Reactivity of Carbon Centres Flashcards
(436 cards)
1
Q
When is a reaction nucleophilic?
A
When the reaction involves the attack of a nucleophile
2
Q
When is a reaction a substitution?
A
One functional group is changed for another
3
Q
What are the two mechanisms for substitution?
A
SN1 and SN2
4
Q
What are SN1 and SN2 reactions dependent on?
A
SN1 reactions follow first order kinetics and are only dependent on conc of electrophile
SN2 reactions follow second order kinetics and are dependent on conc of electrophile and nucleophile
5
Q
What is true about the hydrolysis of alkyl halides?
A
There is different rates for different alkyl halides
6
Q
What is the rate law for SN1 reactions?
A
Rate = k[R₃CX]
7
Q
What is the intermediate in SN1 reactions?
A
Trigonal planar carbocation intermediate
- sp2 hybridised with orthogonal empty p orbital
8
Q
What is the order of reactivity for SN1?
A
3°>2°>1°>Me
Tertiary substituted reactants are more likely to react
9
Q
What is the difference in what reacts between SN1 and SN2?
A
Tertiary - most likely to be SN1
Primary - most likely to be SN2
Secondary - need to consider other reasons
10
Q
Why does increasing R groups lower the activation energy of SN1 reactions?
A
Intermediate becomes more stable which in turn stabilises transition state and therefore decreases Ea
- Due to inductive and hyper conjugation effects as well as Hammonds postulate
11
Q
What is the mechanism for SN1?
A
Two step mechanism
1. Loss of the leaving group, forming carbocation
2. Nucleophilic attack on the carbocation
12
Q
What is the mechanism for SN2?
A
One step mechanism
1. Nucleophile attacks substrate
2. Transition state forms
3. Leaving group leaves and product forms
13
Q
What is the rate law for SN2 reactions?
A
Rate = k[R₃CX][Nu]
14
Q
What is the singular transition state in SN2 reactions?
A
Trigonal bipyramidal transition state where both Nu and X are partially bonded
15
Q
What is the order of reactivity for SN2?
A
Me>1°>2°>3°
16
Q
What is Hammonds Postulate?
A
If two states occur consecutively during a reaction process and hence nearly have the same energy, their interconversion will involve only a small rearrangement
- Simply, the structure of these two states will resemble each other
17
Q
How does Hammonds Postulate relate to SN1 reactions?
A
The structure of the transition state will resemble the structure of the carbocation intermediate
18
Q
What overall determines SN1 order of reactivity?
A
Carbocation stability
More stable carbocation = More reactive
19
Q
How do C-H sigma bonds increase stability in SN1 reactions?
A
Adjacent C-H (or C-C) σ orbitals overlap with the empty p orbital resulting in increased stabilisation
As you increase number of R groups, there is more C-H sigma overlaps so increased stability
20
Q
How can aliphatic carbocations be stabilised?
A
By sigma conjugation
21
Q
How can allylic and benzylic carbocations be stabilised?
A
By conjugation of pi or lone pair electrons
- Resonance forms
22
Q
What is true about unsymmetrical allylic cations?
A
They can result in a mixture of products as nucleophile can attack different carbons
- Either positive charge or end of a pi bond
23
Q
What is true about reactions of benzylic cations?
A
They almost always react at the side chain position and not in the ring
24
Q
What determines reactivity for SN2 reactions?
A
Sterics determine SN2 order of reactivity
As well as T.S. stabilisation
25
How does SN2 work?
- 180 degree angle of attack of the filled orbital of nucleophile on the empty σ* orbital of C-X bond
- New σ bond forming and old σ bond breaking to and from the p orbital on C atom
26
What kind of attack occurs in SN2 reactions?
Back side attack
27
What happens as you increase number of R groups for SN2 reactions?
Increases steric hindrance to back-side attack
So decreases ease of SN2
28
What reactions do allylic and benzylic electrophiles encourage?
Encourage an SN1 mechanism but also react rapidly via SN2
- Effective stabilisation is possible with carbonyl pi bonds
29
What is the relative reactivity of different compounds for SN1 reactions?
Methyl, 1° and ɑ-carbonyl - bad
2° - okay
Alllylic and benzylic - good
3° - very good
30
What is the relative reactivity of different compounds for SN2 reactions?
3° - bad
2° - okay
1° and allylic - good
methyl and benzylic - very good
ɑ-carbonyl - excellent
31
What is the stereochemistry of SN1 reactions?
They proceed with racemisation at the reacting centre
Equal chance of nucleophilic attack above and below
Results in a racemic mixture
- can be measured by optical rotation
32
What is the stereochemistry of SN2 reactions?
They proceed with inversion of stereochemistry at the reacting centre
Nucleophile approaches at 180 degrees from the leaving group
Results in formation of opposite enantiomer
- can be measured by optical rotation
33
How can you control SN1 vs SN2?
Can control via the choice of solvent
34
What are the effects of solvent on SN1 reactions?
An increase in solvent polarity gives an increase in reaction rate
Protic (polar) solvents which can stabilise the anion are best for SN1
35
What part of the molecule is stabilised by solvation?
Leaving group
36
How can solvent polarity be measured?
Via its dielectric constant ε
A measure of the ability of a solvent to screen the electrostatic attraction between + and - charges
37
What happens at a high value of the dielectric constant?
Higher the value, the more stable the ions and the easier it is to separate the charges in the TS of an SN1 reaction
38
Do higher numbers of dielectric constants mean more favourable for SN1 reactions?
No as if a solvent is protic this will adjust the favourability
39
What are the solvent effects on SN2 reactions?
For SN2 reactions with a negatively charged nucleophile, an increase in solvent polarity gives a decrease in reaction rate
Aprotic solvents which do not stabilise the anionic nucleophile are best for SN2
40
What can polar aprotic solvent anions be described as?
They are only weakly solvated and can be described as naked anions
41
What is solvation?
Process where solvent molecules surround and interact with solute particles, stabilising them in solution
42
What happens to leaving groups in both SN1 and SN2 reactions?
The leaving group takes part is the rate determining step
43
What two main factors determine leaving group ability?
The strength of the C-X bond
The stability of X-
44
What can be used as a measure of the stability of X-?
pKa - lower value means more stable X-
45
What happens to ions in protic and aprotic solvents?
Protic - solvated anion
Aprotic - solvated cation and naked anion
46
What is true about nucleophilic substitution on alcohols?
Alcohols do not react with nucleophiles since OH- is a bad leaving group
- Protonation of alcohols with strong acid provides a good leaving group (water)
47
What is key to know about protonation of alcohols to get a good leaving group?
It can happen in primary, secondary or tertiary reactions
It is restricted as need the reaction conditions to be tolerant of acids
Powerful for SN1 chemistry as protic solvents provide H+
48
How can alcohols be converted to halides?
Using phosphorus halides
Use PBr3, PI3 or PCl5
- PCl3 is a corrosive liquid
49
How else, apart from protonation, can alcohols be made into good leaving groups?
Via tosylation
- Made using para-toluene sulphonyl chloride
50
What is the Mitsunobu reaction?
Allows us to put an alcohol directly into a reaction mixture and get an SN2 reaction product
It proceeds via an inversion of configuration
51
What is true about ethers as electrophiles?
They do not react with nucleophiles
Can be made into better leaving groups using protonation
52
What is true about epoxides as electrophiles?
Epoxides are reaction oxygen-containing electrophiles which do not need further activation
- They react with amines cleanly via an SN2 mechanism
53
In SN1 reactions, what does the nucleophile not do?
Determine the rate of reaction
But can determine which product is formed
54
What, related to the nucleophile, determines the product in an SN1 reaction?
The strength of the nucleophile in a potentially nucleophilic solvent
55
What happens in the absence of a strong nucleophile in an SN1 reaction?
A poor nucleophile can still react via an SN1 mechanism
56
In SN2 reactions, what does a nucleophile do?
Determines the rate of reaction
57
For a given attacking atom of a nucleophile, what happens with increasing nucleophilicity towards saturated carbons?
Mirrors increasing basicity and can be used to predict which part of the molecule may react
58
What is the Ritter reaction?
Alcohol to an amide where MeCN (the solvent) is the nucleophile as even though it is a poor nucleophile it is the only available nucleophile so reacts
59
How can we use increasing nucleophilicity towards saturated carbons to determine rate of reaction?
If the nucleophile is stable e.g. low pKa then it is less likely to react
Can help us decide which part of the molecule will react
60
When can pKa be used to explain differing rates of SN2 reactions?
When the nucleophilic is the same e.g. when oxygen is the attacking atom so OH-, PhO-, AcO- etc
61
What is the trend in nucleophilicity towards saturated carbons down a group?
Nucleophilicity increases down a group (in reverse order to basicity)
62
Are soft or hard nucleophiles better for SN2 reactions?
Soft nucleophiles are better (large polarisable with high energy HOMO) compared to hard nucleophiles (small, non polarisable with low energy HOMO)
63
What controls SN2 reactions?
HOMO-LUMO interactions
Rate of SN2 reaction ∝ orbital interaction
Rate of SN2 reaction ∝ 1/ΔE
As ΔE reduces and there is more interaction, rate increases
64
How are SN2 reactions controlled by HOMO-LUMO interactions?
The change in energy between the lone pair on the nucleophile and the LUMO in the electrophile determines rate of reaction
65
How can you take advantage of the trends in soft and hard nucleophilicity in halides?
As you go down the group, the halides become hard nucleophiles
You can do a halide exchange reaction (Finkelstein reaction) taking advantage of this
Sodium iodide is soluble in acetone whereas other sodium halides are not so can swap out leaving group with iodine
66
What are halide exchange reactions often used for?
To obtain a alkyl iodide which is a better leaving group than bromine or chlorine
67
What is a key use for oxygen nucleophiles?
To generate ethers from alcohols in the Williamson ether synthesis (normally using primary alcohols)
68
What conditions are needed for the Williamson reaction to form epoxides?
High dilution conditions are needed to ensure an intramolecular reaction
69
What can sulphur nucleophiles be used for?
Can be used to make thioethers using the Williamson reaction
70
How do we make our nucleophiles (thiols) to use to make thioesters in the Williamson reaction?
Thioacetic acid can react with alkyl bromide via an SN2 reaction to give us a thioester product
This can then be hydrolysed to form our thiol
71
What is the problem with using nitrogen as a nucleophile in a reaction of ammonia and alkyl halides?
Can lead to overalkylation to form NR4+
72
How can primary amines be made?
Azides can be used
Or deprotonated amides can be used
Or cyanide anion
73
Why are amides not good nucleophiles?
They have resonance forms
74
Are phosphine and organophosphines good nucleophiles?
They are excellent nucleophiles and are used to make phosphonium salts (which are used in the Wittig reaction)
75
Why are cyanide anions good nucleophiles?
Charged and sterically unencumbered
76
How do you turn carbonyls from electrophiles into nucleophiles?
Using enolate anions derived from carbonyl compounds
77
In SN1 reactions what happens if you increase the concentration of hydroxide that was being substituted in?
A competing reaction takes place which is an elimination
78
When do elimination reactions happen?
When the nucleophile acts as a base
79
What are the two different mechanisms for eliminations?
E1 - elimination unimolecular
E2 - elimination bimolecular
80
What is the rate law for E2 reactions?
Rate = k[RX][B-]
81
What is the rate law for E1 reactions?
Rate = k[RX]
82
How do you know whether an elimination or substitution will take place?
The basicity of a nucleophile affects it
The size of a nucleophile also affects it
The temperature of the reaction
83
How does the basicity of a nucleophile affect whether elimination or substitution takes place?
Strong, hard bases favour elimination reactions
84
How does the size of a nucleophile affect whether elimination or substitution takes place?
Bulky, hard bases favour elimination reactions
85
How does the temperature of the reaction affect whether elimination or substitution takes place?
Increasing temperature favours elimination reaction
As eliminations always make more products so ΔS>0
- Therefore increasing T means ΔG will be lower
86
How does the position of attack allow for elimination of substitution?
Attack at carbon leads to substitution
Attack at hydrogen leads to elimination
87
For E1 and E2 reactions what does the rate determining step involve?
For E1 only the electrophile is involved
For E2 the electrophile and the base is involved
88
What intermediate is there in E1 reactions?
Carbocation intermediate
89
What is the order of reactivity for E1 reactions?
3°>2°>1°
90
Why do tertiary and secondary carbocations make E1 reactions more reactive?
They are stabilised by orbital overlap - same as for SN1
91
What is the order of reactivity for E2 reactions?
3°>2°>1°
92
Why do tertiary and secondary carbocations increase reactivity for E2 reactions?
Sterics are not really a factor
The more β-hydrogens available the more likely the elimination
A more substituted alkene is more stable and therefore formed more rapidly
- More stable transition state
93
What type of reactions are elimination and substitution?
Elimination is a hard reaction - dominated by charge interactions
Substitution is a soft reaction - dominated by orbital overlap
94
Do allylic and benzylic reatants go via E1 or E2 mechanisms?
Can go via both
95
What favours E1 or E2 mechanisms?
High concentrations of base favours E2
Even very weak bases can undergo E1 reactions
96
What can allow amines to act as good leaving groups?
Quaternary ammonium salts
Protonate tertiary amines to form these
- Means leaving group is charged
97
What can make alcohols good leaving groups?
Methanesulfonyl esters (mesylates) are analogous to tosylates just without the benzene ring
- Mesylates can be formed in situ in elimination reactions
98
What is true about protonating an alcohol to make it a better leaving group?
Can never be used in an E2 reaction as they need to be carried out in strong base so would undo the protonation
99
What is true in a given elimination reaction?
More than one alkene product may be possible
100
How does the substitution of the alkene decide the more favoured product for E2 reactions?
The more substituted alkene is the more favoured product as it is more stable
101
What stabilises transition state in E2 reactions?
E2 transition states have partial double bond character
Therefore same factors that stabilise alkene, stabilise the transition state
102
Why are more substituted alkenes more stable?
More stable due to favourable orbital overlap (more orbital overlap)
Neighbouring beta C-H and/or C-C sigma bonds can overlap with π* orbital of the alkene
103
What product selectivity is observed in E1 reactions?
The same as E2 - more substituted alkene is more favourable
E1 transition state for the second step also has partial double bond character
104
How can you favour the less substituted product in elimination reactions?
By changing the base used in the E2 reaction
- Bulky bases can favour the less substituted alkene product
105
What is the stereochemistry associated with E1 reactions?
The geometry (stereochemistry) can vary and be E or Z
For an E1 reaction the geometry is determined when the proton is removed from the carbocation intermediate
106
What is the stereochemistry associated with E2 reactions?
The geometry can vary and be E or Z
For an E2 reaction, the hydrogen and the leaving group must be antiperiplanar to each other
107
In elimination reactions, how do you favour the E-alkene?
Lower steric hindrance favours formation of E-alkene
108
What do you need for an E2 reaction to proceed?
What is the preferred conformation of this?
The C-H σ bond must be in the same plane as the C-X σ* antibonding orbital
Antiperiplanar as less steric hindrance and more overlap
109
What kind of transition states do E2 eliminations have?
Anti-periplanar transition states
110
Are E2 reactions stereoselective?
Yes however sometimes they can be stereospecific if there is only one possible conformation
111
What do E2 eliminations from cyclohexane require?
They require both the leaving group and the hydrogen to be axial
Axial X is anti-periplanar to C-H bonds compared to equatorial X that is anti-periplanar to C-C bonds
112
What is the third elimination reaction and when can it occur?
E1cB
Anion stabilising groups allow this mechanism to occur
113
What is the rate law for E1cB reactions?
Rate = k[RX][B-]
114
What is the difference between E1 and E1cB reactions?
In E1 reactions the C-X bond breaks first whereas in E1cB the C-H bond breaks first
115
What is the intermediate in E1cB reactions?
A carbanion intermediate
116
What is the regioselectivity of E1cB reactions?
E1cB regioselectivity is fixed by the position of the acidic proton and the leaving group
117
Do E or Z alkenes form from E1cB reactions?
E-alkenes form preferentially for steric reasons
118
What is regioselectivity?
Refers to the preference of a chemical reaction to occur at one direction or position over another where multiple sites exist
119
What is stereoselectivity?
Refers to the preference of a chemical reaction to produce one stereoisomer over another
120
What is a radical?
A atom or molecule with an unpaired electron (free radical)
121
What should having an unpaired electron not be confused by?
Having a charge - although radicals can also be charged (radical ions)
122
How do radicals form?
Form from the homolytic breakage of a bond, which refers to a bond that breaks evenly distributing electrons between the two atoms
123
How can you anticipate if a radical should be charged?
Draw any missing H atoms and lone pairs
Assign all the electrons and lone pairs in the structure to the atom of interest
Count all the electrons in the bond and assign half of them to the atom of interest
Subtract total number number of counted electrons to the outer shell electrons that your atom originally has
124
What is the trend in radical stability?
Radicals tend to be more stable the more substituted the carbon is carrying the unpaired electron
Least stable
- Methyl radical
- Primary radical
- Secondary radical
- Tertiary radical
Most stable
125
What else follows the trend in radical stability?
The homolytic C-H bond dissociation energy when R=CH3
126
What hybridisation do radicals have?
sp2 hybridisation with an orthogonal p orbital carrying the unpaired electron
127
Where is the orbital where the unpaired electron of a radical is in?
Orthogonal to the plane and called the SOMO (Single occupied molecular orbital)
128
In substituted radicals what is responsible for increased stability?
Hyperconjugation
Neighbouring σ bonds can overlap with the orthogonal p orbital resulting in stabilisation
129
Why do methyl radicals not have any stabilisation?
The σ C-H bonds are orthogonal to the SOMO and cannot overlap to it
130
How many possible interactions are available in secondary and tertiary radicals?
Two possible interactions for secondary radicals
Three possible interactions in tertiary radicals
131
How can stabilisation of radicals be greatly increased?
By resonance delocalisation of the unpaired electron
- Far more efficient way to stabilise radicals
132
How do allyl radicals fit into the stability scale for radicals?
Far more stable than tertiary radicals as the unpaired electron can be delocalised onto different atoms
133
What does a great difference in boiling points of radical chain reaction products allow for?
Their separation during industrial production
134
What does methane chlorination require to generate products?
Either high temperatures or light irradiation
- In the light induced reaction, many thousands molecules are formed for each photon absorbed
135
What are the steps to a radical chain reaction?
Initiation - formation of radicals
Propagation
(Non-productive steps)
Termination
136
What are non productive steps that happen in radical chain reactions?
What else is termination steps called?
Steps that do not get you anywhere in the reaction
Termination steps are also called radical recombination
137
How many cycles are completed before termination is observed?
Many thousands
138
What happens in all the radical reactions of di-halogens with methane?
Flourination - explosive and too dangerous for industry
Chlorination - rigorous
Bromination - smooth
Iodination - no reaction
Reactivity of halogens towards alkanes:
F2 > Cl2 > Br2 >> I2
139
What is true about the enthalpy values for the initiation step?
They do not follow reactivity order so can not explain reactivity
140
What explains reactivity of free radical reactions with halogens?
By energy gained by formation of the X-H bond
Combining enthalpies of the two propagation step:
ΔHstep1 + ΔHstep2
Increases as go down G17
Iodine is positive meaning overall reaction is thermodynamically unfavourable
141
What parts of the iodine radical chain reaction can occur?
Generation of iodine radicals can be achieved however they cannot carry the radical chain due to highly endothermic H atom abstraction from CH4 with I·
142
What is true about halogenation of alkanes?
Multiple products can be formed as more than 1 carbon has C-H bonds available
143
How do you explain the relative product proportions of halogenation of alkanes?
You cannot use the ratio of equivalent hydrogens
Relative stability of radical intermediates can explain this
- Tertiary > Secondary > Primary
144
What is the selectivity observed in bromination of alkanes and chlorination of alkanes?
The selectivity observed for bromination of alkanes is far greater than the one observed in chlorination
- Meaning bromination cares more about stable intermediates than proportions
145
What can a transition state be defined by?
The energy state (max point)
A chemical structure
They cannot be measured or detected as are transient chemical species
146
What thermodynamic type of reaction is the bromination and chlorination of alkanes?
Exothermic reaction
147
How can we apply Hammonds Postulate to show why bromination of alkanes is more selective than chlorination?
Bromination is less exothermic
In a bromination, a TS happens late so has a similar structure to alkyl radical compared to the reactant
- Causes stability of radical by hyperconjugation
In a chlorination, a TS happens early and look more similar to Cl radical
- Causes stability of alkyl radical to be less important
Therefore justifying lower selectivity
148
What is the order of stabilisation in the transition state in bromination?
1°<2°<3°
149
What linear alkenes are gases and liquids at room temperature?
ethene to 1-butane - gases
1-pentane to 1-decene - liquids
150
What happens when you have double bond in the middle of the chain?
Has two possible geometries
E/Z (cis/trans) - do not normally interconvert
Can change properties
151
What is the structure of ethene?
sp2 hydrid orbitals of C overlap with H 1s and with each other - generating σ bond framework
Orthogonal p orbitals overlap laterally creating a π bond
152
What are the difference in bond length and bond strength comparing alkenes to alkanes?
Change to sp2 hybridisation results in increased s character of hybrid orbitals
- Shortens C-H bond and increases C-H bond strength
- Double bond between carbons in reflected in increased bond strength and decreased length
153
When is a reaction electrophilic?
The reaction is initiated by an electrophile attacking an electron rich site
154
What can electrophilic addition of alkenes be seen as?
The reverse of E1
155
What is the difference in electrophilic addition with conc H2SO4 and dilute H2SO4?
Water is present in diluted one so reacts with the alkene instead of direct reaction of sulphuric acid
156
What is the change in hybridisation during electrophilic addition?
Carbocation is planar and is still sp2 hybridised whereas other carbon is sp3 in the intermediate
157
What is it called when H2SO4 loses a hydrogen?
hydrogen sulphate or bisulphate ion
158
In addition of conc H2SO4 in electrophilic addition, how do you get to the alcohol?
Using H2O hydrolysis
159
In addition of conc sulphuric acid, why does HSO4- attack the carbocation not water?
Water is a stronger base than HSO4- which implies water is a better nucleophile
So water is always more likely to attack the carbocation
However only HSO4- is available to attack the carbocation as there is only ∼4% water which will all be in its protonated form
160
When two different nucleophiles are present, which one will the carbocation react with?
It will react with the stronger nucleophile
161
What is Markovnikovs rule?
An empirical rule (based on observations)
When adding HX to a double bond, the hydrogen of HX goes to the carbon which already has the most hydrogens
162
What must you say when referring to Markovnikovs rule?
The Markovnikov product is formed because....
Not the product is formed because of Markovnikovs rule
163
What is the difference between regioselective and regiospecific?
Regioselective - one of the possible products is formed in greater amount than the other(s)
Regiospecific - only one possible product is formed
164
Is HX addition to alkene regioselective or regiospecific?
Regioselective so has major/minor product
165
How does hyper conjugation work in carbocations?
Neighbouring C-H σ bond overlaps with empty p-orbital
- They can add electron density to empty p orbital
- More bonds overlapping = higher stabilisation
Resonance also stabilises carbocations
166
What explains Markovnikovs rule?
Selectivity of carbocations due to stability
More stable intermediate is favourite
167
What control is electrophilic addition under?
Kinetic control (faster formation of the more stable intermediate) not thermodynamic control
168
What is a way of mainly getting the minor product in electrophilic addition of alkenes?
Using a radical
169
Is there stereochemistry in addition?
Going from sp2 to sp3 can introduce sterochemistry
- it depends on how the nucleophile attacks the carbocation
- it can attack one either side (top/bottom) of sp2 carbon face - both sites are equivalent so end up with 1:1 ratio of enantiomers
- tend not to be stereoselective
170
What can the addition of bromine to alkenes be used to qualitatively assess?
The presence of a double bond
- Shaking bromine with an alkene affords a colourless solution (orange to colourless)
171
Is the addition of bromine stereoselective?
Yes it is - you would expect equal amount of cis/trans product from syn/anti attack
However not what is observed
172
What is the stereoselectivity of bromination of alkenes?
Anti-addition
- the two bromines add on opposite sides due to bulky Br group
- occurs via a bromonium ion intermediate
173
What is the orbital model of bromonium formation reminiscent of?
What about the nucleophilic attack of bromonium ion?
An SN2 mechanism - both cases a nucleophile is attacking an electrophile
174
How does the bromonium ion undergo nucleophilic substitution?
By backside attack (anti-addition)
175
In bromination of alkenes, what could happen if another nucleophile is present?
It might attack the bromonium ion so you will no longer get a dibromine product
176
For unsymmetrical alkenes, what is true about bromination?
The reaction is regioselective
- Nucleophile attacks the most substituted end of the bromonium (site with most carbocation character)
- Dictated by carbocation stability
177
What is the outcome for bromination of alkenes if the alkene is E or Z?
If it is E then you get a meso compound (non chiral)
If it is Z then you get a racemic chiral mixture
178
What are epoxides?
3-membered rings containing oxygen
Cannot usually isolated - unlike bromonium ion
They are electrophiles
179
What can you use to open epoxides?
Nucleophiles to afford the anti-products
180
What is the difference in reactivity between epoxides and ethers?
Epoxides are fare more reaction than ethers due to their ring strain - they want to open up
181
How can epoxides be generated?
From alkene oxidation
Electron-rich alkenes react with peroxy-acids in a concerted syn addition to give epoxides
182
What is the mechanism for the generation of epoxides called?
What is often used as the peroxy-acid?
'Spaghetti mechanism'
mCPBA
meta-chloroperbenzoicacid
183
What is true about the speed of epoxidation and the electron rich alkene?
More electron rich the alkene the faster the epoxidation is
- More electron donating groups
184
What parts of epoxide reactions are syn or anti?
There is syn addition to form the epoxide (concerted reaction where only syn product can form)
Anti ring opening due to steric hindrance
185
What is the dihydroxylation of alkenes?
Alkenes react with osmium tetroxide in a concerted syn addition to yield 1,2-diols after hydrolysis
It is stereospecific
186
What is the mechanism for the dihydroxylation of alkenes?
A concerted cycloaddition
Can be called 3+2 if talking no of atoms or 4+2 if talking no of electrons
187
What do you get when you use a E or Z alkene for dihydroxylation of alkenes?
Using E: you get a chiral compound with two stereocentres
Using Z: you get a mess compound with a mirror plane
188
What is the anti dihydroxylation of alkenes?
You end up with the anti relationship of the diol
Can be achieved by a similar syn addition to generate an epoxide followed by an anti ring-opening hydrolysis
189
How do you get the triple bond in ethyne?
The two sets of orthogonal p-orbitals overlap to produce two orthogonal π bonds
190
What happens when there is a change to sp hybridisation?
Results in increased s character of the hybrid orbitals
Shortens the C-H bond and increases C-H bond strength
Confers a more acidic character to alkynes
191
When can alkynes be deprotonated?
Terminal alkynes with a C-H bond can be readily deprotonated with strong bases to give a nucleophilic acetylide anion
- Charge on the sp orbital
192
What is the pKa of terminal alkynes?
pKa ∼ 25
193
Which bases can deprotonate alkynes?
Strong bases with pKaH > 25
194
What are acetylide anions good at?
They are excellent nucleophiles and generate new C-C bonds
195
What species will acetylide anions attack?
Alkyl halides
Epoxides
Carbonyls
196
What do wiggly lines indicate in reaction mechanisms?
A mixture of E/Z isomers
197
How do alkynes undergo electrophilic addition?
In the same way as alkenes
Just need 2x the electrophile e.g. 2x HBr
First forms the alkene and then forms a alkane
198
What kind of alkane is formed in the electrophilic addition of alkynes with hydrohalic acids?
A geminal alkane
199
What is the hydration of alkynes?
Alkynes add water at very high temperatures
Terminal alkynes react regioselectively to give methyl ketones
Need either:
- Water, Strong acid and high temp
- Water, gold catalyst and mild temp
200
How can alkynes be partly reduced to alkenes and selectively to either Z or E alkenes?
Z alkenes can be formed by reaction of alkynes with hydrogen gas and a lindlar catalyst
E alkenes can be formed by reaction of alkynes with Na, liquid ammonia and tBuOH
201
What is a lindlar catalyst?
Palladium (0) on calcium carbonate and poisoned with lead acetate and quinoline
202
What does the lindlar catalyst do?
It is a deactivated form of palladium that will selectively hydrogenate alkynes but not alkenes
203
What happens when the catalyst in reduction of alkynes to Z-alkenes is not poisoned?
It will be reduced all the way to alkane (alkene cannot be isolated)
204
What is the reduction of alkynes to E-alkenes called?
Reduction with free electrons
205
How do you do reduction of alkynes to form E-alkenes?
First react sodium with liquid ammonia to form free electrons
Then react this with the alkynes to form a radical anion (which adopts trans geometry) and react it with tBuOH
206
What is borane?
BH3 - highly electrophilic
207
What is hydroboration-oxidation?
A two step process resulting in overall anti-markovnikov addition of water across a double bond
Alkenes react with neutral B-H containing reagents (boranes)
208
What does borane undergo?
Dimerisation to form B2H6
209
Why do boranes react with alkenes?
Electron cloud on alkene is very appealing to empty p orbital on BH3
- Can react 3 times before forming BR3
210
Is the borane addition regioselective?
Yes it is regioselective, with the boron adding to the least substituted end of the alkene
211
What is there to know about the borane addition?
The reaction is concerted
However bond formation is not simultaneous
The C-B bond forms earlier than the C-H bond, leading to a δ+ on more substituted carbon of the alkene
212
What is there to know about the stereoselectivity of hydroboration?
It follows a syn addition
- Addition will occur at the least hindered face of the alkene
213
What are organoboron species useful for?
Useful reagents for modern synthesis
- Reaction of alkyl boranes with alkaline hydrogen peroxide produces alcohols
214
When is the reaction of alkyl boranes with alkaline H2O2 to produce alcohols used?
When you want the OH on the other carbon from the alkene
215
What happens to stereochemistry during the alkyl group mitigation in the oxidation step of hydroboration-oxidation reaction?
Mitigation occurs with retention of configuration of the mitigating group
216
What is the difference between hydroboration and hydration to give alcohols from alkenes?
They give orthogonal products
- H adds to more substituted position (anti-Markovnikov product) in hydroboration-oxidation as B adds to least substituted position
217
What is the Diels-Alder reaction?
The reaction of an electron deficient alkene with a conjugated diene to give a cyclohexane type molecule
Just need heat, no other reagents required
218
Can you get self-condensation of dienes?
Usually rare as electron deficient alkenes are much more reactive than the double bonds of dienes
219
When can the diene react in the Diels-Alder reaction?
It must adopt a s-cis (syn-periplanar) conformation to react
Cyclic dienes that are held in an s-cis conformation are excellent for this reaction
220
What is the stereospecificity of Diels Alder reactions?
Both new C-C bonds must be formed on the same side of the dienophile
Reaction is stereospecific as stereochemistry is preserved
221
What is it important to account for in Diels Alder reactions?
Initial alkene stereochemistry
222
How do alkynes react with dienes?
In the same way as alkenes
They just form a cyclohexdiene product
223
Where can the alkene/alkyne attack from in Diels Alder reactions?
Either the top or the bottom (it is equally probable)
- Substituted groups will position themselves on opposite side
- Groups will always stay in the same direction as C bonds are both formed on the same side
224
What are the different types of aromatic compounds?
Benzene
Polycyclic
Heteroaromatic
Charged cyclic compounds - sometimes
225
Why are benzene and other aromatics unusual?
1. Resonance
2. High thermochemical stability
3. Undergo aromatic substitutions instead of addition reactions
4. Experience NMR ring currents
226
Why are benzene and other aromatics unusual? (resonance)
Structure of benzene is a hybrid of two equally contributing resonance structures
- pi electrons are delocalised over the ring
227
What is the proof of resonance of benzene?
X-ray diffraction showed all benzene C-C bonds are equivalent and 1.39 A
- If benzene was 1,3,5-cyclohexatriene it would have different bond lengths
228
Why are benzene and other aromatics unusual? (thermochemically stable)
It is thermochemically stable due to resonance
- Benzene is much more stable than expected based on heat of hydrogenation calculations
- Theoretical prediction is -360 kJmol-1
- Experimentally determined is -208 kJmol-1
- Due to 'resonance energy' due to conjugation and the perfect overlap of the p orbitals in the ring
229
Why are benzene and other aromatics unusual? (substitution not addition)
Benzene doesn't undergo any regular reactions of alkenes
- Benzene needs a lewis acid catalyst
- When it does react it gives a substitution product with its ring structure intact
230
What are the main reactions that aromatic compounds undergo?
Electrophilic Aromatic Substitution
231
Why are benzene and other aromatics unusual? (NMR ring currents)
Applied field causes circulation of pi electrons, inducing a field
- If H atom surrounded by elements that reduce electron cloud then experiences a higher magnetic field - resonates at higher freq - called deshielding
- Benzene protons are deshielded due to ring currents
232
What is true about protons 'inside' or 'outside' aromatic rings?
Protons inside ring would experience shielding (smaller ppm)
Protons outside ring experience deshielding (larger ppm)
233
How is the induced field relative to the ring current?
The induced field opposes ring current
234
What are the requirements for aromaticity?
Conjugation
Cyclic structure
Planar
235
How is conjugation in aromatics?
In benzene every carbon is sp2 with one p orbital available
The uninterrupted chain of p orbitals comes from alternating double and single bonds (conjugation)
Overall pi systems gain stability by allowing overlap between their p orbitals
236
How do cyclic structures show aromaticity?
p orbitals must be able to overlap with p orbitals on adjacent atoms in a cyclic manner
237
How do planar structures show aromaticity?
Each p orbital must be aligned so pi electron density can be delocalised
238
How does the pi MO diagram for benzene show its stability?
All bonding MOs are filled whereas all anti bonding MOs are empty
239
How many nodes are in different molecular orbitals in benzene?
0,1,2 and 3
240
What is Hückel's rule for aromaticity?
If a molecule has 4n+2 pi electrons we can predict whether a planar ring is aromatic (where n is an integer)
Similar systems with 4n pi electrons are described as anti-aromatic
241
What does it mean for MO diagrams if compounds are anti-aromatic?
There are half-filled orbitals which destabilise it
242
What is true about planar, conjugated cyclic systems with 4n+2 electrons?
They have a closed shell of electrons all in bonding orbitals with a cyclic array of p-orbitals perpendicular to plane of the ring
Exceptionally stable and therefore aromatic
243
What is a Frost-Musulin diagram?
An energy diagram which shows whether a cyclic pi system is aromatic
244
How do you draw the molecular orbitals of a cyclic pi system? (in a Frost-Musulin diagram)
Draw the appropriate polygon, vertex-down and then fill it up with electrons where each vertex is an MO
Centre of circle is zero energy level (bonding orbitals below and anti-bonding above with non bonding at zero level)
245
What is there to know about cyclopentadiene?
It easily deprotonates to give an anion which has a lone pair on carbon
- can contribute to pi bonding (is in a p orbital)
Cyclopentadiene anion is aromatic whereas cyclopentadiene cation is anti aromatic
246
What is true about the hybridisation of a compound?
Wherever possible it will adopt a hybridisation that supports forming of an aromatic system of electrons
e.g. cyclopentadiene anion: carbon changes from sp3 to sp2 so lone pair is now in the p orbital and is fully delocalised
247
How do heteroatoms participate in aromaticity?
By sharing one electron into the delocalised pi system (lone pair not always part of ring pi system)
248
What is true about the lone pair on nitrogen?
It doesn't count as a pair of pi electrons since it cannot overlap with the pi system
249
What is true about pyridine?
We have six electrons in three double bonds so it can be aromatic
Lone pair is available for reaction with protons so is considered basic
Pyridines nitrogen participates in resonance in the same way as a C atom would
250
How do you determine aromatic, anti aromatic and non aromatic?
Does compound contain a ring of continuously overlapping p orbitals?
Is there a Huckel number of pi electrons in the ring?
If non planar with 4n pi electrons then it is non aromatic
251
How can you work out if lone pairs are in p orbitals?
1. Check hybridisation (sp = 2 available p orbitals, sp2 = 1 available, sp3 = 0 available)
2. Look at resonance and conjugation - If placing a lone pair in a p orbital leads to a continuous pi system it is likely to be there
3. Check if adding a lone pair to a p orbital makes up huckels number - likely to be there
252
Upon reaction with electrophiles what do aromatic compounds undergo?
Electrophilic aromatic substitution
253
What is the general SEAr mechanism?
Attack of electrophile by pi bond gives intermediate cation (addition) and loss of a proton from the cation (elimination) to restore aromaticity/regenerate pi bond
Generally under kinetic control
254
What is the rate determining step in SEAr?
The first step through transition state 1
255
What else is the cationic intermediate in SEAr called?
Wheland, arenium, sigma-complex, carbocation or benzonium intermediate
256
What is true about the cationic intermediate in electrophilic aromatic substitution?
It has multiple resonance forms
- Not aromatic but stabilised by delocalisation
257
What evidence is there for the SEAr mechanism to do with isotopes?
Kinetic isotope effect: isotopically substituted molecules exhibit different reaction rates.
Deuterium isotope effect:
- C-D bond slightly stronger than C-H bond
- So reactions would go slower
- When replacing C-H with C-D rate of reaction stays the same so C-H bonds cannot be involved in RDS
258
What does the absence of deuterium isotope effect in SEAr confirm?
That TS2 is not the RDS
259
What evidence does using superacids give us for SEAr?
It can stabilise the carbocation and record NMR spectra on it
260
What happens in nitration with SEAr?
Nitro group (NO2) can be added to benzene in the presence of conc nitric and sulphuric acids (catalyst)
3 steps to the mechanism:
- Electrophile generation
- Attack of pi bond
- Deprotonation
261
What happens in sulfonation with SEAr?
Sulphonyl group (SO3H) can be added to benzene in presence of sulphur trioxide
Can proceed with just sulphuric acid (catalyst) however better with SO3
Reversible at temps above 80 degrees
262
What is 'oleum'?
A solution of sulphur trioxide in sulphuric acid (highly concentrated)
263
What happens in halogenation with SEAr?
Halogens can be added to benzene with use of lewis acid catalysts
- Not needed for activating groups
- Iodination - requires a stoichiometric oxidant promoter (HNO3/H2SO4)
- Fluorination - reacts explosively with aromatics
264
What happens in Friedel-Crafts alkylation?
Alkyl groups can be added to benzene with use of alkyl halides and lewis acid catalysts (AlCl3)
- Does not work for alkenyl and alkynyl halides
- Carbocation rearrangements can occur
265
What can happen in Friedel-Crafts alkylation?
Carbocation rearrangements can occur
(alkyl shifts)
Products are activated relative to starting materials leading to polyalkylation
266
What are 1,2-hydride or alkyl shifts?
Means that an atom or group moves from one carbon to an adjacent carbon
- hydride refers to movement of a hydrogen atom (with its bonding e-)
- alkyl refers to movement of alkyl group to stabilise carbocation
Carbocation will rearrange if ending cation is more stable (e.g. tertiary vs secondary)
267
What happens in Friedel-Crafts acylation?
Acyl groups can be added to benzene with the use of acyl chlorides (or anhydrides) and lewis acid catalysts
- FOr activated aromatics, no lewis acid is required
- Lewis acid is not catalytic as complexes to product
268
When can Friedel-Crafts acylation be useful?
Friedel-Crafts acylation followed by carbonyl reduction is a preferred alternative to any Friedel-Crafts alkylation requiring a primary carbocation as it avoids rearrangements
269
What are all the positions around a benzene ring called relative to attached group?
1 ipso
2,6 ortho
3,5 meta
4 para
270
What must be consider when thinking about SEAr?
The effects of existing ring substituents on 'directing' the SEAr position
271
What can X (substituent on aromatic) be considered as?
Can influence reactivity and regiochemistry
Can be meta-directing or ortho/para-directing
Can be an activating group or a deactivating group
272
What is the difference between an activating group and a deactivating group?
Activating group donates electron density to the ring
Deactivating group withdraws electron density from the ring
273
How do activating or deactivating groups work?
Can occur through both inductive effects (sigma donor/acceptor) and conjugation/resonance effects using a lone pair (pi donor/acceptor)
274
What do activating substituents do to the rate of SEAr?
What about deactivating substituents?
Increase the rate of SEAr reactions relative to unsubstituted aromatic ring
Decrease the rate of SEAr reactions relative to unsubstituted aromatic ring
275
What is true about the halogens when it comes to substituents in SEAr?
They are both sigma acceptors and pi donors
pi donor < sigma acceptor so they are deactivating
However they have lone pairs that can participate in resonance so are ortho/para directing
276
What decides whether a substituent is an ortho, para or meta director?
Depends on how the substituent affects the stability of the carbocation intermediate
277
How should you decide which position the second substituent ends up on in SEAr?
Should draw out all possible attacks in order to find most stable C+
1. Charge is away from EWG
2. Resonance stabilisation
278
What is true about electron withdrawing groups?
Tend to deactivate SEAr and they tend to direct regioselectivity towards meta
Resonance delocalisation of the intermediate explains observed regioselectivty
279
What is true about electron donating groups?
All EDGs are activating as they help stabilise the cationic intermediate so direct to ortho/para positions
280
What does electrophilic aromatic substitution almost always being under kinetic control mean?
The fastest formed compounds are major products
- This will be formed via lowest energy TS
281
What is true for substituents in SEAr like OR or NR2?
Look like they should be deactivating due to electronegativity but are actually activating as they can donate a lone pair into the ring through resonance
282
What are the three different types of directors you can have?
Deactivating meta directors
Deactivating ortho/para directors
Activating ortho/para directors
283
Why is the meta position normally seen with EWGs?
For both ortho and para, one resonance structure places carbocation on ipso position, destabilising the charge
Therefore meta position leads to carbocation furthest away from EWG
284
What causes meta directing groups that are deactivating?
Inductive effect (and conjugation) deactivates starting material so it is less nucleophilic than benzene
Inductive effect (and conjugation) destabilises ortho and para intermediate so prefers meta
285
What causes ortho/para groups that are activating?
Conjugation (sigma)/small inductive effect activates SM and makes ortho/para positions relatively more nucleophilic
It also stabilises ortho/para intermediates so prefers ortho/para
286
What causes ortho/para groups that are deactivating?
Inductive effect of halogen deactivates SM
But conjugation of lone pair makes ortho/para positions relatively more nucleophilic
Conjugation stabilises ortho/para intermediate although overall inductive effect makes all positions relatively less reactive
So prefers ortho/para
287
Statistically what do we expect for ortho/para ratios?
Expect a roughly 2:1 ortho:para
288
What effects the ortho/para ratios?
Theoretical charge density favours the para
Steric effects (large E+ and/or directing substituents) disfavour ortho
Complexation effects can favour the ortho
289
When is an example of ipso directing?
In proto-desulphonylation
290
What can you use substituted groups for in SEAr?
As a temporary directing group
291
What are the rules for disubstituted substrates?
1. The most activating group will 'win' as the directing group
2. Among positions that are similar electronically favoured - the site with the fewest adjacent substituents is more likely to be site of attack
292
What happens when two substituents direct to the same positions?
Called co-operative directing effect
- That's where third substituent will end up
(look out for sterics)
293
What happens in the case of an activating and a deactivating group?
The activating director 'wins'
294
What is best to do when you have multiple substituents?
Colour code all the possible positions first before deciding where it will substitute onto
295
What is the general synthetic check list for SEAr?
- Will E+ react at ring carbon or elsewhere
- Is E+ sufficiently reactive to react with a ring carbon
- Will introducing E+ activate or deactivate the ring
- What orientation relative to existing groups will exist:
-- ortho/para or meta or ipso
-- if ortho/para which one
-- do directing effects cooperate or compete
-- use of temporary directing group?
-- mono or multiple sub
296
What is the other main reaction that aromatics can undergo?
Nucleophilic aromatic substitution, SNAr
297
What must be true for an SNAr reaction to happen?
1. Ring must contain a powerful EWG (normally nitro)
2. Ring must contain a leaving group (usually halide)
3. The leaving group must be either ortho or para to EWG
- If leaving group is meta the reaction is not observed
298
What is the type of mechanism for SNAr and what is the rate law?
Addition-elimination reaction
Rate = k[ArX][Y-]
299
What is true about the RDS for SNAr?
It is attack by the nucleophile on the aromatic ring, disrupting aromaticity
Doesn't involve departure of the leaving group
300
What is the intermediate called in SNAr?
Meisenheimer intermediate
Or cationic/wheland intermediate
301
What do typical substrates have as the nucleophile?
O, N or CN
302
What does the choice of halide reflect in SNAr?
Flouride accelerates SNAr due to its high electronegativity that stabilises the anionic intermediate
F>Cl>Br>>I
303
What is there to know about the leaving group in SNAr?
Halides: ease of sub mirrors electronegativity
Fluoride is a poor LG but its high e-neg lowers energy of RDS
Fluorides often difficult to prepare and unstable so chlorides more generally used
304
What is the role of the EWG in SNAr?
To stabilise the negative charge once it resides on the Meisenheimer intermediate
305
What groups are good at stabilising anionic intermediates in SNAr?
Nitro, Cyanide, methyl ketone
306
Why does the nitro group need to be at either the 4 or 2 position in SNAr?
So that when the nucleophile attacks at the ipso position we can push the charge out onto a substituent (this doesn't work if substituent is on the 3 position)
307
What do SNAr reactions proceed under?
Kinetic control
308
If you arent asked to draw out all the meisenheimer intermediates, what should you draw?
First step where negative charge is pushed onto the EWG
Second step where halogen is pushed out of the molecule
309
What are diazonium salts widely used for?
Widely used as intermediates in organic synthesis due to their ability to undergo nucleophilic substitution to introduce various functional groups
310
How do you form diazonium salts?
Reactions of anilines with nitrosonium salts
311
What mechanisms in aromatics can diazonium salts be used in?
SN1Ar or SRN
312
What is a SN1Ar reaction?
An ipso reaction of diazonium salts with loss of nitrogen gas
313
What is an SRN reaction? (sandmeyer reactions)
A reaction of diazonium salts that uses copper compounds
314
What is different about SN1Ar and SRN compared to SNAr?
No activating anion stabilising groups are required
315
When do diazonium salts undergo SN1Ar and when do they undergo SRN?
In absence of Cu salts they undergo SN1Ar
Using copper(I) salts they undergo SRN
316
What is there to know about SN1Ar reactions?
Rate = k[ArN2+] (unimolecular)
Driving force is loss of N2
Aryl cation is still aromatic but high character of sp2 hybrid orbital - high energy carbocation
317
In diazonium salts what happens with certain 'soft' nucleophiles?
They react at the terminal nitrogen in diazonium ions to product other compounds e.g. diazo dyes
318
What are diazonium salts classified as?
'Ambient' electrophiles
Can react with a soft nucleophile in diazo-coupling or hard nucleophiles in ipso-substitution
319
What mechanism does the formation of diazo dyes use?
SEAr
320
How do you determine the reagents to form a certain diazo dye?
Using retrosynthesis
Analyse which ring is more activated
- This is likely to be nucleophile
Identify starting nucleophile and electrophile
Identify the starting aniline that is necessary to make the diazonium salt
Show all reagents
321
What is the mechanism for nucleophilic aromatic substitution via arynes?
What is a benzene with a triple bond called?
Elimination-addition
Benzyne - could be considered a diradical
322
What products can be formed from nucleophilic aromatic substitution via arynes?
A substituted product on either of the carbons in the triple bond on benzyne
Either ipso where original substrate was or cine second position
Base can attack either carbon position equally
323
What are alkenes that possess electron-donating substituents?
They are nucleophilic so react with electrophiles to produce a carbocation
324
What are alkenes that posses electron-withdrawing substituents?
They are electrophilic
325
How do you know which alkene is more nucleophilic?
It is more nucleophilic if there are more resonance forms, higher electron density and less sterically hindered
326
What do some of the most versatile EWGs contain?
Carbonyl functionality
327
What makes an alkene electrophilic?
If it has an electron deficient pi system
So is next to electron withdrawing groups
328
What are unsaturated carbonyl compounds?
Ambident electrophiles as they can accept nucleophiles at the C on C=O and on further away C on C=C
Two electrophilic sites as both are δ+
329
What are the compounds made when nucleophiles attack an unsaturated carbonyl compound?
If attack C=C then enolate anion formed
If attack C=O then alkoxide formed
330
How can you achieve selective addition on nucleophilic attack on unsaturated carbonyl compounds?
By careful choice of nucleophiles
And the nature of the rest of the compound
331
What is the carbonyl group?
C=O
An extremely important series of interrelated functional groups, displaying a wide range of structural types with large variations in electrophilic reactivity at carbon
332
What can you describe different carbonyls by?
Their 'oxidation level'
Aldehyde/Ketone are less oxidised than others
333
What is true about oxidation levels?
Knowing oxidation level of a carbon atom gives clues about synthesis pathways
You can do simple interconversions within the same oxidation level
334
What is the Bürgi-Dunitz angle?
About 107°
From plane to π* orbital
Describes where the anti bonding orbital is
335
Where does the nucleophile attack a C on C=O?
A nucleophile attacks the π* orbital on the C
Can attack either top or bottom
336
What is the difference in reaction rates between ketones and aldehydes?
Aldehydes normally react faster than ketones that normally react slower
337
Are aldehydes or ketones more electrophilic?
Aldehydes are more electrophilic
- It is bonded to only one electron donating group
338
Why do aldehydes react faster than ketones?
There is less steric hindrance as only one R group in aldehydes
Carbonyl group is more electrophilic as only bonded to one electron donating group
- These groups donate electron density via inductive effects from σC-H to π*C=O
339
What is true about the H atom that is used in inductive effects on the R group in carbonyls?
It is acidic which means the carbonyl compound can act as a acid and lose that proton
340
What can happen when there is overlap making a C-H acidic on carbonyl compounds and the nucleophilic attack is very slow?
The nucleophile can either attack the C on C=O in an addition reaction
Or it can deprotonate the compound by attacking the acidic H leading to the formation of an enolate anion
341
When is nucleophilic attack very slow in carbonyls?
When there is a bulky R group or a bulky/basic nucleophile
- Nucleophile and electrophile behaviour is very suppressed due to steric hindrance so acts as a base
342
What is the approximate C=O bond energy?
What does this mean?
720 kJmol-1
Often reactions re/forming C=O groups cause strong driving forces due to high bond strength of C=O
343
What is the reaction to form cyanohydrins from carbonyls?
A reversible reaction
Forwards reaction: source of HCN
Backwards reaction: NaOH
344
What is the reaction to form hydrates from carbonyls?
A reversible reaction
Forwards reaction: H2O
Backwards reaction: -H2O
345
When can you know a reaction of carbonyls has reached equilibrium?
By analysing when the spectra stops changing
346
What is the reaction of forming hemiacetals from carbonyls?
A reversible reaction
Addition of alcohols to carbonyl compounds catalysed by acid or by base
347
How do you form cyclic hemiacetals?
Intramolecular addition of hydroxy groups to carbonyl groups
Reversible reaction
348
What is a cyclic hemiacetal also known as?
A lactol
349
How can you reduce aldehydes and ketones to give alcohols?
Irreversible reaction
They react with hydride based nucleophilic reagents to give alcohols
Both NaBH4 and LiAlH4 are sufficiently reactive to reduce both aldehydes and ketones
350
What do you get when you reduce ketones and aldehydes?
Primary alcohol when reducing aldehydes
Secondary alcohol when reducing ketones
351
What can't you do when reducing carbonyls to alcohols when using LiAlH4?
Can't use alcohols instead need aprotic solvents as could form alkoxides
As LiAlH4 is highly reactive with protic solvents like alcohols
352
What do aldehydes and ketones react with organometallic compounds to give?
Secondary alcohols from aldehydes
Tertiary alcohol from ketones
353
What reagents do you use to create secondary alcohols from aldehydes and tertiary alcohols from ketones?
Organolithium reagents: RLi
Grignard reagents: RMgBr
354
What is special about cyclic hemiacetals?
They are particularly stable
355
How can you produce acetals?
Hemiacetals can react further with a second ROH molecule in a second acid catalysed process
356
How do we drive the reaction to form acetals in the direction of the acetal product?
Using Le Chatiliers principle
- Use of excess carbonyl or excess R"OH - however could cause potential separation problems
- Removal of water - use of drying agents (MgSO4/molecular sieves) or azeotropic distillation using Dean-Stark apparatus
357
What do acetals serve as for carbonyl groups?
Protecting groups
It protects the carbonyl if trying to do reactions on other parts of molecule
- Makes C less electrophilic and H non acidic
358
What do primary amines react with carbonyl compounds to give?
What about secondary amines?
Imines from primary amines
Enamines from secondary amines
359
At what pH are reactions to form imines and enamines fastest?
Why are these values best?
Generally reactions to form imines are fastest at pH = 4-6
Generally reactions to form enamines are fastest at pH ≈ 4
They are best as they increase the reactivity of carbon without protonating the amine
360
When forming enamines and imines from carbonyls what intermediate compound do you go through?
Hemiaminal
- Compound with one OH group and one NR2 group as well as two R groups
361
How can you form alkenes from aldehydes and ketones?
Aldehydes and ketones react with phosphonium ylides to form alkenes in the Wittig reaction
362
What are ylides?
Compounds with a positive charge and a negative charge, which are directly connected
363
What alkenes are made from phosphonium salts and carbonyls?
Isomeric alkenes when using ketones as they arent very reactive
364
What type of reaction are phosphonium salts generated using?
SN2 reactions usually
365
What is useful about using carbonyls and phosphonium salts to form alkenes?
It gives only a certain alkene in this position so can control position of the double bond
366
What is there to know about the reaction of carbonyls with phosphonium salts?
You use varying strength of base depending on R group on phosphonium salt
You form a stabilised or non stabilised phosphonium ylide and a oxaphosphetane which is unstable
Ph3PO can be tricky to remove from the final mixture
367
How can you selectivity form Z or E alkenes when using phosphonium salts and aldehydes?
If you use a strong base you form a non-stabilised phosphonium ylide and create a Z alkene
If you use a weak base you form a stabilised phosphonium ylide that can be isolated and create an E alkene
368
What reactions do carboxylic acid derivatives undergo with nucleophiles?
Addition elimination reactions so overall substitution
Via a tetrahedral intermediate
369
What happens when you react carboxylic acid derivatives with an anionic nucleophile or a neutral nucleophile?
Anionic Nu: forms a single tetrahedral intermediate
Neutral Nu: forms a two step tetrahedral intermediate where base is needed to remove extra proton from nucleophile
370
What does the C-O bond order of CA derivatives depend on?
Depend on X and may be probed using IR spec
371
Where do electrophiles attack amides?
Via the oxygen not via the nitrogen despite both being nucleophilic
Due to resonance form of amides having a double bond to the N and a single bond to O
372
What happens with decreasing bond order of CA derivatives?
Reduces reactivity towards nucleophiles
Increasing reactivity towards electrophiles
373
What is the trend in IR of CA derivatives?
Decrease in IR stretch of C=O means decreasing bond order
374
What causes a decrease/increase in C-O bond order in CA derivatives?
Increasing nx -> π*C=O interaction reduces bond order (interaction between lone pairs on X and π on C=O)
Increasing nC=O -> σ*C-X interaction increasing bond order (interaction between lone pairs on C=O and σ on C-X
375
What is the correlation between leaving group basicity and reactivity towards nucleophiles?
Negative correlation
As LG basicity increases (and therefore pKa of LGs conjugate acid), reactivity towards nucleophiles decreases
More basic = Less electrophilic
376
How can you synthesise esters?
Acyl chlorides react with alcohols to give esters
The condensation of carboxylic acids and alcohols
377
How can you form amides?
Acyl chlorides react with amines to give amides
378
When HCl is formed in an organic synthesis what often occurs?
You often don't want acid so multiple reagents are used to create a chloride salt instead
379
What can catalyse amide synthesis from amines?
Pyridine which is also the base and the solvent
380
How can you synthesise acyl chlorides?
From reaction of carboxylic acids and thionyl chloride (SOCl2)
381
How can esters be hydrolysed?
Under both acidic and basic conditions
So using H+ which forms carboxylic acid and alcohol
Or using OH- which forms a carboxylate salt
382
How do you convert a carboxylate salt to a carboxylic acid?
React it with acid
383
How can you hydrolyse amides?
Under basic conditions to form carboxylate salt and amine or under acidic conditions to form carboxylic acid and protonated amine
384
What does hydrolysis need?
Water and either H+ or OH-
385
How is the reaction to give amides catalysed by pyridine?
Attacks C on C=O
Kicks out Cl
Gets kicked out by amine
Attacks extra H to form pyridinium salt
386
How are esters hydrolysed under acidic conditions?
Proton attaches to O in C=O
Water attacks C in C=OH
Proton transfer from OH2+ to RO
OH forces double bond and kicks of positive group
Lose H+ to form product
387
How are esters hydrolysed under basic conditions?
OH- attacks C on C=O causes O to become negative before kicking off OR'
Then OR'- attacks H on OH and forms carboxylate anion
388
When converting between oxidation levels during synthesis how does it usually take place?
Without any change to the carbon skeleton
389
How are esters reduced?
Esters are reduced with LiAlH4 to give primary alcohol so need a aprotic solvent and aqueous workup
Esters are normally unreactive towards NaBH4
390
Why are esters normally unreactive towards NaBH4?
It is a significantly less powerful hydride donor
391
How can you achieve chemoselective reactions when compound has both ester and ketone/aldehyde?
React it will NaBH4 and only carbonyl is reduced and a lactone is formed
392
What is the problem with making tertiary amines from secondary amines?
Over alkylation often occurs give NR4+ compounds
393
How can we make tertiary amines to avoid the problem of using secondary amines?
Amides are reduced with LiAlH4 to give amines
So tertiary amides can form tertiary amines?
394
How do you convert acyl chloride to tertiary amide?
React acyl chloride with secondary amine to give tertiary amide
Reduce tertiary amide using LiAlH4 to form tertiary amine
395
What might take place during the oxidation of primary alcohols?
Oxidation of aldehydes to carboxylic acids may take place
396
How can you avoid the oxidation from aldehydes to carboxylic acids from primary alcohols?
Use selective reagents not chromic acid
e.g. PDC/PCC and CH2Cl2
Intermediates are chromate esters
397
Why is chromic acid not a very good reagent to use?
It is corrosive and very acidic
398
How do you oxidise primary alcohols into carboxylic acids?
React primary alcohol with H2CrO4 and water to produce aldehyde intermediate
This will react with H2CrO4 and water to produce CA
399
What is Jones' reagent?
CrO3 in aqueous sulphuric acid
(aqueous H2CrO4)
400
What does the oxidation of secondary alcohols need and what does it give?
Needs Jones' reagent and gives ketones
Intermediates are chromate esters
Redox step is rate determining
401
What determines the rate of alcohol oxidation?
Morre hindered alcohols react quicker due to RDS being redox and not chromate ester step
402
What does oxidation of tertiary allylic alcohols give?
Unsaturated carbonyl compounds
Needs PCC and intermediates are chromate esters
403
What does the oxidation of ketones give and what is the reaction called?
What reagent does it need?
It gives esters and called the Baeyer-Villiger reaction
Needs a peracid and forms the ester and a carboxylic acid
404
How do you know which R group the oxygen goes on in oxidation of ketones?
Goes on the more substituted of the two R groups
C->O migration is regioselective
405
What is true about the C->O migration in oxidation of ketones to give esters?
Regioselective - O goes on more substituted of two R groups
Stereospecific - configuration of migrating carbon atom is retained
406
What are the methods of synthesis of nitriles?
From primary amides by dehydration (loss of water)
From SN2 reaction of haloalkanes with cyanide anion (new carbon bond formed (homologation))
407
What do you need to get nitriles from primary amides?
What kind of reaction is it?
Dehydrating reagents
e.g. POCl3 or P2O5
Redox-neutral reaction
408
What can nitriles be converted to and what do you need for each one?
Primary amides via acid/base hydrolysis
Ketones via organolithium reagent and acid work up
Amines via reduction (LiAlH4 and aqueous workup)
Aldehyde via DIBAL and acid work up (reduction)
409
What is special about nitriles in organic synthesis?
They can act as otherwise impossible to create nucleophiles e.g. CN- can act as CONH2- which you cannot actually create
410
Where will most nucleophiles attack a nitrile?
At the carbon on the C triple bond N
411
What is tautomerisation?
Where a single compound exists in two interconvertible structural forms that differ by position of H atom and double bond
In dynamic equilibrium
412
What is keto-enol tautomerism?
A dynamic equilibrium between a keto tautomer (stable carbonyl) and an enol tautomer (conjugate acid of enolate anion)
Equilibrium lies far to keto tautomer
413
How can you catalyse tautomerisation?
By acid or base
414
What does the position of equilibrium in keto-enol tautomerism depend on?
Structural factors
- Intramolecular H bonds in enol tautomer can increase stability
External factors
- Solvent
- Temperature
415
How can we estimate extent of enolate anion formation from carbonyl compounds?
From knowledge of the pKa values of carbonyl and conjugate acid of the base
416
How do we get more enolate anion in the equilibrium between carbonyl compounds and enolate anions?
We want to favour deprotonation of alpha hydrogen
- Increase the strength of the base (higher pKa)
- Base must be a relatively poor nucleophile, especially if its a weaker base, as the conc will be higher
417
For more enolate anion formation what must be true about the pKa values of carbonyl compound and base?
pKa of the conjugate acid of the base should be significantly higher than the carbonyl compound
418
What is true about enolate anions?
They are ambident: alkylation can take place on carbon and on oxygen
They never exist on their own - always bonded to a metal at the negative oxygen
419
What do you get if you get O-alkylation or C-alkylation of enolate anions?
O-alkylation: gives you an enol ether
C-alkylation: gives you a carbonyl compound
Both react via SN2
420
How do you favour C-alkylation or O-alkylation from enolate anions?
To favour C-alkylation:
- Less electropositive M (Li) -> more covalent O-M character
- Softer leaving group X (Br/I)
To favour O-alkylation:
- More electropositive M (Na/K) -> more ionic O-M character
- Harder leaving group (O-based: OSO2Tol; OSO2CF3)
421
What do reactions of nucleophilic enolates with alkylating agents need?
1. Aprotic solvent
2. A strong base to maximise equilibrium concentration of enolate
3. A sterically hindered base to minimise nucleophilic attack on carbonyl
4. A more covalent O-M bond to maximise C-alkylation
Therefore LDA in THF fits this and react it with haloalkane
422
What can be alkylated using LDA and THF?
Nitriles and enolate anions using haloalkanes
423
How do enolate anions react with carbonyl compounds?
In the aldol reaction
424
What are the two potential products from the aldol reaction and how do you convert from one to the other?
Aldol addition product from main reaction
If react it with acid then you get the aldol condensation product
425
How do you catalyse the aldol reaction?
Using weaker base or by acid
426
What is the Claisen condensation?
Enolates reacting with acylating agents such as esters
Forms an intermediate of a β-ketoester - ketone group on the beta carbon from ester group
427
What is good about the claisen condensation?
Forms a stable enolate
428
What is true about enamines with relation to enolate?
They are enolate surrogates which react with electrophiles
Generally require more reactive electrophiles than enolates
429
What are surrogates?
Different compounds that mimic the behaviour of another compound but are more stable/better selectivity or control over reaction
430
How do enamines react with reactive electrophiles?
In an SN2 mechanism
431
How can β-ketoesters be used in the reaction of enolates with acylating agents such as esters?
They are formed from this reaction - Can further react to form stable enolates
Formation of the stable enolate suppresses the reverse reaction in the acylation of enolate anions
432
How can we exploit the acidity of β-ketoesters?
In C-C bond forming reactions
The additional electron withdrawing carboxy group may then be removed by hydrolysis and spontaneous decarboxylation
433
When exploiting the acidity of β-ketoesters what is it synthetically equivalent to?
An enolate derived from a ketone but more acidic
So decreases chance of an unwanted elimination and easier to form
434
What does synthetically equivalent to mean?
Serves the same purpose as
435
What is true about enolates derived from β-ketoesters compared to enolates formed from ketones?
They are more delocalised and less basic
- Means weaker bases work well in enolate formation and that reactions with some electrophiles may be catalysed by base
436
How can enamines be used in synthesis?
To convert ketones to larger compounds with a new C-C bond and an extra carboxy group
Reaction can be catalysed by secondary amines
