Block 6 - Functional Groups 2 Flashcards
Alcohol - naming priority
Alcohol functional group takes priority for numbering the parent alkyl chain
Alcohol - solubility
Small alcohols (up to C5) water soluble
Alcohol - acid or base
OH group of alcohol, under appropriate conditions, has ability to react either as an acid or base
Formation of either conjugate base (alkoxide) or conjugate acid (oxonium ion) is usually the first step in reaction of alcohols
Alkyl halide hydrolysis
Nucleophilic substitution (SN1 or SN2)
Nucleophile: H2O or OH-
Forms alcohol
Acid catalysed addition of H2O to alkenes
Electrophilic addition
Nucleophile: H2O
Requires acid (usually H2SO4)
Hydroboration-oxidation of alkenes
Anti-markovnikov's rule Electrophilic addition (followed by oxidation) Reagents: 1. B2H6, 2. OH-, H2O2 (reverses selectability, where most substituted = minor) B added to least substituted end of C=C bond, and then replaced with OH
Reduction of aldehyde
Nucleophilic addition
Reagent: 1. NaBH4 or LiAlH4, 2. H3O+
Forms 1° alcohol
Reduction of ketone
Nucleophilic addition
Reagent: 1. NaBH4 or LiAlH4, 2. H3O+
Forms 2° alcohol
Reduction of ester
Nucleophilic addition
Reagent: 1. LiAlH4, 2. H3O+
Forms 1° alcohol
RMgX
Grignard reagent
Addition of RMgX to methanal
Reagent: 1. methanal, 2. H3O+
Forms 1° alcohol
Addition of RMgX to other aldehydes
Reagent: 1. aldehyde, 2. H3O+
Forms 2° alcohol
Addition of RMgX to ketones
Reagent: 1. ketone, 2. H3O+
Forms 3° alcohol
Addition of RMgX to Z (ester or acid chloride)
Reagent: 1. ester / chloride, 2. H3O+
2 equivalents of Grignard reagent + ester / acid chloride added –> 3° alcohol
Phenols
Hydroxy (OH) group directy bonded to sp2 C of an Ar
Weakly acidic, as the phenoxide anion (conjugate base) is resonance stabilised
Aromatic rings - the more delocalised a charge is…
The more stable a molecule is
The more stable the conjugate base…
The more acidic the parent acid
Aromatic ring substituents - Electron Withdrawing Groups vs Electron Donating Groups
EWG:
Increase acidity as they stabilise the phenoxide anion
Groups that are deactivating towards electrophilic aromatic substitution will be electron-withdrawing
EDG:
Decrease acidity, as they destabilise the phenoxide anion
Groups that are activating towards electrophilic aromatic substitution will be electron-donating
Faster way (than SN2) of converting (primary) alcohols to alkyl chlorides
SOCl2, with pyridine
SOCl2 is a more nucleophilic source of Cl
Alcohol - nucleophilic substitution - alcohol acts as…
The electrophile
Alcohol to ether
Alcohols/alkoxides act as nucleophiles in a substitution reaction to give an ether
O- of alkoxide reacts with R-Br –> OR + Br-
Elimination of alcohol
Reagent: conc H2SO4 + heat
1° alcohol - E2 mechanism; won’t be in competition with SN2 as HSO4- is a very weak base and no nucleophilic
2° alcohol - either E1 or E2 mechanism
3° alcohol - E1 mechanism (stable carbocation)
Alcohol - oxidation
Involves breaking C-H bonds and forming C-O bonds
For oxidation to occur, must be at least 1 H attached to the C –> tertiary alcohols can’t be oxidised
Alcohol: Oxidation - 1° alcohol to aldehyde or COOH
Reacting with H2CrO4 (strong):
ROH –> [RCHO] –> RCOOH
Reacting with PCC (mild):
ROH –> RCHO
Alcohol: Oxidation - 2° alcohol to ketone
Reagent: H2CrO4
2° alcohol –> ketone
No further oxidation
Forming an alkyl halide from an alcohol involves formation of an _______ species
Oxonium
Forming an ether from an alcohol involves formation of an _______ species
Alkoxide
Forming an alkene from an alcohol involves formation of an _______ species
Oxonium
What is the chemistry of aldehydes and ketones governed by
Polarised C=O bond
Presence of lone pairs on C=O oxygen
Aldehydes and ketones - shape
C of C=O is sp2 hybridised (flat)
Aldehydes and ketones - oxidation
Aldehydes can be oxidised to c. acids in presence of a strong oxidant (H2CrO4)
Ketones can’t be oxidised as there’s no H on the C=O C to remove
Aldehydes and ketones - reactions
Nucleophilic addition reaction
For strong Nu, acid must be added after the Nu
For weak Nu, acid must be added with the Nu
Aldehydes and ketones - nucleophilic attack rates
Nucleophilic attack is the RDS, and depends on how +ve the sp2 C is; more +ve –> faster reaction
Fastest —————> Slowest
Methanal –> Aldehyde –> Ketone
Trend due to both electronic and steric effects
Aldehydes and ketones - addition of oxygen nucleophiles
1 equivalent --> 1 OH and 1 OR group bonded to C; known as hemiacetal - nucleophilic addition 2 equivalents (excess) --> 2 OR groups bonded to C; known as acetal - substitution
Aldehydes and ketones - forming imines
Ammonia or primary amines react with an aldehyde or ketone via addition followed by elimination (of water) to yield an imine
N is a better nucleophile than O so reaction doesn’t require addition of acid catalyst
Imines formed generally unstable but common intermediates
Imine, oxime and hydrazone compounds
Imine: G = -R, reagent = NH2R (amine) Oxime: G = -OH, reagent = NH2OH (hydroxyl amine) Hydrazone: G = -NH2, reagent = NH2NH2 (hydrazine)
Carbohydrates - classifications
Complex and simple
Complex carbohydrates
Consist of two or more simple sugars that are joined together
Hydrolysis of complex carbohydrates breaks them down into the constituent monosaccharide units
Monosaccharides
Simple sugars
Consist of a single carbon chain (usually 3-6 Cs long) with one carbonyl group (aldehyde or ketone) with hydroxy groups attached to remaining carbons
Disaccharides and polysaccharides
Complex sugars
Monosaccharide - classifications
Aldose (contains an aldehyde)
Ketose (contains a ketone)
Enantiomers - multiple stereocentres
For a compound with multiple stereocentres, all stereocentres must be reversed to generate the enantiomer
Reversing some but not all in the molecule gives a diastereomer
Relationship between no of stereocentres, stereoisomers and pairs of enantiomers
No of stereoisomers = 2^n (where n is no of stereocentres)
No of pairs of enantiomers = 1/2 the no of stereoisomers
D / L-sugars - notation is determined by…
The stereochemistry of the centre furthest from the C=O group
D / L-sugars
D sugar: stereocentre is R
L sugar: stereocentre is S
Sugars - cyclic hemiacetal
One of the alcohol groups can react with the aldehyde or ketone to form a cyclic hemiacetal
Sugars - cyclic hemiacetal formation; size and stability
Only 5 and 6-membered cyclic hemiacetals form easily
Size of ring depends on relative stabilities of possibilities
Many carbohydrates exist in an equilibrium between open-chain and cyclic forms
Sugars: Anomers - stereocentres
At C-1 in the cyclic form, a new stereocentre is formed
The two hemiacetal forms of a sugar are _________
Diastereomers
Anomers
Diastereomers that differ in configuration at only one asymmetric carbon
Anomers - classifications
α-anomer: when the C1 OH group and C5 CH2OH are trans
β-anomer: when the C1 OH group and C5 CH2OH are cis
System is in equilibrium, so amount of each form depends on relative stability of α and β-anomers - each anomer has 2 potential chair conformers –> total of 4 chair structures to be compared
Anomers - optical rotation
α:β ratio is 36:64
When a sample of either pure anomer is dissolved in water the optical rotation slowly changes to +53°
Mutorotation
Mutorotation
Spontaneous change in optical rotation observed when a pure anomer of a sugar is dissolved in water and equilibrates to an equilibrium mixture of anomers
Monosaccharides - ester and ether formation
OH groups present in carbohydrates (including anomeric one) can be converted to esters and ethers
H of alcohols replaced by CH3 (ether), or by CH3C=O (ester)
Glycoside
Acetyl of a sugar is called a glycoside
Stable to water
Not in equilibrium with an open chain form
Don’t show mutorotation
Monosaccharides: Forming ester - reagent
(CH3CO)2O
Monosaccharide: Forming ether - reagent
CH3I / Ag2O (mild reagents)
Hemiacetal and glycoside - reagents
Hemiacetal –> glycoside: CH3OH/H+
Glycoside –> hemiacetal: H3O/H+
Disaccharide formation
When acetal is formed with OH of a second sugar acting as an alcohol, a disaccharide forms
Glycoside bonds can form between the anomeric C on one sugar and any of the hydroxyl groups on other sugars
Carboxylic acids - acidity
Moderately weak acids
Ability to delocalise -ve charge in carboxylate anions –> more stable than alkoxides
Overall acidity of organic compounds containing an -OH group
Carboxylic acid > phenol > alcohol
Carboxylic acids - acidity (pKa) correlates with…
The electron donating or withdrawing effect of substituents
Groups either stabilise (withdrawing groups) or destabilise (donating groups) the carboxylate ion formed upon deprotonation
Increased stability = increased acidity
Carboxylic acids - EDG and EWG
EDG decrease acid strength (increase pKa)
EWG increase acid strength (decrease pKa)
Alkyl halide to carboxylic acid - Grignard addition
RX —Mg and dry ether—> R-MgX
R-MgX + CO2 –> R-CO(OMgX) —H3O+—> R-CO(OH)
Alkyl halide to carboxylic acid - nitrile
Nucleophilic substitution
RBr —(-)CN—> RCN —H3O+—> R-COOH
Where addition of H3O+ is hydrolysis
Only works for alkyl R groups
Carboxylic acids: Nucleophilic acyl substitution involves…
Addition followed by elimination (two steps)
Slow step is addition of nucleophile
Carboxylic acids: Reactivity order
Fastest to slowest:
Acyl chloride > acid anhydride > ester > amide > carboxylic acid
Acid anhydride
R-CO(OCOR)
Nucleophilic acyl substitution: Slow step
First step is slow step, so leaving group ability of Y in second step (fast) can’t affect relative rates of nucleophilic acyl substitution
Instead, rate of nucleophilic attack at carbonyl C in first step varies with Y, i.e. size of 𝛿+ charge on C=O (which is also dependent on Y)
Nucleophilic acyl substitution: If group Y is electron-withdrawing…
e.g. Y = Cl
The polarisation of the carbonyl group will be affected; the C becoming more positive
Therefore reacts relatively rapidly with a nucleophile in RDS
Nucleophilic acyl substitution: If group Y is electron-donating…
e.g. Y = OR or NR2
It will make the carbonyl C less positive
Therefore reacts relatively slowly with a nucleophile in RDS
Anhydride - reaction rate
Lies between acid chloride and ester, because while there is the possibility of donation from the O, it results in an unfavourable resonance hybrid (adjacent +ve charges)
Amides - reaction rate
Least reactive
Donation from lone pair on nitrogen is dominant resulting in a carbonyl group with much less 𝛿+
Lone pairs on N are more readily donated than on O
How are acid chlorides prepared
By reaction of a carboxylic acid and SOCl2
HCl and SO2 (g) are formed as bi-products in reaction
Reaction is non-reversible
Anhydride general structure
R-C-O-C-R1
|| ||
O O
Formation of carboxylic anhydrides
- Reacting COOH with a dehydrating agent (e.g. P2O5) –> results in only symmetrical anhydrides
- Reacting acid chloride with COOH –> results in both symmetrical and asymmetrical anhydrides
Acyl chloride / anhydride to amide reaction
RCOCl —R1-NH2—> RCO-NHR1 + HCl (strong and reactive)
Nucleophilic acyl substitution
Anhydride uses same reagents, but instead of giving HCl as bi-product, it gives COOH as bi-product; less reactive than HCl
Acyl chloride / anhydride to ester reaction
RCOCl —R1-OH—> RCO-OR1 + HCl (strong and reactive)
Nucleophilic acyl substitution
Anhydride uses same reagents, but instead of giving HCl as bi-product, it gives COOH as bi-product; less reactive than HCl
Acyl chloride to anhydride reaction
RCOCl —R1COOH—> RCO-OCOR1 + HCl (strong and reactive
Nucleophilic acyl substitution
Acyl chloride / anhydride to carboxylic acid reaction
RCOCl —H2O—> RCO-OH + HCl (strong and reactive)
Nucleophilic acyl substitution
Anhydride uses same reagents, but instead of giving HCl as bi-product, it gives COOH as bi-product; less reactive than HCl
Acyl chloride - Grignard reagent
Yields 3° alcohol
Reagent: 1. 2R1-MgX, 2. H3O+
Nucleophilic acyl substitution (forms ketone), followed by nucleophilic addition (forms 3° alcohol)
Acyl halide + alcohol –>
Ester + HCl
Carboxylic acid + alcohol –>
Ester + H2O
Requires large excess of alcohol (either methanol or ethanol)
Hydrolysis of esters
RCOOR1 —H2O/H3O+—> RCOOH + R1-OH (bi-product)
RCOOR1 —H2O/OH(-)–> RCOO- + R1-OH (bi-product)
Nucleophilic acyl substitution
Ester reaction with amine
RCOOR1 —R2-NH2—> RCONHR1 + R2OH
Nucleophilic acyl substitution
Reduction of esters
Nucleophilic acyl substitution followed by nucleophilic addition
RCOOR1 —1. LiAlH4, 2. H3O+—> RCH2OH + R1OH
Ester reaction with Grignard reagent
RCOOR1 —1. 2R2MgX, 2. H3O+—> 3° alcohol
Nucleophilic acyl substitution followed by nucleophilic addition
Base-promoted hydrolysis of esters (saponification)
Strong nucleophile OH- used; no catalyst required
Final carboxylic acid is in its conjugate base form (deprotonated)
Acid-catalysed hydrolysis of esters
Weak nucleophile H2O used; acid catalyst required
Final carboxylic acid is in its conjugate acid form (protonated)
4 reactive intermediates
Formation of 1°, 2° and 3° amides
1° amide: acid chloride (or acid anhydride) + ammonia
2° amide: acid chloride (or acid anhydride) + RNH2
3° amide: acid chloride (or acid anhydride) + R2NH
Hydrolysis of amide
Much less reactive towards nucleophilic acyl substitution, so hydrolysis requires strong aqueous acid or base
e.g. 70% aq. H2SO4 + heat, then OH- (in second step) to deprotonate the NH3+
Amide - acidity/basicity
Neutral –> very stable
Absence of basicity and low reactivity towards nucleophiles are due to resonance interaction, effectively decreasing availability of lone pair of electrons in nitrogen
Amine - N
Tetrahedral (sp3 hybrisdised)
Classified as 1°, 2° or 3° for 1, 2, or 3 alkyl or aryl groups directly bonded to N
Quaternary ammonium salts
Compounds with 4 groups attached to N
N has a positive charge
Aliphatic amines
N is directly bonded to an sp3 carbon
Aromatic amines
N is directly bonded to an sp2 carbon of an aromatic ring
Amine - naming
Where amine is the principle functional group, the suffix amine is used
Where amine functional group is considered a substituent, the prefix amino is used
Prefix N- is used to indicate a group is directly bonded to the N and not a branch on the C backbone
Amino acids
Bi-functional compounds containing both an amine and a carboxylic acid
α-amino acids: amine group is found on adjacent C (α-carbon) to the carboxylic acid
α-carbon of amino acids
With exception of glycine (R=H), the α-carbon of an amino acid is a stereogenic centre –> 2 enantiomeric forms possible
Naming amino acids
Uses L/D rather than S/R
Amine - basicity
Lone pair of electrons on N can act as a base or as a nucleophile
Exception of quaternary amines
Amine - pKa
The higher the pKa for the conjugate acid (ammonium salt), the more basic the amine
For simple alkylamines, pKa ≈ 10-11 (in aqueous solution)
Amine - pKa trends
Least basic —–> most basic
NH3 < CH3NH2 < (CH3)2NH
Inductive effects of alkyl/methyl groups pushes its electrons onto the N –> increased electron density –> increased basicity / pKa
(CH3)3N lies between NH3 and CH2NH2
Steric interaction due to crowding –> decreased basicity / pKa
Arylamines (aromatic amines) vs alkylamines
In aqueous solution, simple arylamines are much weaker bases than simple alkylamines
Due to delocalisation of lone pair of electrons on N into aromatic ring, making them less available to act as a base
Aromatic amines - EWG and EDG
EWG: decrease basicity / pKa
EDG: increase basicity / pKa
Amine - substitution (SN) of alkyl halide with NH3, RNH2 or R2NH
R-X + NH3 –> R-NH3+ –> R-NH2
Here, the product is more basic/nucleophilic, so continues to react with other alkyl halides
–> R-NH-R1 –> (R)3-N –> (R)4-N+Br-
Usually results in mixtures due to product being more reactive
Amine and aryl halides - nucleophilic substitution
Aryl halides (Ar) don’t undergo nucleophilic substitution to form an amine
Best way to make Ar-NH2
Reduce Ar-NO2
Ar-NO2 —1. Fe/H3O+, 2. OH(-)—> Ar-NH2 —CH3Br—> Ar-NHCH3
Reduction to form an amine
Nitrile, 1° amide, imine and oxime: undergo reduction with 1. LiAlH4, 2. H3O+ to form RCH2-NH2 (1° amine)
2° amide and N-substituted imine: undergo reduction with 1. LiAlH4, 2. H3O+ to form RCH2-NHR1 (2° amine)
3° amide: undergo reduction with 1. LiAlH4, 2. H3O+ to form RCH2-NR1R2 (3° amine)
-CN to -NH2
Reduction
1. LiAlH4, 2. H3O+
Amine reaction with acyl chloride
Acylation
1° or 2° amine reaction forms amide + HCl
3° amine doesn’t react with acyl chloride - no H on N that can be substituted
Amino acids - amphoteric property
Can act as either acids or bases
Amino acids - acid solution
Overall charge is 1+
NH3+ and COOH group
Amino acids - neutral solution
Molecule exists as a zwitterion - neutral charge
NH3+ and COO- group
Fully soluble in water
Amino acids - basic solution
Overall charge is 1-
NH2 and COO- group
Amino acids can link together…
Into long chains by forming amide bonds between the NH2 group of one amino acid and the COOH group of another
Dipeptide
2 amino acids combine to form a dipeptide
Forms CONH bond
Amino acids - naming convention
N-terminal amino acid (free NH2) to the left
C-terminal amino acid (free COOH) to the right
e.g. Gly-Ala: N terminal is at Gly, C terminal is at Ala
Amide bond formation - complexity
If you mixed 2 amino acids (e.g. Gly-Ala), would get a mixture of dipeptides (e.g. Gly-Ala, Ala-Gly, Gly-Gly, Ala-Ala)
If side chain contains a reactive functional group, then even more combinations are possible
Peptides vs proteins
Chains < 50 amino acids = peptides
Chains > 50 amino acids = proteins
Amide bond - shape
Planar, with N-H oriented 180 degrees to C=O
Structural organisation of proteins
Primary: amino acid sequence in peptide chain
Secondary: H-bonding alters local peptide geometry producing coils
Tertiary: disulphide bonds alter entire protein shape
Quaternary: diff proteins aggregate to form new structures
Radical (free radical)
An atom, molecule, or ion that has one or more unpaired valence electrons
Highly reactive towards other substances
How can radicals be generated
Homolytic bond cleavage - one electron from the bond ends up on each of the atoms which were formerly bonded
Basic steps in radical reactions
Initiation: Homolytic bond cleavage of a weak bond to generate 2 radicals. Usually facilitated by light (hv) or heat
Propagation: A free radical reacts with a molecule with no unpaired electrons to generate a new radical (and new covalent bond). No net change in no of radical species present
Termination: Eventually, a radical may combine with a second radical, generating a species with no unpaired electrons
Radical reactions - when does propagation end
Propagation is a repeating cycle, and will keep going until all the starting material is consumed, or termination occurs
Conc of radical species
In most radical reactions, conc of radical species are low –> radicals more likely to interact with a non-radical (propagation) than with a second radical (termination)
Radical stability
The more stable a radical is, the more likely it will survive long enough to encounter a second radical
Thus, stable radicals are more likely to react via termination than unstable radicals
What is a factor that increases radical stability
Delocalisation (ability to form resonance hybrids)
