chem 352 exam 2 concepts

enols

electron rich, nucleophiles, react more than alkenes because -OH has powerful electron donating resonance

β-dicarbonyl

enol form predominates due to conjugation and intramolecular H-bonding between carbonyl and hydroxyl group

tautomerization

acid: protonation precedes deprotonation

base: deprotonation precedes protonation

biological: two keto-enol tautomerizations; enzyme allows deprotonation and protonation to occur in same step

enolate

formed when base removes hydrogen from α carbon due to increased acidity from carbonyl group; formed from aldehydes, ketones, esters, and β-dicarbonyl compounds

acidity of alcohols and ketones

alcohols more acidic than ketones; ketones are stabilized but the only hydrogens are on carbons which are harder to remove

esters are less acidic because oxygens DONATE in resonance conjugate base which destabilizes

enolate formation

formed in acid/base equilibrium; stronger base forms more enolate and favors side with weaker acid

small amount of product: -OH, -OR

large amount of product: H-, -NR2, LDA

LDA

strong non-nucleophilic base, bulky isopropyls hinder N

-78 C, THF as solvent

Bu-Li used to deprotanate LDA-amine, not used in reaction due to nucleophilic properties that would react at carbonyl instead

kinetic enolate

faster, reacts at less substituted enolate; favored by strong nucleophilic base (LDA), polar aprotic solvent used to avoid re-protonation of enolate (THF), low temperatures to avoid equilibrating to thermodynamic enolate (-78 C)

thermodynamic enolate

strong base, protic solvent, forms small amount of enolate to allow for equilibrium and formation of lower energy, more substituted enolate

EtOH, NaOEt (commonly used because only one base is present and is made by adding sodium to flask)

room temperature, 25 C

racemization

3 sp2 carbons, trigonal planar

enolate reprotonates α carbon to re-form carbonyl with equal probability from both directions

avoid strong bases to avoid racemization

halogenation at α carbon

aldehyde/ketone with X or H on alpha carbon forms α-halo aldehyde or ketone (all halogens but F)

acetic acid is both solvent and acid catalyst

elimination: Li2CO3, LiBr, DMF

substitution: Sn2 with nucleophile

direct enolate alkylation

deprotonation followed by nucleophilic attack with unhindered methyl and primary alkyl halides to form racemic mixture (elimination of secondary alkyl halide)

problems: sequential dialkylation; elimination of sensitive reactants

malonic ester synthesis

hydrolize esters to carboxy groups with acid and water to form β-diacid, heat destabilizes and causes loss of CO2 and cleavage of C-C bond to form carboxylic acid

can form rings from chains with halogen at each end (dihalide)

malonic ester / acetoacetic ester retrosynthesis

locate α carbon on COOH and identify bonded alkyl groups; break into alkyl halides and CH2(COOEt)2

acetoacetic ester synthesis

converts ethyl acetoacetate to ketone with 1-2 alkyl groups on α carbon

advantages

1. LDA more expensive than NaOEt

2. acetoacetic ester synthesis better for dialkylation

3. enolate less basic → less elimination

dehydration

all alcohols dehydrate in acid, but only β-hydroxy carbonyl compounds dehydrate in base; when α,β-unsaturated carbonyl compound is also conjugated with double bond or benzene, water elimination is spontaneous and β-hydroxy carbonyl groups cannot be isolated

IRREVERSIBLE

stability compensates for hydroxide as poor leaving group, same pKa as base, no net negative

heat required unless additional conjugation is present

crossed aldol reaction

aldol reaction between two different carbonyls

only synthetically useful with no α hydrogens → 1 product

formaldehyde and benzaldehyde commonly used

increase yield with excess, unhindered electrophilic carbonyl

can occur twice on one ketone

directed aldol reaction

clearly defines nucleophilic enolate, which reacts at electrophilic carbonyl carbon

both carbonyls can have hydrogens on α carbon because one enolate is prepared with LDA

part with carbonyl in product is enolate

add water after, want to avoid early protonation of enolate or base

intramolecular aldol reaction

used to make 5 or 6 membered rings

though smaller ringed enolates are possible, strain prevents it from actually occurring

5 → 6 membered rings via ozone cleavage

generally irreversible due to elimination

claisen reaction

two molecules to ester react under presence of alkoxide base to form β-keto ester, full equivalent of base needed to deprotonate (NOT BASE CATALYZED); loss of leaving group occurs to form substitution product

only esters with 2-3 hydrogens on alpha carbon because acidic protons between carbonyls can be de/re-protonated, driving reaction forward by producing a reactable product (removes product to form more keto ester)

crossed claisen and related reactions

two different esters when only one has alpha hydrogens; one product formed in presence of base (usually ethyl formate and ethyl benzoate used)

ketone + ester: enolate generally formed from ketone, best when ester has no alpha hydrogens; forms β-dicarbonyl NOT β-keto ester

ethyl chloroformate + diethyl carbonate

1. formation of enolate

2. nucleophilic addition to carbonyl

3. elimination of leaving group

dieckmann reaction

intramolecular claisen reaction of diesters to form five and six membered rings

biological claisen

enzymes in active site H-bond to lower energy and make reaction possible at biological pH (due to formation of negatively charged enolate)

michael reaction

enolate of one carbonyl and α,β-unsaturated carbonyl

robinson annulation

ring formation combining Michael reaction with intermolecular aldol reactions from enolate and α,β-unsaturated carbonyl

forms six membered ring, two sigma bonds, and one pi bond

either in -OH/H2O, -OEt/EtOH + HEAT!!!!

when drawing products, place alpha carbon of compound that becomes enolate next to β carbon of α,β-unsaturated carbonyl and join appropriate carbons

always forms cyclohex-2-enone ring

benzene

four degrees of unsaturation, highly unreactive; planar and all C-C bond lengths are equal due to overlap of six adjacent p orbitals

conjugated dienes more stable than two C=C, benzene do not undergo typical additions; substitutions only, all degrees unsaturation retained

kekule

1. molecular formula C6H6

2. all H’s are equivalent

3. each C forms 4 bonds

varying bond length

monosubstituted benzene

name substituent and add “benzene”

disubstituted benzene

use ‘ortho’, ‘meta’, or ‘para’ to designate relative position of substituents; then alphabetize substituents preceding benzene

if common root, name molecule as derivative of monosubstituted benzene

polysubstituted benzene

number to give lowest set of numbers around ring, alphabetize substituent names, when substituents are part of common root, name molecule as derivative of monosubstituted benzene, designate as C1

huckel’s rule

aromatic compound must be cyclic, planar, completely conjugated, and contain and particular number of pi electrons

cyclic

each p orbital must overlap with p orbitals on two adjacent atoms

planar

adjacent p orbitals aligned so pi electrons can be delocalized

conjugated

must have a p orbital on every atom in ring

number pi electrons

aromatic: cyclic, planar, completely conjugated, 4n+2 pi electrons

antiaromatic: cyclic, planar, completely conjugated, 4n pi electrons

aromatic compounds with a single ring

completely conjugated rings larger than benzene are also aromatic if they are planar and have 4n+2 pi electrons

aromatic compounds with more than one ring

forms poly-cyclic aromatic hydrocarbons; number of resonance structures increases

charged aromatic compounds

cyclopentadienyl: cyclic, planar, completely conjugated, six pi electrons; stabilized by five resonance structures

tropylium cation

planar carbocation, conjugated due to empty p orbital, 6 pi electrons

aromatic heterocycles

is lone pair localized on heteroatom or delocalized pi? lone pairs on atom already part of double bond cannot be delocalized in ring

pyridine: six pi electrons, localized lone pair occupies sp2 perpendicular to delocalized pi, p orbital on N overlaps with adjacent p → complete conjugation

pyrrole: six pi electrons (4 from pi, 2 from delocalized electrons), p orbital on each atom, cyclic and planar

deoxyribonucleic acid

valence bond theory

covalent bond formed by overlap of two atomic orbitals and electron pair in resulting bond shared by both atoms

molecular orbital theory

region of space in molecule where electrons are likely to be found; a set of n atomic orbitals forms n molecular orbitals

inscribed polygon method

predicts relative energies of cyclic, completely conjugated compounds

1. draw polygon inside circle with vertices touching circle and one vertice pointed down

2. draw line horizontally through center, MO below are bonding, MO at line are non-bonding, MO above are antibonding

3. add electrons beginning with lowest energy MO. all bonding MOs and HOMOs completely filled in aromatics, no pi electrons occupy antibonding MO

electrophilic aromatic substitution

benzenes react with electrophiles, favor reactions that keep ring intact

carbocation always para or ortho to C-E bond

weak base can be used to deprotonate H adjacent to C+ due to large driving force to be aromatic

halogenation

benzene reacts with Cl2 or Br2 in presence of Lewis acid catalyst; lewis acid reacts with dihalide to form lewis acid base complex that weakens and depolarizes dihalide bond

nitration and sulfonation

introduction of two new functional groups, requires strong acid; nitro group can later be reduced to NH2 group

friedal crafts alkylation

treatment of benzene with alkyl hallie and lewis acid to form alkyl benzene, transfer from one alkyl group to another; vinyl halides and aryl halides do NOT react; rearrangements can occur and will occur with 3+ C; functional groups that form carbocations may be used as starting materials

friedal crafts acylation

benzene ring related with acid chloride and AlCl to form ketone, transfer of one acyl group to another

no rearrangements due to resonance stabilized carbocations

intramolecular friedel crafts

starting materials with benzene AND electrophile, forming new ring

biological friedal crafts

allylic diphosphates contain good leaving group and are a source of allylic carbocations

substituted benzenes

substituents increase or decrease electron density

inductive effects

stem from electronegativity and polarizability of substituent group; atoms more EN than carbon pull electron density away from carbon and exhibit electron withdrawing inductive effect; polarizable alkyl groups donate electron density and exhibit electron donating effect

resonance effects

electron donating when structures place negative charge on carbons of benzene ring; electron withdrawing when resonance structures place positive charge on carbons of benzene ring

electron donating

atom Z with lone pair bonded directly to benzene ring (lone pair + pi bond)

electron withdrawing

EN Z separated from benzene by additional carbon

neutral O or N bonded directly to benzene

resonance effect dominates and net effect is electron donation

halogen X bonded to benzene

inductive effect dominates, electron withdrawal

C6H6-Y=Z: both electron withdrawing, two effects reinforce one another

toulene

faster than benzenes, electron donating CH3 activates benzene ring; ortho, para director

nitrobenzene

slower than benzenes; electron withdrawing NO2 groups deactivates benzene ring; meta director

ortho, para directors and activators

-R, -NHCOR, -OR, -OH,-NR2

ortho, para deactivators

-F, -Cl, -Br, -I

meta directors and deactivators

-CHO, -COR, -CO2R, -CO2H, -CN, -SO3H, -NO2, -NR3+

hammond postulate

stable carbocation lowers energy of transition state and increases rate of reaction; electron donors stabilizes and electron withdrawing groups destabilize carbocation

halogenation of activated benzenes

benzenes activated by strong electron donating groups undergo polyhalogenation at all H ortho and para to donor (OR, NHR, NR2)

monosubstitution: Br2, no catalyst - products less reactive than reactants due to deactivation related to benzene

friedel crafts limitations

most difficult electrophilic aromatic reactions; do not occur when benzene ring is substituted with strong activators and deactivators

electron withdrawing - not e- rich enough

strong activators: also strong lewis bases, deactivates charge

polyalkylation

use excess benzene to avoid

two substituents reinforce

new substituent located on position directed by both groups

two substituents oppose

more powerful activator wins

two meta substituents

no substitution occurs BETWEEN due to crowding

halogenation of alkyl benzenes

Br2, Hv or light: addition of Br onto most substituted C on alkyl

Br2, AlBr3: ortho or para to alkyl

oxidation of alkyl benzenes

arenes with at least one benzylic C-H oxidized with KMnO4 to benzoic acid

reduction of aryl ketones to alkyl benzenes

harsh conditions, difficult

clemmensen: Zn(Hg), HCl, heat

wolff-kishner: NH2NH2, -OH, heat

reduction of nitro groups

nitro readily reduced to amino group

H2, Pd-C

Fe, HCl

Sn, HCl