basic

alpha protons are acidic and will react with base

O is basic

acidity trend in acid derivatives

acid halide > ketone > ester > amide

• acid halide most acidic bc inducitive effect of very e- neg X. X is not a good resonane donator, so little resonance stabilizer bc no N to donate e- pair.

  • has the least stable CB —> more acidic molecule

• amide is the most basic because it has the best resonance forms as N donates e- pair. the alpha H becomes less acidic and less likely to deprotonate.

  • the negative charge on the O shows resonance delocalization and electron density pulled from N to O

better electron donating abilities makes the molecule more stable and less acidic —> most basic (the amide)

how do alcyl halides react

via addition elimination

• are very reactive due to dipole facing O —> X

acid halide + carboxylic acid —> anhydride

acid halide + H2O —> carboxylic acid

acid halide + ROH —> ester

acid halide + H-NR2 —> amide

mech for addition-elim of alycl halides

O from ROH adds to carbbonl carbon as nucleophile, arrow from bond to O

O makes double bond, Cl LG

Cl- base deprotonates H from ROH (use pyridine or amine if doing amine)

• same mech for all reactions

carboxylic acid + SOCl2 + ROH,pyridine (bulky base)

—> ester

• need to use this method to make t-butyl esters

alycl halide —> ketone

R-CuLi

• cant use grignard, because will react twice after product is formed whereas cuprates dont react with ketones

reduction of alcyl halides

• alcyl halide —> ROH

  • 1) LiAlH4 2) H+ workup- because very strong

• alcyl halide —> aldehyde

  • 1) LiAl(OtBu)3H 2) H+ workup

    • more bulky and less reactive- will react with reactive alycl halide, but not strong enough to react with less reactive aldehyde

anhydride reactions

anhydride + H2O —> acid

anhydride + ROH —> ester

anhydride + RNH —> amide

symmetrical anhydrides reactions

symmetrical anhydrides will give 2 products with reaction, because will react at both carbonyl carbons

esters properties

slow reactions, catalyst helps, OR is a poor LG

ester hydrolysis to carboxylic acid

ester + TsOH,H2O,acetone,heat —> carboxylic acid + EtOH

• padped reverse reaction of ester formation

ester under basic conditions- saponification: ester + -OH,H2O,heat —>

—> carboxylate ion + EtOH

mech

• -OH adds to carbonyl C, arrow to O

• O to double bond, OR is LG

• -OR attacks H from O-H, O gets negative charge

  • CH3OH byproduct

ester + 1)-OH,H2O,heat 2) H+ workup

—> carboxylic acid

• needs acid workup to make this product, without it will get carboxylate ion

ester —> carboxylic acid

carboxylic acid —> ester

ester —> carboxylic acid

• add H2O

carboxylic acid —> ester

• add ROH

transesterification

one ester to another ester

• OMe ester + EtOH,TsOH,heat —> OEt ester

converting an ester to an amide

ester + amine,heat —> amide

ester + 1) grignard 2) H+ workup

grignards add twice, so will get OH and 2 of the R groups in product

ester + 1) LiAlH4, Et2O 2) H3O+, H2O

replaces OR with OH, removes carbonyl

• very strong reducing agent

ester + 1) DIBAL, -78°C 2) H3O+, H2O

makes aldehyde

• replaces OR with H, keeps carbonyl

DIBAL is bulky version of LiAlH4 (Al with 2 isobutyls and an H)

• is less reactive than LiAlH4 because of sterics

ester + 1) LDA, 0° 2) R-Br

adds R-Br to alpha carbon

• via intermediate enolate

  • problem: side reaction-claisen condensation

amide reaction conditions

are the least reactive derivative so reactions will require heat

amide hydrolysis: acid vs basic

acidic: amide + H2SO4,H2O,heat —> carboxylic acid + (+)amide group with 2 extra Hs added

basic: amide + NaOH,H2O,heat —> carboxylate ion(-) + amide group with 1 extra H

amide + 1) -OH,H2O,heat 2) H3O+,H2O

carboxylic acid

• even tho step 1 is base, to end with acid product, last step must be acidic

mech

• PADPED like ester hydrolysis

amide reduction to ROH

amide + 1) LiAlH4, THF 2) H3O+,H2O 3) -OH,H2O

• same amide molecule but carbonyl O replaced with 2 Hs

  • N bonds don’t break as easily

  • use basic workup at end to end with basic amine product

mech

• from ws

amide + 1) DIBAL 2) H3O+,H2O

makes aldehyde- replaces amide group with H

• because of DIBAL sterics, so less reactive

hoffmann rearrangement

amide + Br2,NaOH,H2O

• C=O gets removed and replaced with the amide group

  • loses a carbon

• CO2 byproduct

mech

• from ws

amidate

amide group with one less H- so has negative charge

nitrile hydrolysis

acidic: R-CN + H2SO4,H2O,heat —> R-COOH (carboxylic acid)

basic: R-CN + 1) -OH,H2O,heat 2) H3O+, H2O —> R-COOH (cabroxylic acid)

acidic mech: PADPED

• first step protonate N

basic mech: start with addition and get carboxylate ion product unless adding H+ workup

when to do PADPED vs addition-elimination

when you have a bad nucleophile like H2O, you are under acidic conditions and need to protonate- so do PADPED

when you have a good nucleophile (like -OH) you dont need to protonate so can do addition-elimination

nitrile + organometallic

R-CN + CH3Li + 1) THF, 2) H+,H2O —> remove N, becomes ketone with R group on other side

3 methods of nitrile reduction

• R-CN + 1) DIBAL 2) H3O+,H2O —> aldehyde

• R-CN + 1) LiAlH4,THF 2) H3O+,H2O —> replace N with NH2

• R-CN + H2,cat Pt —> replace N with NH2