CHEM 215-2 Exam 1

organic synthesis, ch 18-21; some questions are kinda repeats with different context/wording

why are aldehydes (O=CH) more reactive than ketones (O=C)? → two reasons

1. aldehydes are less sterically hindered

2. ketones have 2 EDGs while aldehydes only have 1, so carbon in aldehyde is more delta positive and more likely to experience Nuc attack

metal hydride (irreversible)

aldehyde/ketone [2] → ?
1,2 or 1,4 addition?

alcohol with lone H
always 1,2-addition

metal hydride (irreversible)

imine ([2], N=C) → ?
1,2 or 1,4 addition?

amine
always 1,2-addition

metal hydride (irreversible)
* why does it only work with LiALH4

nitrile ([3], CN) → ?
1,2 or 1,4 addition?

amine
always 1,2 addition

only works with LiAlH4 (hammer) because it’s more reactive, can reduce [3] to [1] → which is why it needs to be introduced in separate steps

enolization (irreversible)

enolizable = at least one hydrogen on its alpha carbon

H2 ↑

organometallic, e.g. Grignard (irreversible)

aldehyde/ketone [2] → ?

alcohol with R group

organometallic, e.g. Grignard (irreversible)

carbon dioxide (O=C=O) → ?

organometallic, e.g. Grignard (irreversible)

nitrile ([3], CN) → ?

metal hydride mechanism
* what do LiAlH4 and NaBH4 act as?

LiAlH4 and NaBH4 = H- (strong base)

Nuc attack of H- on central carbon to reduce C=O bond, then protonation of O (acid workup)

enolization mechanism
* enolate is a deprotonated carbonyl, which is defined by C=O

NaH = H- (non-nucleophilic, strong base)

H- deprotonates alpha carbon to form enolate through resonance, and hydrogen gas (H2) leaves the mixture

organometallic, e.g. Grignard mechanism

MgHal has a positive charge & is a spectator ion

Nuc attack of R- on central carbon to reduce C=O bond, then protonation of O (acid workup)

Wittig olefination; olefin = alkene (irreversible)

Wittig reagent is a phosphonium ylide, where a ylide is a compound with opposite charges on adjacent atoms where both atoms have an octet

organometallic reagents are incompatible with…

…acidic groups such as OH and NH

this is because Grignard and organolithium reagents are powerful bases that cannot be used as nucleophiles on compounds which contain acidic hydrogens

Wittig reaction mechanism

formation of the PO box!

cyanohydrin formation (reversible)

aldehyde/ketone [2] → ?

cyanohydrin formation mechanism

Nuc attack of CN- on central carbon to reduce C=O bond, then protonation of O (acid workup)

imine/Schiff base formation (reversible)

what are the
1. reagents
2. conditions
3. products?

1. aldehyde/ketone [2], RNH2 (1º amine)

2. H+ catalyst, buffered 4-5 pH

3. imine (C=N)

enamine formation (reversible)
note: first five steps are the same as imine formation

what are the
1. reagents
2. conditions
3. products?

1. aldehyde/ketone [2], R2NH (2º amine)

2. H+ catalyst, buffered 4-5 pH

3. imine (C=N)

reductive amination (reversible)

this produces a new amine (e.g. 1º → 2º) through 2 steps

1. amine → imine through imine/Schiff base formation

2. reduction (e.g. with NaBH4 or LiALH4)

how can reductive amination occur in ONE STEP

with modified borohydride reducing agents

e.g. sodium cyanoborohydride, NaBH3CN, and sodium triacetoxyborohydride, NaBH(OAc)3

Wolff-Kischner reaction (reversible)
* only with Class A carbonyl

aldehyde/ketone [2] → ?

C=O is completely deleted and replaced with two H, N2 ↑

hydrate formation (reversible)

aldehyde/ketone [2] + ? → hydrate

what’s another name for hydrate?

H2O, H+ catalyst

forms a geminal diol

hemiacetal/acetal formation (reversible)

1. aldehyde/ketone [2] + ? → hemiacetal

2. ““ + ? → acetal

1. ROH (1 equiv), H+ catalyst

2. ROH (excess), H+ catalyst

cyclic acyl formation (reversible)

aldehyde/ketone [2] + ? → cyclic acyl

glycol diol, H+ catalyst

base-catalyzed nitrile hydrolysis (reversible)

nitrile (class B carbonyl or [3]) + H2O and ? → ?

H2O with base (e.g. NaOH) catalyst

• OH Nuc attack the C in nitrile

forms an amide (class B, redox-neutral)

acid-catalyzed nitrile hydrolysis (reversible)

nitrile (class B carbonyl or [3]) + H2O and ? → ?

H2O with acid (e.g. H+) catalyst

• H bonds to EN N in nitrile

forms an amide (class B, redox-neutral)

aldol reaction summary

enolate ion reacts with a class A carbonyl compound to form a β-hydroxycarbonyl

base catalyzed enol addition mechanism (reversible)

OH- deprotonates α-carbon to create enolate, carbanion in resonance structure bonds to class A carbon

base catalyzed enol condensation mechanism (reversible)
* simple mechanism

OH- deprotonates α-carbon to make OH a decent leaving group

acid catalyzed enol addition mechanism (reversible)

acid (H+) protonates O, α-carbon is deprotonated by water to create alkene that bonds to class A carbonyl at β-carbon

acid catalyzed enol condensation mechanism (reversible)

turn OH → H2O (good LG), α-carbon is deprotonated by water to create alkene

mnemonic for aldol reactions :D

how to make a “crossed aldol reaction” useful?

1. choose an electrophile that lacks α-hydrogens (e.g. aryl aldehydes)

2. Directed Aldol Reaction: add a very strong base, especially useful if there are multiple enolizable protons

intramolecular aldol reaction

reduction, [H]

a decrease in the number of bonds to electronegative atoms and/or increase in the number of bonds to hydrogen

oxidation, [O]

an increase in the number of bonds to electronegative atoms and/or a decrease in the number of bonds to hydrogen

Clemmensen reduction
* only with Class A carbonyl
acidic conditions, no mechanism
class A carbonyl + HCl → deletes C=O bond

what are the catalyst and condition?

Zn(Hg) and Δ

Mozingo Reduction
* only with Class A carbonyl

stepwise thioacetal formation → Raney nickel hydrogenation

general mechanism of alcohol oxidations

Oxidations of Alcohols: Jones oxidation

1° alcohol + strong harsh condition → ?

carboxylic acid

Oxidations of Alcohols

weaker oxidation of 1° alcohol → ?

aldehyde

Oxidations of Alcohols
oxiding agents are H2 with Pd,Pd/C,Pt, or Ni catalyst

secondary alcohol + oxidizing agent → ?

ketone

Oxidations of Alcohols
oxiding agents are H2 with Pd,Pd/C,Pt, or Ni catalyst

tertiary alcohol + oxidizing agent → ?

NR—no reaction!!

LiAlH4 and NaBH4 do ___-addition while cuprates do ____-addition

LiAlH4 and NaBH4 do 1,2-addition while cuprates do 1,4-addition

how can we completely delete a C=O bond and replace it with 2 hydrogen atoms? 3 ways

1. Wolff-Kischner: NH2NH2, KOH, heat

2. Clemmensen: Zn(Hg), HCl

3. Mozinga

how can we add water across a double bond? 2 ways

1. water + acid (Markovnikov)

2. hydroboration (anti-Markovnikov)

   1. BH3, THF

   2. H2O2, NaOH (aq)

what is LDA?

a bulky strong base that can be used to direct a crossed aldol reaction

C=O → alcohol and nitrile group on the C

KCN, HCN at 0°C

CN → CNH (double bond)

H2 (1 equiv), Pd/C

CN → CNH2 (single bond)

H2 (excess), Pd/C

how do we oxidize an alcohol to class A carbonyl (3 ways)

C—OH → C=O

3 options not three consecutive steps!

1. PCC

2. NaOCl, AcOH (bleach and vinegar)

3. CH2Cl2 (anhydrous)

when does a crossed Aldol reaction occur?

condensation reaction between two different aldehyde or ketone molecules in a protic solvent, like water or alcohol, when the nucleophile and electrophile are different

what reactions are redox-neutral? how can you confirm this

hydrolysis, condensation, and hydration reactions

calculating the oxidation state of relevant carbons and seeing that it doesn’t change from the starting material to the product

how do we oxidize an alcohol to a carboxylic acid (3 ways)

[1] → [3]g

3 options not three consecutive steps!

1. CrO3

2. Na2CrO7

3. K2CrO7

needs to be in H2SO4, H2O