carbonyls - acetals + imines + enols

Question 1

how are acetals formed + why?

Answer 1

via nucleophilic attack of the O of carbonyl, which then also acts as the LG, this mechanism involves the lewis basicity of the lone pairs on O - specific to aldehydes/ketones
- normally nucleophiles add to carbon to give a tetrahedral intermediate but this is limited to carbonyl derivatives with LGs

Question 2

what are the 3 types of acetal?

Answer 2

hydrate - where both OR groups are just OH (essentially a hydrated aldehyde/ketone, a dihydroxy group, very difficult to isolate)
hemi-acetal - where on OR group is OH (these are very difficult to isolate)
acetal - where both OR groups aren’t OHs (can be isolated)

Question 3

how are hemiacetals synthesised?

Answer 3

they form very slowly when aldehydes/ketones are reacted with alcohols - rate of formation increases by either acid or base
in acid:
- O of carbonyl attacks H+ from acid, becoming protonated
- this makes the δ+ C even more electrophilic, the π* orbital of C=O lowers in energy, allowing the alcohol to react with it better, as it is a poor nucleophile
in base:
- base reacts with alcohol via deprotonation to increase its reactivity, its HOMO is higher in energy and can interact with π* LUMO of C=O
- deprotonated alcohol attacks δ+ C and the carbonyl bond is broken

Question 4

are cyclic hemiacetals more or less stable + why?

Answer 4

cyclic hemiacetals are much more stable, as entropic gain of collapse back to aliphatic hemiacetals is -ve = unfavoubable

Question 5

how are acetals synthesised?

Answer 5

they form very slowly when aldehydes/ketones are reacted with alcohols - rate of formation increases by only acid, hydrolysed by base
- carbonyl is protonated by acid, making C more δ+
- alcohol attacks δ+ C and carbonyl bond is broken
- PT to shift extra proton from alcohol to hydroxy group, now = water, a better LG
- alcohol O reforms carbonyl bond and water leaves
- alcohol attacks δ+ carbonyl C and carbonyl bond breaks
- proton loss produces product
excess water must be removed to prevent hydrolysis via backwards reaction

Question 6

how can water be removed from a system?

Answer 6

drying agents, dean stark trap, molecular sieve

Question 7

what is always seen in an acetal system before nucleophilic attack?

Answer 7

an oxonium ion

Question 8

give one use of the acetal functional group

Answer 8

they are good protectors/maskers of ketones/aldehydes - especially cyclic acetals formed from diols

Question 9

give 4 disadvantages of using protecting groups

Answer 9

reduces yield, time intensive, expensive, inefficient - but most importantly, it gives the chemist control, this is essential

Question 10

name 1 other type of acetal + function

Answer 10

sulfur acetals = same as regular but S atoms instead of O - these are useful orthogonal protecting groups

Question 11

what carbonyl group are imines reminiscent of?

Answer 11

ketones/aldehydes
characterised by a C=N bond which behaves similarly to C=O, but is just slightly less reactive due to smaller electronegativity difference

Question 12

how are imines synthesised?

Answer 12

formed when primary amines react with aldehydes/ketones in an analogous reaction to acetal synthesis, this is a reversible reaction in acidic conditions so pH needs to be controlled throughout
this is a 2 step process - addition + elimination
- lone pair of amine attacks electrophilic C and carbonyl bond is broken
- PT neutralises deprotonated O and protonated N, becoming a neutral charge amine and hydroxy group
- O on hydroxy group attacks proton from acid, becoming water = better LG
- C=N bond formed and water leaves forming iminium ion
- deprotonation of N produces imine product

Question 13

how can yield of imines be improved?

Answer 13

reaction is reversible under acidic conditions, so removal of water helps to keep equilibrium on the right side

Question 14

what affects the rate of imine hydrolysis?

Answer 14

not all imines hydrolyse the same - ease of hydrolysis depends on how good the N is as a leaving group when protonated, bulkier imines = slower rate due to steric hinderance and burgi-dunitz angle of attack
also reactivity - aliphatic imines > aromatic imines

Question 15

what is the iminium ion reminiscent of?

Answer 15

oxonium ion - N version of this basically

Question 16

why is N a better nucleophile than O

Answer 16

O is not a great nucleophile despite lone pairs as both are held tightly by O due its its high electronegativity whereas N is more happy to share its lone pair

Question 17

why does pH need to be very carefully controlled during the production of an imine?

Answer 17

if pH<4 = too acidic, inhibits attack as acid protonates basic amine, so its no longer a nucleophile
if pH>6 = too basic, not enough H+ in system to protonate OH into H2O so it can leave

Question 18

what are the 2 forms of aldehydes/ketones?

Answer 18

aldehydes/ketones exist in 2 tautomeric forms, enol/ketol, which is a alkene + alcohol mix
R-C(=O)-H/R –> R=C(-OH)-H/R

Question 19

what is an enamine?

Answer 19

the enol version of an imine, they are tautomeric forms of eachother
R=C(-NH2/R2)-H/R

Question 20

how can enamines be formed?

Answer 20

like the tautomerisation of aldehydes/ketones to enols/ketols, the reaction of imine to enamine happens so quickly that the enamine isn’t very present
using a secondary amine to form the imine can change this equilibrium, as it forms an iminium ion = very reactive intermediate, pushing the equilibrium towards enamine, for this to happen however the aldehyde/ketone needs to have an α acidic proton to lose

Question 21

outline the anatomy of imines

Answer 21

overall electrophilic
dipole of C=N bond means the C is very δ+ and so can react with nucleophiles
N has lewis basic lone pair
has α acidic proton

Question 22

outline the anatomy of enamines

Answer 22

overall more nucleophilic
N doesn’t have a lewis basic lone pair anymore as its delocalised into π-system and pushes into π bond, it is electron rich at α carbon

Question 23

outline the reactivity of imines

Answer 23

imines can react with hydride sources + carbon based nucleophiles just like ketones + aldehydes, as nucleophile attacks electrophilic C

Question 24

outline the reactivity of enamines

Answer 24

enamines are more nucleophilic, and so can react with electrophiles to form a new bond, similar to alkenes, this gives iminium species which can react in other ways

Question 25

outline how the acetal + imine formation is similar

Answer 25

both have an addition step to form a tetrahedral intermediate, except for acetal O is protonated first both then undergo proton transfer to form a hemiacetal/hemiamenal both undergo elimination of water using lewis basic l.p on O/N this forms oxonium/iminium ion, both are reactive electrophilic intermediates

Question 26

what is the purpose of reductive amination?

Answer 26

formation of secondary amines from aldehydes the best + most controlled way to make secondary amines

Question 27

give 1 disadvantage of the amine + alkylhalide method of producing secondary amines

Answer 27

the secondary amine product is more reactive than the starting amine, so if left over alkyl halide is in the mixture it will react again, forming another more reactive species - monoalkylation is difficult - reductive amination avoids this

Question 28

what are the 2 important factors to control during reductive amination?

Answer 28

choice of reducing agent and pH must be carefully selected + controlled (moderate pH~6)

Question 29

what are the reagents used for reductive amination?

Answer 29

a primary amine + hydride

Question 30

what is the purpose of the hydride in reductive amination?

Answer 30

specific hydrides used are NaBH3CN or NaBH3R similar these are mild reducing agents, strong enough to reduce the iminium but not strong enough to reduce the aldehyde

Question 31

how are secondary amines formed from aldehydes via reductive amination?

Answer 31

- N attacks electrophilic carbon with lone pair, carbonyl bond is broken - PT neutralises deprotonated O and protonated N, becoming a neutral charge amine and hydroxy group - O on hydroxy group attacks proton from acid, becoming water = better LG - C=N bond formed and water leaves forming iminium ion - hydride attacks δ+ C via nucleophilic H and C=N bond breaks, forming secondary amine

Question 32

what is the purpose of the strecker reaction?

Answer 32

natures method for synthesising amino acids - used for synthesising unnatural amino acids

Question 33

how are amino acids formed from aldehydes via strecker reaction?

Answer 33

- N attacks electrophilic carbon with lone pair, carbonyl bond is broken - PT neutralises deprotonated O and protonated N, becoming a neutral charge amine and hydroxy group - O on hydroxy group attacks proton from acid, becoming water = better LG - C=N bond formed and water leaves forming iminium ion - -CN attacks δ+ C via nucleophilic H and C=N bond breaks, forming secondary amine + nitrile - acid hydrolysis of CN to form carboxylic acid, forms amino acid

Question 34

state a consideration when forming enols from asymmetrical carbonyls

Answer 34

2 possible enols can form - if a particular enol is desired the reaction needs to be altered

Question 35

which enol formed from an asymmetrical alkene is more stable?

Answer 35

the more substituted alkene is more stable

Question 36

what is the effect of multiple carbonyl groups on enols?

Answer 36

additional carbonyl groups offer stability + allow conjugation - 6 membered ring system forms with the 2 carbonyl Os connected by a single H - this is spectroscopically visible

Question 37

how can enols be formed?

Answer 37

formation can be forced via acid catalysis - carbonyl O attacks proton, becoming protonated - water attacks α acidic proton, causes C=O bond to break and removes +ve charge on O - enol product formed + acid reformed

Question 38

describe the acidity of carbonyls

Answer 38

carbonyl acidity is moderate, pKa ~20-30, less than water/carboxylic acids, more than sp3 groups acid strength is affected by stability of conjugate base, strength of H-X bond, where X = substituent/R group to carbonyl

Question 39

what governs reactivity in a C=O bond?

Answer 39

O has more of the charge, C has more of the HOMO, so reacts via the carbon

Question 40

what are standard organic pKa values measured in + why?

Answer 40

typically found with solvent DMSO, not water, as water helps to stabilise the carbanion and so pKa values tend to be lower

Question 41

how does charge distribution affect organic compounds?

Answer 41

if -ve charge is more spread out/pushed onto heteroatoms e.g. N/O, this is stabilising as they are more electronegative and want the electron density - this stabilises conjugate base

Question 42

what are the 2 possible enol/enolate products formed in the α deprotonation of an asymmetrical carbonyl?

Answer 42

thermodynamic product and kinetic product

Question 43

compare the kinetic enolate and the thermodynamic enolate reactivities

Answer 43

kinetic enolate is less substituted + less stable + more reactive, whereas the thermodynamic enolate is more substituted + more stable + less reactive

Question 44

compare the kinetic enolate and thermodynamic enolate preparation techniques

Answer 44

the kinetic enolate prefers strong, sterically hindered bases that are non nucleophilic in excess so there can be no other proton source or equilibrium being set up, so when being made a small amount of ketone is added to lots of base, prefers shorter reaction times, electrophile is added after its made the thermodynamic enolate prefers to react in excess ketone and with strong nucleophilic bases, very long reaction times allow an equilibrium to be set up and for excess ketone to reprotonate which later settles, so when made electrophile needs to be in situ becuase so little is made, and the reaction can be left for a long time

Question 45

compare the kinetic enolate and thermodynamic enolate reaction conditions

Answer 45

kinetic enolate is produced at cold temps, -78C typically thermodynamic enolate is produced at high temperatures, at or above room temp

Question 46

how does enolisation affect a carbonyl compound?

Answer 46

- conjugation is a driving force in chemistry, enols can be used to give a more stable molecule via protonation of carbonyl + allows double bond to be moved around - racemisation, any stereogenic centre next to a carbonyl will be destroyed by enolisation - enols are ambident = has 2 nucleophilic sites hard electrophiles react with carbonyl O, this is where all the charge is located, forms a new O-X bond with electrophile X soft electrophiles react with the π system/carbon, reactive due to orbitals

Question 47

what is α-halogenation

Answer 47

the halogenation of a ketone/aldehyde as a halogen substitutes with the α-acidic proton, occurs via enol

Question 48

what conditions are needed for α-halogenation?

Answer 48

acidic conditions - under these conditions the reaction can only happen once as halogen substituent pulls electron density from carbonyl reducing reactivity basic conditions - here multiple α-halogenation is possible because addition of the halogen stabilises the enolate under basic conditions, and the product α proton pKa is lower than the initial α H so the product is more acidic + reactive

Question 49

how are halogenated compounds produced via the α-halogenation of carbonyls?

Answer 49

under acidic conditions: - α proton attacks electrophilic carbonyl C, carbonyl O attacks acid and becomes protonated - this forms enol, O attacks C to reform carbonyl bond, alkene attacks dihalide - dihalide breaks and carbonyl oxygen proton is lost and product is formed under basic conditions: - base attacks α proton which attacks electrophilic carbonyl C, carbonyl bond breaks forming enolate - carbonyl bond is reformed and alkene attacks dihalide which breaks - base attacks α proton again which attacks carbonyl C, carbonyl bond breaks forming enolate - this can repeat again to substitute more halogen atoms onto the same carbon

Question 50

what is α-alkylation

Answer 50

the alkylation of a ketone/aldehyde as an alkyl group substitutes with the α-acidic proton, occurs via enol

Question 51

what is the general mechanism reactions of enolates occur by?

Answer 51

they have 2 steps - enolate formation from carbonyl, and addition of R group/alkylation

Question 52

is multiple alkylation possible?

Answer 52

yes - for the thermodynamic enolates which react with electrophile in situ of formation, any left over base will react with product of alkylation causing multiple alkylation

Question 53

what functional groups can undergo alkylation?

Answer 53

any carbonyl species with an α acidic proton that can be deprotonated can form an enolate and therefore undergo α-alkylation: aldehyde, ketone, dicarbonyl, nitrile some enol equivalents can also undergo α-alkylation: enamines, enol-ether type of things, silyl enol ethers

Question 54

generally how are compounds produced via the α-alkylation of carbonyls?

Answer 54

- O/heteroatom next to alkene attacks δ+ C reforming carbonyl, alkene then attacks electrophile - forms product with electrophile/alkyl substituent

Question 55

how are compounds produced via the α-alkylation of enamines?

Answer 55

this reaction occurs via alkylating agent such as haloalkanes, forming the corresponding ketone - N attacks δ+ C to form C=N bond, this attacks δ+ C adjacent to halogen, which breaks the bond with halogen - this forms substituted product, water attacks δ+ C causing C=N bond to break and neutralising +ve N ion - PT transfers +ve charge from water to N - O of OH group attacks δ+ C forming carbonyl bond, protonated N group leaves - product is alkylated ketone

Question 56

what accommodations are needed for silyl enol ethers undergo α-alkylation?

Answer 56

silyl enol ethers are less reactive than enolates, like enamines, so they require very reactive electrophiles or activation via lewis acid, they also form ketones

Question 57

what type of enolate can be used to ensure the kinetic product is obtained + what is 1 limitation?

Answer 57

Li enolates, these are most common, also K/Na enolates can be used and are moer reactivr because counterion is less closely bonded to the O - these are formed depending on which base is used, a Li containing base would obviously be needed this works well with ketones but not aldehydes as they are too reactive and Li enolate formed will react with itself and self condense

Question 58

how does alkylation of esters work?

Answer 58

esters have an α acidic proton, pKa~30, and the alkylation mechanism works similarly, however they can also react with their own enolate via claisen condensation, so much be kept cold to avoid this

Question 59

how does alkylation of carboxylic acids work?

Answer 59

carboxylic acids react similarly, and have α acidic protons of pKa ~5 - this is very acidic and so can react with any base, so nucleophilic bases can be sued

Question 60

what is micheal addition?

Answer 60

aka conjugate addition, 1,4-addition involved α, β unsaturated carbonyls as electrophiles = the addition of a nucleophile to an electron deficient alkene

Question 61

why can carbonyls undergo conjugate addition?

Answer 61

when a carbonyl is attached to an alkene, the alkene goes from being electron rich to electron deficient, this can be seen through resonance structures the driving force of the reaction is the formation of a new C-C bond

Question 62

what is unique about conjugate addition of α, β unsaturated ketones?

Answer 62

α, β unsaturated ketones have 2 electrophilic carbons, however the reaction still has complete regioselectivity, because the 2 sites have different reactivities: - the δ+ carbonyl C is very charge dense, electrostatics dominate and so can react with highly charged hard nucleophiles e.g. grignards, organolithiums (where charge is localised) - the β carbon has a lower charge density and so orbital interactions dominate, so it reacts with soft nucleophiles e.g. enolates, thiols, organocopper/cuprates, amines (where charge is more spread out)

Question 63

how does the nature of the carbonyl functional group affect what kind of conjugate addiciotn takes place?

Answer 63

hard nucleophiles/electrophiles prefer 1,2 addition, soft nucleophiles/electrophiles prefer 1,4 addition in order of decreasing proportion of direct C=O addition/increasing favour or 1,4 over 1,2: acyl chlorides adjacent to alkenes aldehydes adjacent to alkenes ketones adjacent to alkenes esters adjacent to alkenes amides adjacent to alkenes

Question 64

how does EWGs impact carbonyl?

Answer 64

presence of EWGs in α positions to carbonyl greatly reduces pKa of α proton, making deprotonation easier

Question 65

how do 1,3-dicarbonyls react intrestingly?

Answer 65

they have low α proton pKas, meaning these molecules can be deprotonated by weak bases alkoxide bases and solvents must be matched to the side group, e.g. use NaOEt + EtOH for Et side group or NaOMe + MeOH Me side group otherwise transesterification will occur, meaning the ester side groups will swap as base + solvent are in such excess

Question 66

what kinds of 1,3-dicarbonyls can undergo decarboxylation + how can you tell this is the reaction?

Answer 66

specifically 1,3-dicarbonyls where at least 1 side group is an ester occurs via reagents: 1. NaOH, H2O 2. HCl aq + heat