Midterm #1 Flashcards
describe a 1,2- addition
ch. 22 slide 6:
a nucleophile attacks the carbonyl carbon and then the double bond goes to the oxygen.
products formed:
FS: enolate and a nucleophile attached to former carbonyl carbon (treat with acid to form…)
SS: hydroxide and a nucleophile (alcohol formed)
describe a 1,4- addition
ch. 22 slide 6:
a nucleophile attacks one of the carbons of the double bond. The double bond pushes up to form a double bond with the carbonyl carbon. the double bond of the carbonyl goes up to the oxygen.
products formed:
FS: an enolate is formed and the Nu is attached to where it attacked (treated with acid to form…)
SS: carbonyl regained and Nu attached. (no alcohol formed)
what addition is kinetically controlled
1,2- addition and it is generally irreversible
what addition is thermodynamically controlled
1,4- addition and it is typically reversible. it is also more stable because carbonyls are more stable
hard vs. soft nucleophiles and examples of each
hard sites: have their lone pair and charge very localized and are not polarizable. ex. grignard / organolithium. hard acids prefer hard bases.
soft sites: have their lone pair either quite delocalized, or in a large orbital. ex. organocuperates. soft acids prefer soft bases.
describe orbital reactivity
- orbitals closer in energy react forwardly
- orbitals further apart in energy don’t
how can the alpha carbon be deprotonated
by a reasonably strong base
describe alpha carbon pka values
Ch. 22 slide 12
- due to resonance stability of the anion (charge and space), the pka values are lower
would a carbonyl with an alkene/ketone have a higher/lower pka, compared to a carbonyl with an ester
Ch. 22 slide 12
a carbonyl with an alkene/ketone would have a pka around 16-20. This has a lower pka because groups can share electron density.
a carbonyl with an ester would have a pka around 25 because the oxygen is an EDG which destabilizes
how would having two carbonyls on a compound affect pH?
ch.22 slide 13
- the pka would be even lower
there would be three alpha carbons that have hydrogens. see resonance forms
why would a compound with just two carbonyls have a lower pka than a compound with two carbonyls and an extra oxygen attached?
ch.22 slide 13
- the oxygen is an EDG via resonance, which is destabilizing because it is donating into a negative charge.
keto enol tautomerization in basic conditions
ch.22 slide 14
- the base attacks a hydrogen on the alpha carbon.
- forms an enolate which shifts to form a double bond between carbons
- acid workup forms enol form
- since there are two alpha carbons, the compound could be protonated from either side. follow regioselectivity rules and draw the most stable form as the product. This mechanism is similar to E2, which is direct and with no rearrangements.
keto enol tautomerization in acidic conditions
ch.22 slide 14
- carbonyl oxygen attacks the acid
- unstable carbonyl formed which shifts to form a carbocation via resonance
- an enol form was produced
- under acidic conditions, you don’t get an enolate, you go right to an enol. enolates are helpful because they are easier to control. this is similar to an E1 mechanism because it can rearrange (less certainty).
what reactants push keto / enol tautomerization under basic conditions
LDA because it is a strong and big base. small bases don’t work because SN2 would be able to happen.
what reactants push keto / enol tautomerization under acidic conditions
an acid. this process is reversible
does the equilibrium favor keto or enol form
ch. 22 slide 16
The preference for the keto or enol tautomeric form depends on…
- Resonance stabilization –> keto form is more stable when there is resonance stabilization of the carbonyl group. Ex. conjugated systems or when the carbonyl group is adjacent to an EWG.
- Steric effects –> Steric hindrance affects the stability of the enol form. If there are bulky groups near the potential enol site, the enol form may be disfavored due to steric repulsion.
describe the halogenation of the alpha carbon (acidic)
ch. 22 slide 18
halogens are electrophilic - the enol / enolates are nucleophilic
- extra acidic hydrogens can continue to react to form halogenated products, however, these new EWGs make it difficult to keep halogenating. its especially bad to have EWGs and a carbocation right next to each other
explain how alpha halogenation to alpha beta unsaturated ketones occurs
ch.22 slide 19
- a monosubstituted halogenation can easily produced an alpha-beta unsaturated ketone
- the halogen is a good LG for E2
explain the halogenation of the alpha carbon under basic conditions
Ch.22 slide 21
reagents: X2, basic
FS: the enolate is in equilibrium with enol
- the X is an EWG, which is good because you’re distributing electron density. this makes it more reactive, which is why it can proceed further than in acidic conditions.
Produces: a haloform
SS: the haloform (C-X3) is a great LG, so OH comes in to form a tetrahedral intermediate. this leaves a carboxylic acid derivative.
describe LDA use in reactions via an enolate
ch.22 slide 22
- 1 equiv of LDA and aprotic THF are used to produce products
- with LDA, you have a lot of control. you can stop it.
- with NaOH, its more disorganized. LDA is preferred.
describe the reaction via an enolate
- enolates are formed through a base mediated reaction
- one of the best bases for this is LDA - strong and non-nucleophilic
what happens to the products if the pka of the products are the same
you get a mixture of products
how does the equivalents of LDA used affect the halogenation
1 equiv gives monohalogenated
2 equiv gives dihalogenated
this is because using LDA prevents the cleavage of the haloform
explain how enolates are great nucleophiles and what do you have to worry about for the reactant when using them
- enolates can be used to form carbon-carbon bonds (i.e., an alkylation)
- if the reactant is symmetrical, you dont have to worry about kinetic / thermodynamic control
where is the enolate nucleophilic
at the alpha carbon
what does dess martin (DMP) do
oxidizes –> turns -OH into double bond O
what does NaH do to an -OH
becomes ONa
What does CH3I do when added to an enolate
adds the CH3 to the O-
kinetic vs. thermodynamic
see Ch.22 slide 28
Kinetic control: A reaction in which the product ratio is determined by the rate at which the products are formed. “sterics” (irreversible)
Thermodynamic product: The more stable product formed in a chemical reaction.
Thermodynamic control: A reaction in which the product ratio is determined by the relative stability of the products. “electronics” (reversible)
what temp must LDA be at and why
Ch. 22 slide 29
- LDA must be at -78 degrees celsius. this is because kinetic control must be irreversible. even though LDA is very bulky and it should go to the less steric (kinetic position), due to the pka it goes to the thermodynamic position. so it must be cooled.
what product is favored when the base pka is close to the alpha C-H pka
the thermodynamic product is favored
explain how carbonyls can react with themselves
see Ch.23 slide 5
- carbonyls can act as both nucleophiles and electrophiles, so they can react with themselves (one attacks the equivalent of another)
what groups do keto and enol forms of molecules react as
keto –> reacts like a carbonyl group
enol –> reacts like an alkene
what is the keto form
H3C-carbonyl- H
what is the enol form
H2C=C-OH
|
H
draw the mechanism for the aldol reaction
draw
what is the best group to use for an aldol reaction
if E+ is an aldehyde, it works better because it is less sterically hindered. a ketone still works, though
describe an aldol reaction
it is a reaction between a nucleophile and an electrophile. a new bond is formed between the alpha carbon and the carbn that was formerly the carbonyl carbon. it forms conjugated double bonds between two carbons and a water is produced
where does the carbon double bond for an aldol condensation go?
the more stable (conjugated) location is favored (ex. C-CH3 is more favored than C-H)
what reactants are used for the aldol condensation
describe the E1cB process of the aldol condensation
see ch. 23 slide 9
- due to the conjugation (i.e., increased stability) condensation can occur under basic conditions, as well. However, the mechanism is neither E1 nor E2
draw mechanism
when can the aldol condensation occur without heat
ch. 23 slide 10
if the compound produced has increased conjugation, the condensation occurs spontaneously. this is due to resonance
draw resonance examples
where will the aldol condensation reaction attached to if reacted with LDA at -78 degrees C
the kinetic side because LDA
what does [H] symbolize
reduction (gaining atoms)
what does [O-]
oxidation (losing atoms)
how can you control a crossed aldol condensation reaction without LDA
two main routes:
1. use one carbonyl that lacks alpha-hydrogens
2. use kinetic control wit LDA
3. make your enolate first (slowly)
4. use knowledge of EWGs / EDGs to facilitate reactivity
how do you control a crossed aldol condensation by adding the enolate first
add one equivalent of LDA on only the reactant you want it to (to form the enolate), then add the other reagent
how can you control a crossed aldol condensation by using a carbonyl that lacks alpha-hydrogens
add a coupling partner that cannot form an enolate
how do you control a crossed aldol condensation using pka
ch.23 slide 17
ex. a compound with lower pka would deprotonate most easily and would be the donor, the other compound would be the acceptor
describe the claisen condensation
its similar to an aldol reaction, though with esters –> so a tetrahedral intermediate will be present.
- crossed claisens are controlled in the same manner as an aldol
draw the claisen condensation reaction
draw it
what is the difference between the claisen condensation and the aldol addition rxn
ch. 23 slide 22
claisen condensation:
- forms a pi bond by elimination of RO-
- produces a beta-keto ester
- forms a tetrahedral intermediate
aldol addition:
- the protonation of O-
- produces a beta-hydroxyaldehyde
how do unstable vs. stable intermediates impact claisen rxns
The stability of tetrahedral intermediate depends on the ability of the groups attached to the new tetrahedral carbon atom to leave with the negative charge.
how do enolates change if they are conjugated
see slide 24 ch. 23
- conjugate addition is usually soft/soft interaction, so a soft base can facilitate conjugate addition
- ” harder” enolate is one with just the enolate ion
- “softer” enolate is one with the enolate and a carbonyl right next to it
*both are considered soft Nus, but one is a bit harder
**both are considered 1,4- additions
describe a michael addition
- a 1,4- addition to a conjugated enone/enal –> one needs a weak Nu
what is an enone
C=C-carbonyl-C
what is an enal
C=C-carbonyl-H
draw the michael addition mechanism
draw it
what is a quick way to identify if a michael addition has occurred
see ch.23 slide 27
if a 1,4- addition has a occurred then its michael
ex. a double bond oxygen is a good indication that 1,4- occurred vs. just the -OH (which is 1,2-)
tert butyl pka
18
when does an amine act as an acid
-N-
H
pka = 36-38
when do amines act as bases or nucleophiles
-N(+)-
H2
pka = 11
why cant amines exist biologically in their acidic form
their pka is too high, so leveling effect can occur –> the hydrogen would deprotonate water
what bonding types do primary amines engage in
- H-bonds
- dipole-dipole
- LDF
what bonding types do secondary amines engage in
- H-bonds
- dipole-dipole
- LDF
what bonding types do tertiary amines engage in
- no-h-bond
- dipole-dipole
- LDF
draw primary vs. secondary vs. tertiary amines
ch. 24 slide 4
identify the pkas of the amines in slide 6 of ch.24
what pka tell you about this reaction: HA + H2O <–> H3O+ + A-
pka tells you the acidity to form these products (as stability increases, the pka decreases)
how do primary and secondary amines differ in terms of resonance and induction stabilization?
see slide 7 of Ch. 24 and draw resonance structures
how does induction impact the pka of amines
see slide 8 of Ch. 24
EWG stabilizes amine (since they would have a pos charge if the proton was removed) - pka of groups with EWG (more induction) are lower
how does hybrid character affect the pka of amines
see slide 9 of Ch. 24
more sp^2 character means more s character. more s character means greater EN on carbon which makes it a greater EWG, stabilizing the compound (lower pka)
answer practice question on slide 10 of ch. 24
how to determine which amine would be the strongest base
ch. 23 slide11
look for:
- conjugation (where positive charge would be based on resonance) and how to destabilizes that charge
OR
- where the lone pair is most reactive
how can you change the solubility of amines in aqueous systems, and at what pH would water solubility be greatest
ch. 24 slide 13
deprotonating –> increases pka
protonating –> decreases pka
lower pkas are more water soluble
draw mechanisms on slide 14 of ch. 24 (-NH2 + CH3Br)
CH3-N(+)H2
|
R
how do you form an imine and an enamine from an aldehyde / ketone
see slide 15 of ch.24
draw the gabriel synthesis
see ch. 24 slide18
what makes an NH hydrogene between two carbonyls more acidic
resonance stabilization
how can you reduce an imine to an amine
slide 19 ch. 24
reduce it [H]
what does 1) R2NH 2) NaBH3CN do to a five membered ring attached to double bond O
slide 19 ch. 24
creates a tertiary amine
how to turn NO2 to NH2
H2, Pd/C
how to turn CN to primary NH2
[H]
what does Br2, hv do to a benzene with a methyl
ch.24 slide 21
add a Br to the end of the methyl
what does NaCN do to a benzene with CH2-Br attached
ch.24 slide 21
adds CN in place of Br
what does NaBH4 and water do to a benzene with CH2-CN attached
ch.24 slide 21
becomes CH2-CH2-NH2
what happens when you add Mg, Et2O to a benzene with Br attached
ch. 24 slide 22
becomes benzene with MgBr
whats an imine
R-N=C-R2
whats an enamine
R2N-C=CR-R2
what does an aldehyde and a primary amine react to produce
an imine
what does a ketone and a secondary amine react to produce
an enamine
how do you produce an imine
ch. 24 slide 15/16
aldehyde and a primary amine with trace acid
how do you produce an enamine
ch. 24 slide 15/16
ketone and a secondary amine with trace acid
explain the conjugate addition of enones/enals with an amine
ch.24 slide 17
1,4- addition
how can amines be synthesized via SN2
the gabriel synthesis for primary amines
direct amine SN2 for tertiary amines
explain the gabriel synthesis
ch.24 slide 18
- prepares primary amines
- H is acidic due to resonance stabilization
what are the reactants for a gabriel synthesis
ch.24 slide 18
Compound and then
- MOH
- R-LG
what are the reactants for a gabriel synthesis
ch.24 slide 18
R2NH + R-LG
if given a cyclopentanone, how do you make an imine
ch.24 slide 19
NH3
if given cylopentanimine, how do you make a primary amine
ch.24 slide 19
NaBH3CN (H –> reduce it)
if given cyclopentanone, how do you make a secondary amine
ch.24 slide 19
- RNH2
- NaBH3CN
-NO2 to -NH2
H2, Pd/C
if given cyclopentanone, how do you make a tertiary amine
- R2NH
- NaBH3CN
-CN to -NH2
[H]
OR
- NaBH4
- H2O
a benzene is reacted with
1. Br2, FeBr3
2. Mg, Et2O
what is produced?
see ch.24 slide 22
biggest thing to look for when identifying aromatic conpounds
if an sp^3 carbon is present –> NOT AROMATIC
what is pyrrole
ch.24 slide 26
five mem ring with NH
resonance vs. induction in the context of pyrrole vs. pyrrolidine (aromatics)
ch.24 slide 27
resonance sustains electron dense core in the ring; induction has electronegativity where the EN atom is
pyrrole
ch.24 slide 27
5 mem ring with double bonds and NH
pyrrolidine
ch.24 slide 27
5 mem ring, no double bonds, NH
what is delocalization energy
the extra stability a compound has as a result of having delocalized electrons
what compounds have the most delocalization energy
options:
furan
thiophene
5 mem ring with carboanion
pyrrole
benzene
(what compounds are the most aromatic) 1=most aromatic
- benzene
- 5 mem ring with carboanion
- thiophene
- pyrrole
- furan
what compounds are the most reactive?
options:
furan
thiophene
5 mem ring with carboanion
pyrrole
benzene
what are the least delocalized compounds 1=most reactive
- pyrrole
- furan
- thiophene
- benzene
draw the resonance structure for pyrrole
ch. 24 slide 29
where does bonding occur for pyrrole
ch. 24 slide 30
C-2
do not use LP on nitrogen for bonding with an electrophile because it is not nucleophilic (resonance structure)
what is the pka of protonated pyrrole
-3.8
why should you protonate at C-2? can you protonate at C-3?
ch. 24 slide 33
if you protonate at the nitrogen you destroy aromaticity. protonating at C-2 is more stable because there are three resonance contributors. C-3 only has two resonance contributors that would move the positive charge, which is why C-2 is more stable than C-3.
where would furan protanate
C-2
what is the major product for furan with a methyl on C-2 reacted with Br2
ch. 24 slide 35
methyl on one C-2, Br on the other C-2
benzene attached to a five mem. ring with NH and a double bone, where would Br2 attach
ch. 24 slide 36
C-3 (C-2 would break benzene aromaticity)
when a benzene is attached, protonating at C-3 leaves the ring intact.
pka of hydroiodic acid
~10
pka of hydrobromic acid
~9
pka of hydrochloric acid
~6
pka of sulfuric acid
~3
pka of a hydronium ion
H2O(+)-H
~1.7
pka of sulfonic acids
~1
pka of hydrofluoric acid
3.2
pka of carboxylic acids
4
pka of protonated amines
9-11
pka of thiols
13
pka of malonates
13
pka of water
14
pka of alohol
17
pka of ketone / aldehyde
20-24
pka of nitrile
25
pka of ester
25
pka of alkyne
25
pka of sulfoxide
31
pka of amine
~35
pka of hydrogen
36
pka of alkene
~43
pka of alkane
~50
periodic table acid trend
as EN increases and atomic size increases, relative acidity increases.
however, large, but high EN negatively charged atoms are more basic (ex. F is more acidic then I or Br) because larger atoms can stabilize the negative charge easier.
what makes a compound a stronger base
more stable, the stronger the base
pka and stability rule
the more stable a compound is after it loses a hydrogen atom, the lower it’s pKa
