Organic Chemistry Flashcards
1
Q
Relative Nucleophilicity
A
electron pair donor (HOMO) to an electrophile
-ve charge > lone pair > pi-bond > sigma bond
2
Q
Relative Electrophilicity
A
electron pair acceptor (LUMO)
empty orbital > pi* orbital > sigma* orbital
3
Q
Why does Nu: attack C=O group and specifically C atom of C=O
A
- Electrostatic attraction: electron rich Nu: attack electron poor C of C=O (large dipole)
- C and O are sp2 hybridised
- lone pairs on O are perpendicular to pi-system and are in sp2 HAOs
- Largest coefficient in the pi* is on C: strongest interaction with Nu: is with C
4
Q
Angle of attack (Nucleophilic addition to C=O)
A
107 degrees
- ideal angle of attack > 90 to C=O (max orbital overlap with slightly ‘splayed out’ pi*)
- repulsion from filled pi-bonding forces Nu: attack at more obtuse angle (e- density in pi bond repels Nu: e- density)
5
Q
Why is the nucleophilic attack by the H- ion itself not a known reaction
A
H- not well matched for interaction with C more diffuse 2p orbital contribution to LUMO (pi* of C=O group)
H- anion prefers to interact with H-X not C=O as filled 1s orbital (H-) is ideal size to interact with H atom’s contribution to sigma* orbital of H-X bond
6
Q
Reduction of C=O group with hydride (NaBH4) - mechanism
A
7
Q
Synthesis of Alkyl, Aryl and Vinyl Organometallic Reagents
A
8
Q
Synthesis of Alkynyl Organometallic Reagents (Mechanism)
A
9
Q
Deprotonate alkyne with strong nitrogen base (NaNH2) to generate organometallic species (mechanism)
A
10
Q
Reaction of Organometallic Compounds (mechanism)
A
11
Q
Organometallic reagents R-Li and R-MgBr are incompatible with water
A
12
Q
Form Hydrates from aldehydes/ketones
A
Add H2O
13
Q
Form hemiacetals and acetals from aldehydes/ketones
A
Add alcohol
14
Q
Aldehyde/ketone + water (mechanism)
A
15
Q
Significant concentrations of hydrate usually only formed from aldehydes
A
- increase size of R groups attached to C of C=O: harder to form hydrate as we move from bond angle of 120 in SM to one of 109.5 in hydrate - harder to form hydrate product with larger R groups as steric clash in product greater in starting C=O compound
- ring strain factors: strained ring - hydrate formation favourable due to release of ring strain with decreased bond angle
16
Q
Hemiacetal formation from aldehyde/ketone (acid catalysis) - mechanism
A
Acid catalysis: make C=O group more electrophilic
17
Q
Hemiacetal formation from aldehyde/ketones (base catalysis) - mechanism
A
Base catalysts: make Nu: more electrophilic
18
Q
Why is acetal formation from hemiacetal done through acid catalysis only
A
to make OH group a good leaving group (cannot happen under basic conditions)
19
Q
Acid catalysis acetal formation from hemiacetal (mechanism)
A
20
Q
Quantify leaving group ability with pKa
A
the lower the pKaH the better the leaving group
21
Q
pKa of HI/pKaH of I-
A
-10
22
Q
pKa of HCl/pKaH of Cl-
A
-7
23
Q
pKa of H2SO4/pKaH of HSO4-
A
-3
24
Q
pKa of HSO4-/pKaH of SO4 2-
A
2
25
pKa of CH3CO2H/pKaH of CH3CO2-
4.8
26
pKa of H2S/pKaH of HS-
7
27
pKa of NH4+/pKaH of NH3
9.2
28
pKa of C6H5OH/pKaH of C6H5O-
10
29
pKa of CH3CH2OH/pKaH of CH3CH2O-
15.9
30
pKa of propanone
20
31
pKa of ethyne
24
32
pKa of NH3/pKaH of NH2-
33
33
pKa of C6H6/pKaH of C6H5-
43
34
pKa of CH4/pKaH of CH3-
48
35
Anion stability (linked to electronegativity of elements)
Increase electronegativity of atom which -ve charge sits
Decrease pKa
Increase anion stability
Increase leaving group ability
36
Anion stability (delocalisation of negative charge)
More resonance forms
Decrease pKa
Increase anion stability
Increase leaving group ability
37
Anion stability (strength of A-H bond)
Weaker A-H bond strength
Decrease pKa
Increase anion stability
38
Effect of hybridisation on pKa
s orbitals held closer to nucleus than p orbitals
e- in s orbitals are lower in energy and more stable
more s character an orbital has, the more tightly held are the e- in it
pKa: sp < sp2 < sp3
39
3 factors for nucleophilic substitution at the carbonyl group
1. Strength of incoming nucleophile
2. Reactivity of Carbonyl Group
3. Leaving Group Ability
40
Strength of incoming nucleophile (Nucleophilic substitution at carbonyl group)
Higher pKa of HNu, the better the Nu:
Good nucleophiles are poor leaving groups
41
Reactivity of carbonyl group (nucleophilic substitution at carbonyl group) - Inductive effect
- electronegativity of group adjacent to carbonyl C and withdrawal of e- density through sigma-framework
- greater +ve charge on carbonyl C
- more reactive it would be to Nu: attack
42
Reactivity of carbonyl group (nucleophilic substitution at carbonyl group) - Conjugative effect
- delocalisation of lone pair from attached group (X) into pi* carbonyl system
- reduces +ve charge on carbonyl C
- makes C=O less reactive towards Nu: attack
Order of strength of lone pair donation: Cl < O < N
- Cl worst: donating from 3rd rather than 2nd shell
- C is better matched for donation from O and N: all in same row of periodic table
43
Summary of reactivity of different carbonyl groups
44
Reactivity of carbonyl group (nucleophilic substitution at carbonyl group) - Leaving Group Ability
45
Reduction of acid chlorides/anhydrides to alcohols with NaBH4
46
Reduction of esters to alcohols using LiAlH4
LiAlH4 is a stronger reducing agent
47
Reduction of carboxylic acids to alcohols using borane (BH3)
LiAlH4 reduces carboxylic acids relatively slowly and NaBH4 will not work: not reactive enough
48
Reduction of amides to amines using LiAlH4
49
Summary of hydride reducing agents for carbonyl groups
50
Reaction with acid halides/anhydrides with organometallic reagents
51
Reaction with acid halides/anhydrides with organometallic reagents (mechanism)
- SM more reactive than ketone
- acid chloride/anhydride will react with organometallic species more quickly than ketone
- if 1.0eq of organometallic species present: major product will be the ketone
52
Reaction with esters and organometallic reagents
53
Reaction with esters and organometallic reagents (mechanism)
- ketone more reactive than ester SM: reacts with organometallic species more quickly than ester SM
- if 1.0 eq of organometallic species is present, at end of reaction, major product will be alcohol double addition product with around 50% of SM
54
Reaction with carbon dioxide and organometallic species to form carboxylic acids
55
Summary of organometallic species reactions
56
Ease of hydrolysis of carbonyl group species and conditions for each
57
Acid-mediated hydrolysis of esters (mechanism)
- protonating carbonyl O: more susceptible to attack by nucleophiles
- protonating the leaving group: lowers pKaH and makes it a better leaving group
- in ester case: acid catalyst regenerated - process truly catalytic in acid
58
Acid-mediated hydrolysis of amides (mechanism)
Acidic conditions:
- protonating carbonyl O: more susceptible to attack by nucleophiles
- protonating the leaving group: lowers pKaH and makes it a better leaving group
- in amide case: amine that leaves is protonated under acidic conditions, meaning that 1.0eq of acid used up in reaction - not catalytic in acid
59
Base-mediated hydrolysis of esters and amides (mechanism)
Basic conditions:
- create a -vely charged Nu: (more reactive) - increased overall reactivity
- deprotonating the carboxylic acid product, putting the eqm over irreversibly towards the hydrolysis products
60
Summary of hydrolysis reactions and conditions
61
Summary of esterification with different compounds and conditions
62
Large nucleophiles are usually soft nucleophiles (large and 'fluffy') - high HOMO
- Small HOMO-LUMO gap means reactions dominated by FMO interactions
- Low charge density (often uncharged) means electrostatics are not important
63
Small nucleophiles are normally hard nucleophiles (small and 'punchy') with a low HOMO
- Large HOMO-LUMO gap means cannot be dominated by FMO interactions
- High charge density means electrostatics important: reaction driven by electrostatics but orbtials still used for reaction
64
Summary of the 2 types of nucleophiles (hard and soft)
65
Nucleophilic substitution at saturated carbon: SN1 and SN2 general reaction scheme
SN1
Rate = k[substrate]
SN2
Rate = k[substrate][Nu]
66
SN1 and SN2 progressions of reaction v energy plot
67
Factors whether nucleophilic substitution occurs: substrate structure (steric hindrance)
SN2 reactions become less likely the more substituents there are on the C centre being attacked by the nucleophile
- the more numerous the substituents on central C therefore, the more difficult it will be to form this transition state (higher energy due to greater steric clashes when reduced bond angles present)
SN1 more likely the more substituents on central C because of stabilisation of carbocation rather than steric hindrance
68
Factors influencing carbocation stability in SN1 reactions (hyperconjugation/sigma-conjugation)
Why is the planar structure preferred in carbocation
- bond angle of 120 keeps the C-R bonds as far away from one another as possible, minimising repulsion of bonding pairs of electrons
- electrons are placed into bonds which contain greatest amount of s-orbital character and this system is therefore lower in energy when sp2 hybrids (33% s) are used than sp3 (25% s)
69
Factors influencing carbocation stability in SN1 reactions (hyperconjugation/sigma-conjugation)
Relative rate in terms of carbocation:
3 > 2 > 1 > Methyl
70
Factors influencing carbocation stability in SN1 reactions (pi-bond donation) - double bonds/aromatic rings
- pi bonds can donate through conjugation where +ve charge is stabilised by delocalisation
- more double bonds to which +ve charge can conjugate, the more stabilised the carbocation
71
Factors influencing carbocation stability in SN1 reactions (lone pair donation)
- Lone pair donation is strongest of all stabilising effects
In acid catalysed acetal formation from hemiacetal is SN1
- SN2 mechanism is very unlikely at such a crowded centre (O lone pair HOMO) will struggle to place electrons into C-O sigma* (LUMO)
- corresponding SN1 mechanism is so efficient with neighbouring RO group present (intramolecular process, where the O lone pair can stabilise carbocation intermediate)
72
Factors which influence carbocation stability in SN1 reactions (summary)
1. Adjacent sigma bonds (sigma-conjugation or hyperconjugation): the more of these there are, the more stabilised the carbocation
2. Adjacent pi-bonds: benzene ring better than isolated double bond due to increased number of resonance forms possible
3. Lone pair of electrons
73
Factors which influence transition state stability in SN2 reactions (2 major types of group for stabilisation)
Both electron-donating and withdrawing substituents are able to stabilise the SN2 transition state
74
Factors which influence transition state stability in SN2 reactions
For carbonyl group, stabilisation of transition state is not the only reason that SN2 reactions proceed with such speed. What is the other factor
75
For the SN2 reaction process, discuss the relative rate of each substrate from left to right (increasing rate)
1. steric hindrance
2. pi-conjugation in TS but more hindered than Me
3. least hindered
4. more pi-conjugation in TS than allyl combats hindrance
5. C=O pi* conjugation in TS
76
Discuss the SN1 or SN2 mechanism of each substrate with alkyl groups attached
77
Discuss the SN1 or SN2 mechanism of each substrate with groups other than simple alkyl groups attached
78
Stereochemical consequence of SN1 and SN2 reaction process
SN1: racemic mixture
SN2: single enantiomer
79
Stereochemical outcome in an SN1 reaction: racemic mixture
Mechanism of SN1 reaction proceeds via a planar carbocation, incoming Nu: may attack the carbocation either from top face or bottom face resulting in a 1:1 mixture of enantiomers
80
Stereochemical outcome in an SN2 reaction: single enantiomer
SN2 gives inversion of stereochemistry at the C atoms that has been attacked - if reaction begins with a single enantiomer, product will be a single enantiomer: no racemisation
81
SN1 or SN2 at sp2 centres
No SN1 or SN2 nucleophilic substitution at sp2 centres
82
Nucleophile affecting SN1 reaction process
SN1 reaction process: nucleophile not important
- RDS is loss of leaving group so good and bad nucleophiles all give products
- nucleophile need not be deprotonated to make it more reactive as nucleophile is attacking highly reactive carbocation
83
Nucleophile affecting SN2 reaction process
Nucleophile very important as plays part in RDS
For carbonyl group, nucleophilicity parallels basicity almost exactly and pKa scale can be used for this
- species that readily forms new bonds to H (a strong base with high pKa value) will also readily form bonds to C (higher pKa of HY, the better the nucleophile Y)
84
SN2 reaction process: Nucleophile strength
Atom forming the bond is the same over the range of nucleophiles
Nucleophilicity does parallel basicity in this case
The anions of weakest acids are the best nucleophiles
85
SN2 reaction process: Nucleophile strength
Atom forming the bond is not the same over the range of nucleophiles
pKa does not matter as small differences in electronegativity is less important in SN2 process
SN2 reactions dominated by HOMO-LUMO interactions means that soft nucleophiles will react best in SN2 reactions
electrophile the same, the lower down the periodic table the nucleophilic atom is found:
- larger the atom
- higher in energy its lone pair (HOMO)
- closer in energy are the HOMO of nucleophile and LUMO of electrophile (sigma*)
- better HOMO-LUMO interaction between nucleophile and substrate
- more favourable for SN2
86
Leaving group ability for SN1 and SN2 reaction processes as departure of leaving group involved in RDS (Halides: F, Cl, Br, I)
2 main factors:
- C-X bond strength
- Halide ion stability
Decrease in C-X bond strength and greater anion stability, I- is best leaving group and F- not good with other halides in between
87
Leaving group ability for SN1 and SN2 reaction processes as departure of leaving group involved in RDS (OH derivatives)
OH- not usually a leaving group in nucleophilic substitution at saturated C
3 major factors:
- pKa of water is 15.7: not good leaving group
- Nu: often basic enough to remove the proton instead
- Even if it did displace the OH- anion, OH- is basic and could remove the proton from alcohol anyway, preventing further reaction
88
To make OH better leaving group for nucleophilic substitution: protonation
OH- not good leaving group (pKaH = 15.7 (H2O)) converted to OH2+ which is a good leaving group (pKaH = -1.7 (H3O+))
reaction would not proceed in absence of acids
89
To make OH better leaving group for nucleophilic substitution: sulfonate ester formation (mechanism)
OTs is a good leaving group (pKaH = -1.3 (TsOH))
pKaH of pyridine = 5
Best option to use tosylate is where acidic conditions cannot be used (e.g. C-C bond formation using an organometallic reagent as nucelophile)
90
Leaving group ability for nucleophilic substitution reactions: why are ethers generally unreactive in nucleophilic substitution
- very little bond angle strain
- C-O bond is very strong
- alkoxide anion is similar in its leaving group ability to the OH- anion (pKa of alcohols is usually 15-18, water is 15.7): alkoxides not good leaving groups
91
Leaving group ability for nucleophilic substitution reactions: epoxides
- C-O bond weaker due to less good overlap and severe bond angle strain
- C and O sp3 hence desired bond angle is 109.5 but in 3 membered rings it is constrained to 60 to 49.5 smaller than angle desired
- release of ring strain make them good electrophiles in SN2
92
Stereochemistry of epoxide opening
If epoxide ring is fused to another ring, SN2 reaction must occur with inversion
93
Leaving groups summary for SN1 and SN2
Halides:
- I- is best halide leaving group, F- worst
Hydroxy derivatives:
- OH must be derivatised in order to react as a leaving group, either protonated (if acidic conditions) or made into a sulfonate ester
- ethers are common hydroxy derivative but not very reactive towards Nu: attack. Exceptions are when ether is protonated (as for alcohols), making a better leaving group or when ether is highly strained 3-membered epoxide ring
94
Solvent for SN1 reaction process
Polar, protic solvents
Polar protic solvents encourage formation of ions in RDS as they will solvate both of the intermediate ions
95
Solvent for SN2 reaction process
Polar, aprotic solvents are best
- SN2 reactions use an anion as Nu: which will be added to the reaction with its cation counterion paired up with it
- Polar aprotic solvents solvate cations well but not anions making anions more reactive Nu:
96
Solvent types and dielectric constants for SN1 and SN2
97
Summary of SN1 and SN2 preferential reaction
1. Substrate structure: most important factor for SN1 or SN2 process
2. Nucleophile: important for SN2 but not SN1
3. Leaving group: important for both as in RDS for both
4. Solvent: polar, protic for SN1 and polar, aprotic for SN2
98
E1 vs E2: rate of reaction
E1:
rate = k[RL]
E2:
rate = k[RL][Nu]
99
E1 elimination process in terms of orbitals
- Formation of carbocation, alkene-forming step to proceed, C-H sigma bond attached to proton being removed must be parallel to empty p-orbital for best overlap
2 HOMO-LUMO interactions:
1. lone pair on B: (HOMO) with C-H sigma* (LUMO)
2. C-H sigma bond (HOMO) with empty p-orbital (LUMO)
this results in formation of BH plus alkene (leaving group is Br- and departed already in RDS)
100
E2 elimination process in terms of orbitals
Most efficient overlap to take place is C-H sigma-bond and C-Br sigma* bond must lie antiperiplanar to one another
2 HOMO-LUMO interactions:
1. lone pair on B: (HOMO) with C-H sigma* (LUMO)
2. C-H sigma bond (HOMO) with C-Br sigma* (LUMO)
101
Stereochemical outcome of E1: form 2 distinct products due to restricted rotation about double bond
E1: trans/E isomer is the major product
| - minimisation of steric clash: putting group on opposite sides (trans) means less steric clash
102
Stereochemical outcome of E2 elimination
C-H sigma and C-X sigma* must usually be antiperiplanar to elimination, outcome depends on arrangement of the substitutents in the starting material (rotation can now no longer give product which minimises steric clash between groups attached)
103
Discuss leaving group abililty for E1 and and E2 for these leaving groups
104
Factors which determine whether elimination or substitution occurs
1. Substrate structure: typical SN1 reaction substrates can work well with E1; those which work well in SN2 reaction processes are good for E2
2. Basicity of nucleophile: strong bases give elimination
3. Size of nucleophile: large Nu: give elimination
4. Temperature: high temperatures favour elimination
105
Discuss substrate types and how well they would react through E1 or E2
Outcome is the same whether reactions proceed by E1 or E2 but important to recognise that they are not linked to SN1 or SN2 reactions respectively: flexibility in pathway which can occur
106
Substrates which cannot eliminate by either E1 or E2 mechanism
Not possible to draw the elimination mechanism (neither E1/E2 are possible): with these substrates, no hydrogens in right place
107
Basicity of nucleophile to determine whether elimination or substitution
pKa values of different compounds
Strong bases give mainly elimination where weak ones give nucleophilic substitution
108
Size of nucleophile: whether substitution or elimination will occur
For Nu:, attacking a C atom in an SN2 substitution reaction means 'squeezing' through substrate substituents to access the sigma*
Accessing more exposed alpha-H atom in an elimination reaction is much easier
Bulky basic nucleophiles - elimination favoured even for primary halides
109
Temperature: whether substitution or elimination will occur
Higher temperatures favour elimination
Entropy: 2 molecules to 3 in elimination and 2 molecules to 2 in substitution
dS greater
reaction where dS is more positive becomes more favourable (dG becomes more negative)
110
Summary of nucleophiles and substrate structures, which would go through SN2/SN1/E1/E2
- R-X derivatives where R-Me cannot eliminate: as there are no appropriately placed protons - reactions always proceed via SN2 regardless of Nu:
- Increasing branching: favours elimination - increased carbocation stability for E1 and increased numbers of protons available for elimination by either mechanism
- Strongly basic hindered nucleophiles: elimination unless impossible
- Good (weakly basic) nucleophiles: SN2 unless substrate tertiary, in which case intermediate cation E1/SN1
111
Electrophilic addition of H-X to C=C (unsymmetrical double bond) - mechanism
- Higher energy reactive carbocation intermediate has a higher energy transition state on path to its formation
- formation of more stabilised cabocation intermediate during RDS is faster due to lower energy pathway via lower energy transition state
- more alkyl groups enhances the rate of reaction as more stable carbocation intermediate
112
Bromination and Iodination of C=C double bond (mechanism)
113
Stereochemical outcome of bromination and iodination of C=C double bond
114
Halohydrin formation and reaction (mechanism)
115
Stereochemical outcome of halohydrin formation
116
Formation of epoxide from a trans-halohydrin (mechanism)
Halohydrin treated with base, alcohol is deprotonated and a rapid SN2 reaction follows: halide expelled as leaving group and epoxide formed
can be done on linear or cyclic structures but in case of trans-halohydrin product formed on 6-membered ring, stereochemistry is set up well to react in this process
117
Formation of epoxide from m-CPBA from alkene (mechanism)
118
Stereochemical outcome of epoxide formation with m-CPBA
Both new C-O bonds are formed on same face of alkene's pi-bond, geometry of alkene is reflected in stereochemistry of epoxide
cis-alkenes give cis-epoxide
trans-alkenes give trans-epoxide
119
Hydroboration: addition of water with opposite regioselectivity (conditions of reaction)
120
Hydroboration: addition of water (BH3 mechanism)
With BH3, always point out that these steps will occur 3 times, giving rise to maximum then of 3 product molecules for every molecule of borane that was used
Do not repeat mechanism
121
Hydroboration: addition of water (2nd step mechanism: H2O2, NaOH, H2O)
122
Stereochemical outcome of hydroboration
Boron and hydrogen add to double bond, stereochemical outcome from reaction process overall is the syn addition of H and OH to double bond
123
Steric hindrance adjacent to a ring double bond: influence on stereochemical outcome
Less hindered face becomes favoured over the more hindered face
124
Carboxylic acid to acid chloride (reaction conditions)
Add SOCl2
125
Alkene to Alkane (reaction conditions)
H2, Pd/C (cat), ROH
