Reactivity-And-Control Sos PDF

Reactivity and Control for Organic Synthesis 1
Reac%vity and Control for

Organic Synthesis
O
O
MgBr O
O
Me Me
CuBr•SMe2
O O
Which group reacts?
Where does it react? chemoselective - enone reacts in preference to lactone (ester)
regioselective - 1,4- not 1,2-addition to enone
How does it react? (dia)stereoselective - one major diastereomer formed
︎ Advanced Organic Chemistry: Parts A and B, Francis A. Carey, Richard J. Sundberg

Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren

Molecular Orbitals and Organic Chemical Reac<ons, Ian Fleming

Heterocyclic Chemistry, John A. Joule, Keith Mills

︎ there are many different types of selec%vity in organic synthesis:

Chemoselec%vity – func%onal group discrimina%on

Regioselec%vity – product structural isomer discrimina%on

Stereoselec%vity – product stereoisomer discrimina%on

︎ we will be primarily concerned with:

Chemoselec%vity – i.e. selec%vity between two func%onal groups

O O NaBH4 OH O
ketone reduced in preference to ester
OMe OMe

Regioselec%vity – i.e. selec%vity between different parts of the same func%onal group
Cl Cl Cl
O Me MeMgBr Me OH Me HNO3, H2SO4 NO2
+
Me Me Me Me
NO2
direct addi%on in preference to conjugate addi%on ortho and para products in preference to meta product
O O
O MgBr O chemoselec%ve -‐ enone reacts in preference to lactone (ester)
Me Me regioselec%ve -‐ 1,4-‐ not 1,2-‐addi%on to enone
CuBr•SMe2 (dia)stereoselec%ve -‐ one major diastereomer formed
O O
︎ acidity and basicity

︎ nucleophilic alipha%c subs%tu%on

nucleophilic aTack on carbonyl groups

electrophilic aroma%c subs%tu%on

nucleophilic aroma%c subs%tu%on

forma%on of rings

Hard and SoU

direct and conjugate addi%on

lithium halogen exchange, and directed lithia%on

reduc%ve amina%on

Brønsted (1879-‐1947) defini%on: an acid is a proton donor

a base is a proton acceptor
acid HA is the source of a proton H+
HA H+ + A-‐
remember that the solvent (not usually drawn) acts as the base and deprotonates the acid HA
conjugate acid
HA + solvent solvent•H+ + A-‐

conjugate base
HA + H2O H3O+ + A-‐
K = [________
H3O+][A-‐] Ka =________
[H3O+][A-‐] i.e. Ka =K[H2O] water is in such large excess (as solvent)
equilibrium constant
[HA][H2O] [HA] that its concentra%on effec%vely does
not change
Ka > 1, equilibrium lies more to the right ∴ stronger acid i.e. HA is a stronger acid than H3O+ and A-‐ is a weaker base
than H2O

Ka < 1, equilibrium lies more to the leU ∴ weaker acid i.e. A-‐ is a stronger base than H2O and HA is a weaker acid
than H3O+
Ka values span a huge range ca. 1012 to 10-‐50 therefore much more convenient to use a logarithmic scale
What is the concentra<on of pure water?

Logarithms – a reminder
the logarithm of a number is the exponent to which another fixed value (the base, b) must be raised to
produce that number
x = by logbx = y we will use log10 log10xa = alog10x log10xy = log10x + log10y log10x/y = log10x -‐ log10y
pKa = -‐log10Ka ∴ Ka = 10-‐pKa

higher pKa, smaller Ka, equilibrium lies more to the leU ∴ weaker acid

lower pKa, larger Ka, equilibrium lies more to the right ∴ stronger acid
[H+][A-‐]
________ [A-‐]
____
pKa = -‐log10Ka = -‐log10 = -‐log10[H ] -‐ log10
+
[HA] [HA]
pH
[A-‐]
∴ pKa = pH -‐ log10 ____
[HA]
rewri%ng the above gives the Henderson-‐Hasselbalch equa%on:

[A-‐]
∴ pH = pKa + log10 ____
[HA]
if [HA] = [A-‐] then pH = pKa (remember log10 1 = 0)

pH = -‐log10[H+] at neutral pH, 7 = -‐log10[H+] ∴ [H+] = 10-‐7 M

at higher pH, [H+] < 10-‐7 and solu%on is basic (i.e. less acidic)

at lower pH, [H+] > 10-‐7 and solu%on is acidic.

lower pH – more acidic higher pH – less acidic

for water pH = 7 this refers to the following equilibrium
Ka = [________
H3O+][HO-‐]
H2O + H2O H3O+ + OH-‐
[H2O]
[H3O+][HO-‐] = Kw -‐ ionisa%on constant of water and is a constant in aqueous solu%on – its value is easy to find

water has pH = 7 ∴ -‐log10[H+] = 7 ∴ [H+] = 10-‐7 M [H+] = [HO-‐] = 10 -‐7 M

∴ [H+][HO-‐] = 10-‐7•10-‐7 = 10-‐14 = Kw ∴ pKw = -‐log10Kw = 14
Calculate the pH of a 0.1 M solu<on of aqueous sodium hydroxide
pKa = -‐log10Ka ∴ Ka = 10-‐pKa HA H+ + A-‐
strong acids have Ka > 1 and ∴ pKa < 0 weak acids have Ka < 1 and ∴ pKa > 0

moderately strong acids Ka ≈ 1 and pKa ≈ 0
(generally view acids with pKa -‐2→+2 as moderately strong acids)
strong acids include: pKa weak acids include: pKa
CF3SO3H -‐14 ace%c acid 4.76
HCl ≈-‐7 NH4+ 9.2
H2SO4 ≈-‐3 water 15.74
H3O + -‐1.74 HC≡CH 25
NH3 38

the vast majority of organic compounds are weak acids
Calculate the pKa of H3O+
Note: the strongest base in aqueous solu<on is HO-‐ and the strongest acid is H3O+

any acid stronger than H3O+ is deprotonated by H2O to give H3O+

any base stronger then HO-‐ deprotonates H2O to give HO-‐
in a mixture of two acids or two bases: the difference in the pKa’s gives us the log of the equilibrium constant,
and the ra%o of the Ka’s gives us the equilibrium constant
Worked example: how much acetylene would be deprotonated on treatment with hydroxide in aqueous solu9on?

HC≡CH + HO-‐ HC≡C-‐ + H2O
[HC≡C-‐][H2O] [HC≡C-‐][H3O+] [H3O+][HO-‐]

Keq = _____________ and Ka HC≡CH = ___________ Ka H2O = ________
[HC≡CH][HO-‐] [HC≡CH] [H2O]
Ka HC≡CH
∴ Keq = ______ = 10-‐25/10-‐15.74 = 1015.74/1025 = 10-‐9.3
Ka H2O
i.e. only 1 in 1 billion molecules of acetylene would be deprotonated at equilibrium – to deprotonate acetylene
use a solvent which does not have a pKa < 25 and use a stronger base – e.g. NaNH2 in liquid NH3
HC≡CH + H2N-‐ HC≡C-‐ + NH3
pKa NH3 = 38 pKa HC≡CH = 25 ∴ Keq = 10-‐25/10-‐38 = 1013

some pKa values in water and DMSO

OH
CF3CH2OH MeOH H2O tBuOH
12.5 15 15.74 9.95 17

(23.5) (28) (31.2) (18.0) (29.4)
Me Me
H
Me NH3 Me N Me Me N Me
H2
Me
10.6 10.75 11.05
O O O O O CO2H
HO2C HO2C
HO OH Me OH F3C OH OH Ph OH CO2H
O2N
3.6, 10.3 4.76 -0.25 2.45 4.2 3.02, 4.38 1.92, 6.23
(12.3) (11)
Ph Ph
CH4 H2 HC CH
Ph
48 43 ~36 23 25 15
Remember: lower pKa = stronger acid; higher pKa = weaker acid

we are going to generally look at pKa values in water

the majority of organic reac%ons are not conducted in water

generally pKa values when measured in organic solvent – typically DMSO – are higher then those measured in
water

this is a consequence of the organic solvent being less good then water at solva%ng the conjugate base

it is generally the case that the trend in pKa values in water and DMSO is very similar

pKa H2O in H2O = 15.74 pKa H2O in DMSO = 32; pKa AcOH in H2O = 4.76 pKa AcOH in DMSO = 12.3
when predic%ng or ra%onalising pKa values (i.e. the strengths of organic acids and bases) we need to consider
three things:

i)  strength of the H-‐A bond;
ii)  effect of hybridisa%on;
iii)  effect of conjuga%on/delocalisa%on
Most important factor in acid strength is the stability of the conjugate base A-‐
most important is to draw the equilibrium: then look at the stability of the conjugate base
Worked example: explain why phenol is more acidic than methanol

Step 1: draw equilibria for both species
Step 2: evaluate stability of the conjugate base

CH OH CH O + H+ equilibrium A
3 3
OH O
+ H+ equilibrium B
Two factors work to stabilise the phenoxide anion
O
i) delocalisa%on
one of the oxygen lone pairs is in a ‘p’-‐orbital which can overlap with the
π-‐system of the aroma%c ring
Remember: these structures are

O O O O just different ways of drawing the
same species – the charge is not
actually moving around the ring
ii) induc%ve effect

The aroma%c subs%tuent is sp2 hybridized (vs sp3 hybridized in methanol) and hence has more ‘s’ character. The
higher propor%on of ‘s’ character means that the electrons see more effec%ve nuclear charge.

i.e. sp2 hybridised carbons are more electron-‐withdrawing (electronega%ve) than sp3 hybridised carbons
both of the above factors stabilise the phenoxide anion with respect to methoxide
∴ equilibrium B lies further to the right than equilibrium A and hence phenol is the stronger acid
most important is to draw the equilibrium: then look at the stability of the conjugate base
Predict which of the following two phenols is the stronger acid.

OH OH
O2N
NO2
Worked example: explain the following order of acid strengths

methane (pKa = 48); benzene (pKa = 43); HC≡CH (pKa = 25)

Step 1: draw equilibria for the three species
Step 2: evaluate stability of the conjugate base

CH4 CH3 + H+ eq. A anion in sp3 orbital – 25% s-‐character H H
H
+ H+ eq. B anion in sp2 orbital – 33% s-‐character
HC CH HC C + H+ eq. C anion in sp orbital – 50% s-‐character HC C
acetylide anion more stable than C6H5-‐ which is more stable then CH3-‐

∴ equilibrium C lies further to the right than equilibrium B which lies further to the right than equilibrium A
and hence acidity order is as shown.
Explain the acidity of the following compounds

CN
CH3
H3C H3C
pKa (DMSO) 43 30.8 44 18
how about bases? Brønsted -‐ base is a proton acceptor. There are two ways to deal with bases.
Let’s start with a base A-‐
A-‐ + H2O HA + HO-‐
Kb = ________
[HA][HO-‐] pKb = -‐log10Kb Kw = [H3O+][HO-‐] ∴ Kb = ________
[HA]Kw Ka =________
[H3O+][A-‐] ∴ Kb =Kw/Ka
[A-‐] [A-‐][H3O+] [HA]
∴ pKb =14 -‐ pKa
stronger base – lower pKb
weaker base – higher pKb
it is inconvenient to have two scales and chemists just use pKa to talk about the strengths of acids and bases
i.e. look at the ability of the conjugate base to act as a base.
acid HA + H2O H3O+ + A-‐ conjugate

base
base conjugate
acid
How do you find out which is the stronger base – t-‐butoxide, or acetate?
look at the pKa’s – here tBuOH holds onto the proton to a much greater extent than ace%c acid, or to put it another
way tBuO-‐ much more readily accepts a proton than acetate and hence tBuO-‐ is a stronger base.

tBuOH pKa = 17 Higher pKa = weaker acid and
tBuO + H+
hence stronger conjugate base.
O O
+ H+ pKa = 4.76 Lower pKa = stronger acid and
Me OH Me O
hence weaker conjugate base.
Example
butane is a very weak acid (pKa ~ 43) but butyllithium is a very strong base
H2SO4 is a strong acid (pKa -‐3.0) but HSO4-‐ is a very weak base.
The problem of amines

what do we mean by the ques%on “what is the pKa of ammonia?”

strictly speaking this refers to the following equilibrium:
NH3 NH2 + H+ pKa ~ 38 i.e. ammonia is a very weak acid and H2N-‐ is a very strong base
but we might be asking, how good a base is NH3 – which means we need the pKa of ammonium NH4+
pKa ~ 9.2 i.e. NH3 is a weaker base than HO-‐ (pKa H2O = 15.74)
NH4 NH3 + H+ to get around this possible ambiguity we should be specific in asking for the
pKa of the conjugate acid of ammonia (some%mes given the symbol pKaH)
i.e. of ammonium
Important to know some pKa’s

compound pKa (water) compound pKa (water) compound pKa (water)
O
CH4 48 15 HN NH 6.95
Me NH2
O O 5.21
NH3 38 13 NH
MeO OMe
O O O
HC CH 25 11 4.76
EtO Me Me OH
O
25 OH 10 H2CO3 3.6, 10.3
Me OtBu
O
20 CH3NO2 10 NH3 4.6
Et Et
O
tBuOH 17 NH4 9.24 -‐0.25
F3C OH
O O
MeOH 15 9 CF3SO3H -‐14
Me Me
comparing any 2 acids: conjugate base of acid with higher pKa will deprotonate acid with lower pKa
e.g. BuLi will deprotonate HC≡CH; NaOMe will deprotonate dimethyl malonate etc.
for excellent tabulated pKa values for a large number of organic compounds see: hVp://evans.harvard.edu/pdf/
evans_pka_table.pdf and hVp://www.chem.wisc.edu/areas/reich/pkatable/index.htm
1) Explain the following pKa orders:

OH OH OH O O O O O O
(a) (c) < <
Me Me Me OMe MeO OMe
< <
most acidic least acidic
Me Me
lowest pKa higest pKa
NO2 NO2
most acidic least acidic
lowest pKa higest pKa
(b) O O O (d)
Me Me Me
> >
< < Me Me
Me Me Me Me N N Me N Me
Me H H H
O Me Me
most acidic least acidic most acidic least acidic
lowest pKa higest pKa lowest pKa higest pKa
2) Which of the following is more basic?
(a) (b) (c) N Me

N
Me O-Na+ Me S-Na+ Me N Me
NH Me
N
H
3) Explain the pKa’s of maleic and fumaric acid:
CO2H
HO2C HO2C
CO2H
3.02, 4.38 1.92, 6.23

4) How might you carryout the following transforma<ons?
(a) H O Me O
O O
H H
TBDPSO TBDPSO
(b) O O O O O O
Me
OMe Me OMe Me OMe
Me
O O O
(c)
OMe OH OH
HO HO MeO
H
NH2 N Me
(d)
O
HO HO
(e)
OH OH OAc OAc
NH2 NH2
HO AcO
OH OH OAc OAc
5) Explain the following transforma<ons?
O O O
(a) OEt EtO, EtOH
OEt OEt
O
O O
Me O EtO, EtOH
O
(b) Me
OEt OEt
6) In water, the basicity of the amines below is as follows, explain.
Me NH2 < Me N Me < Me N Me

H
Me
7) Predict the product of the following reac<on.
O Br
LDA,
Ph OMe
Me
enantiopure
“When two molecules collide, three major forces operate.

(i) The occupied orbitals of one repel the occupied orbitals of the other.
(ii) Any posi%ve charge on one aTracts any nega%ve charge on the other (and repels any
posi%ve).
(iii) The occupied orbitals (especially the HOMOs) of each interact with the unoccupied
orbitals (especially the LUMOs) of the other, causing an aTrac%on between the molecules.”
Molecular Orbitals and Organic Chemical Reac9ons I. Fleming

this means that reac%ons generally have both a charge and an orbital component. Reac%ons can be predominantly
charge controlled, predominantly orbital controlled, or a mixture of the two.

nucleophiles and electrophiles were classified by Pearson as HARD or SOFT – R. G. Pearson, Chemical Hardness, John
Wiley & Sons, 1997.

Hard nucleophiles (and electrophiles) are small and highly charged and have high electronega%vity (i.e. have a large
charge:radius ra%o) – they have a low energy HOMO.

Sob nucleophiles (and electrophiles) are larger and have lower electronega%vity and are more polarizable – they have a
high energy HOMO.
Bases (Nucleophiles) Acids (Electrophiles)
Hard Hard
H2O, HO-‐, F-‐, RCO2-‐, Cl-‐, ROH, H+, Li+, Na+, K+, Mg2+, BF3
RO-‐, NH3, RNH2
Intermediate Intermediate
PhNH2, N3-‐, NC-‐, Br-‐ carboca%ons
SoN SoN
I-‐, RS-‐, RSe-‐, S2-‐, RSH, RSR, R3P, Ag+, Pd2+, I2, Br2, radicals
alkenes, aroma%cs, R-‐
Hard nucleophiles have low energy HOMO’s and a high SoU nucleophiles have high energy HOMO’s and they are
charge:radius ra%o polarizable
Hard electrophiles have high energy LUMO’s and a high SoU electrophiles have low energy LUMO’s and they are
charge:radius ra%o polarizable
charge dominates their reac%vity orbital interac%ons dominates their reac%vity
hard
electrophile
soft
electrophile
soft
nucleophile
hard:hard soL:soL
charge control orbital control
hard
nucleophile
Generally the case that:

Hard nucleophiles tend to react well with hard electrophiles
i.e. the reac<on is predominantly charge controlled

Sob electrophiles tend to react well with sob nucleophiles
i.e. the reac<on is predominantly orbital controlled
Recently the HSAB theory has been disputed see:

H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. Int. Ed., 2011, 50, 6470
Bases (Nucleophiles) Acids (Electrophiles)

Hard Hard
Generally the case that:
Hard nucleophiles tend to react well with hard electrophiles H2O, HO-‐, F-‐, RCO2-‐, Cl-‐, ROH, H+, Li+, Na+, K+, Mg2+, BF3
i.e. the reac<on is predominantly charge controlled RO-‐, NH3, RNH2
Intermediate Intermediate
Sob electrophiles tend to react well with sob nucleophiles PhNH2, N3-‐, NC-‐, Br-‐ carboca%ons
i.e. the reac<on is predominantly orbital controlled
SoN SoN
I-‐, RS-‐, RSe-‐, S2-‐, RSH, RSR, R3P, Ag+, Pd2+, I2, Br2, radicals
alkenes, aroma%cs, R-‐
the principle of hard/soU acid bases has been applied to a large number of chemical reac%ons
H
HO H O 2H2O faster than HO Br Br HO Br + Br
H
Br
Br
Br H
faster than H O H
H
Recently the HSAB theory has been disputed see:

H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. Int. Ed., 2011, 50, 6470
Ambident nucleophiles R
O :Base
O M O O
RX +
alkyla%on of enolates H R
O-‐alkyla%on C-‐alkyla%on
with enolates the majority of the charge is, as expected, on the oxygen atom

charged electrophiles aTack oxygen e.g. protons, carboca%ons

soU electrophiles will generally aTack carbon – largest HOMO coefficient

in general, in enolate reac%ons the oxygen atom is associated with a metal ion and solvent and hence
both of these variables affect the ra%o of C:O alkyla%on

to maximise C-‐alkyla%on use a lithium base (strong O-‐Li bond) and an alkyl halide in THF (soU-‐soU
interac%ons)

to maximise O-‐alkyla%on use a highly coordina%ng solvent (e.g. HMPA), a potassium base, and an alkyl
sulfonate
Ph
O O Ph OH
+ Ph Br
DMF 97% 0%
CF3CH2OH 7% 85%
Ambident nucleophiles
X = A B

Me
OTs 88% 11%
K O O Me X O O O O
+ Cl 60% 32%
OEt HMPA OEt OEt
Br 39% 38%
A B Me
I 13% 71%
A. L. Kurts, A. Masias, N. K. Genkina, I. P. Beletskaya, O. A. Reutov, Tetrahedron, 27, 4777
in a similar manner, deprotonated secondary amides alkylate on nitrogen with alkyl halides

neutral secondary amines alkylate on oxygen with hard alkyla%ng agents
MeO
Explain these two transforma<ons

H CO2tBu CO2tBu
O O
O N NaH, MeO Cl O N
O DMF O
R H R H
H
O N CO2tBu EtO N CO2tBu
K2CO3, Et3O BF4
CH2Cl2
R R' R R'
A. Endo, S. J. Danishefsky, J. Am. Chem. Soc., 2005, 127, 8298.
Nucleophilic SubsTtuTon at a saturated carbon two limi%ng mechanis%c cases – SN2 and SN1 – mechanis%c
con%nuum between these extremes
SN2 – subs<tu<on, nucleophilic bimolecular SN1 – subs<tu<on, nucleophilic unimolecular
example: MeI + NaOH → MeOH + I-‐ example: Me H2O Me
Me Cl Me OH
Me Me
rate = k[substrate][nucleophile] rate = k[substrate]
i.e. rate dependent on both substrate and nucleophile i.e. rate is independent of nucleophile
‡
R
(-) (-)
Nu LG
R' R'' Me Me
Me
Me
R Nu Me X Me
Nu LG Me Me Nu
R'' R
R' Me
Nu R''
R'
concerted reac%on, single transi%on state stepwise reac%on, via an intermediate -‐ the 1st step
no intermediate is formed is rate determining (forma%on of C+), 2nd step is fast
favoured by 1° substrates and some 2° substrates favoured by 3° substrates and some 2° substrates

requires good nucleophile and leaving group requires good leaving group and solvent that stabilises
carboca%ons
SN1 reac%on enanTomers

‡
X X (-) Nu R''
step 1 R' Nu step 2 R R'
R' (+) R
R R R'
R'' R R' R'' Nu
R''
R''
SN1 reac%ons proceeds via a discrete carbenium ion and forma%on of the carbenium ion (step 1) is usually the
rate determining step

the lowest energy conforma%on of carbenium ions is planar

trapping of the carbenium ion by a nucleophile (step 2) is generally fast
the nucleophile can trap the carbenium ion from either side, hence enan%oenriched substrates should
be expected to give racemic products under SN1 condi%ons – c.f. SN2 reac%ons go with strict inversion of
configura%on

hence the rate of the reac%on is not affected by the added nucleophile

the stability of carbenium ions is in the order ter%ary > secondary > primary due to hyperconjuga%on

H hyperconjuga%on is the overlap of filled C-‐H (or C-‐C) σ-‐bonding orbital with the
CH3 empty p-‐orbital resul%ng in a lowering in energy of the system i.e. stabilisa%on
H
CH3
H
Nomenclature of carboca%ons proposed by Olah J. Am. Chem. Soc., 1972, 94, 808.
HyperconjugaTon
dona%on of C-‐H σ-‐bond

electrons in empty p orbital empty
p-orbital
H filled σ C-H
CH3 orbital
H
CH3
H energy of the bonding electrons reduced
system stabilised
greater number of C-‐H (or C-‐C) σ-‐bonds the greater the extent of hyperconjuga%on and the greater stabilisa%on
carbenium ion stability therefore goes in the order: tertiary secondary primary
R R > R R > R
R
carbenium ions have been observed by NMR and X-‐ray crystal structure analysis

a recent X-‐ray structure of the t-‐butyl ca%on (anion is CHB11Cl11) shows the planar
nature of the carbenium ion. E. S. Stoyanov, I. V. Stoyanova, F. S. Tham, C. A. Read;
Angew.Chem., Int.Ed. 2012, 51, 9149

conjuga%on with alkenes, arenes and lone pairs, also stabilises carbenium ions
conjuga%on with alkenes, arenes and lone pairs, also stabilises carbenium ions
benzyl ca%on stabilised by delocalisa%on
ψ3
X
energy of
ψ2
allyl ca%on stabilised by delocalisa%on isolated p-‐orbital
ψ1
RO X RO RO
α-‐heteroatom subs%tuted ca%ons stabilised by delocalisa%on

allyl ca%on more stable
than energy of p-‐orbital –
conjuga%on is stabilising
Which orbitals are overlapping in the stabilisa<on of α-‐heteroatom-‐subs<tuted ca<ons?
the more stable the carbenium ion the faster SN1 reac%on
rates of hydrolysis of alkyl chlorides in 50% aqueous ethanol (adapted from Organic Chemistry, Clayden, Greeves
and Warren, 2nd Edi%on, OUP 2012)
2° chloride, not that

stable C+ not good at SN1 1° but allylic 1° but benzylic
butyl iso-propyl allyl benzyl
1° chloride Cl
∴ SN2 Cl Cl
Cl
0.07 0.12 1.0 4.0
methallyl tert-butyl cinamyl dimethallyl

allylic
ca%on is 2° Cl
Cl allylic
at one end Cl Cl ca%on is 3°
at one end
91 2100 7700 130000
3° chloride 1° but allylic

very good at SN1 and benzylic
as a carbenium ion is formed during an SN1 reac%on a polar solvent is required for reac%on

the best solvents for promo%ng SN1 reac%ons are polar pro%c solvents such as water and alcohols (they can
readily solvate the carbenium ion as well as the leaving group (by hydrogen bonding – see later))
solvent water ethanol ace%c acid DMSO DMF

dielectric
80 25 6.2 46 38
constant ε
solvent acetone EtOAc THF ether hexane
dielectric
21 6 7.5 4.3 1.9
constant ε
rela%ve rate of solvolysis (i.e. reac%on with solvent as the nucleophile) of tert-‐butyl bromide is 3 x 104 %mes
faster in 50% aqueous ethanol than in neat ethanol
Explain the rela<ve rates of solvolysis of the

following alkyl bromides in 80% aqueous ethanol δ- H H
In polar solvent the δ+ OH
carbenium ion is solvated by δ- δ- O Oδ-
H H H
polar solvent. It is easier to HO δ+ δ+ +
H LG H H
Br cluster water molecules
Br OH H O Oδ-
Br around the carbenium ion H δ+ δ- δ- H H
1 10-6 10-14 and the leaving group than HO
δ-
ethanol molecules
Nucleophilic SubsTtuTon at a saturated carbon
SN2 – subs<tu<on, nucleophilic bimolecular example: MeI + Na+OH-‐ → MeOH + Na+ I-‐
rate = k[substrate][nucleophile] ‡
H
H (-) (-) H
HO H I HO I HO H I
H H
H H
H HOMO of nucleophile (nucleophile lone pair) aVacks

I the back side of the carbon atom as it is pulng
H electrons into the C-‐I σ* orbital
H

at the transi%on state the central carbon atom is bonded to 5 other atoms – hence fundamentally SN2
reac%ons are difficult reac%ons

the trajectory of approach is along the path of the bond to the leaving group – evidence from Eschenmoser’s
experiments
O O O O O O
S
O
S
O
S
OH
reac<on shown to be
X
exclusively intermolecular
CH3 NaH CH3 CH3
Eschenmoser, Helve<ca
S O S O S O Chim. Acta 1970, 53, 2059
O O O
H3C H3C H3C
trajectory results in inversion of configura%on between star%ng material and product
‡
Me
Me (-) (-) Me
Nu H LG Nu LG Nu H LG
Et Et
Et H
the rate of an SN2 rec%on is influenced by the nature of the substrate, the nucleophile, the leaving group and,
with anionic nucleophiles, the associated counterion, and the solvent
What makes a good nucleophile? – i.e. what gives a fast reac%on with an electrophile

nucleophilicity is related to basicity but is significantly more complex

if the atom we are comparing is the same then nucleophilicity does parallel basicity.
O
HO > PhO > > H2O > ClO4
Me O

basicity is a measure of electron pair dona%on to a proton (generally under equilibra%ng condi%ons)

nucleophilicity is electron pair dona%on to another atom, frequently carbon, generally under kine%c condi%ons

factors which influence nucleophilicity include: charge, electronega%vity, solvent, size, bond strength

Note: the order of nucleophilici<es is also dependent on the nature of the leaving group
Charge
charged species are more nucleophilic than their neutral counterparts
this is expected as nucleophiles are electron pair donors so the more electron rich the nucleophile the beTer donor it is
O O NH NH2
Me O more nucleophilic than Me OH more nucleophilic than
Me S more nucleophilic than Me SH BuLi is obviously more nucleophilic than butane
ElectronegaTvity
nucleophilicity is related to basicity, but significantly more complex as it involves dona%on of an electron pair to any
atom, whereas basicity is dona%on of an electron pair to H+

in the same row of the periodic table more basic means more nucleophilic

∴ going from leU to right across the periodic table nucleophilicity decreases the more electronega%ve atom is the
weaker nucleophile as it holds on to its lone pairs of electrons more %ghtly and is less able to donate an electron pair to
form a bond.
CH3 > NH2 > HO > F NH3 > H2O > HF
most basic least basic most basic least basic

most nucleophilic least nucleophilic most nucleophilic least nucleophilic
this does not necessarily mean we will get good yields in SN2 reac%ons with these anions as they are also
very basic and hence other reac%on pathways can dominate
Solvent
in polar pro%c solvents (e.g. water, MeOH, AcOH) nucleophilicity increases going down the group – again the less
electronega%ve atom is the more nucleophilic
δ-
F < Cl < Br < I in polar pro<c solvents the most δ+ OR
electronega<ve atom has the highest charge δ- H
density and forms the strongest hydrogen RO δ+ δ+
H F H
least nucleophilic most nucleophilic bonds with the solvent therefore the OR
nucleophile is shielded from aVacking the H δ+ δ-
electrophile and the reac<on is slower RO
δ-
in polar apro%c solvents (e.g. DMSO and DMF) the order of nucleophilicity can invert when compared with polar
pro%c solvents as the solvent has weaker interac%ons with the nucleophile. Frequently reac%ons are much faster in
these solvents compared with in water

MeI + Cl MeCl + I

for the halides under some condi%ons, nucleophilicity now decreases going down the group and again parallels
basicity (here the most electronega%ve atom is the best nucleophile). Here charge control appears to be domina%ng
the reac%on
F > Cl > Br > I
most basic least basic

most nucleophilic least nucleophilic

with uncharged nucleophiles, nucleophilicity increases going down the group – here orbital control appears to be
domina%ng – the nucleophile with the highest energy HOMO reacts the fastest
PR3 > NR3 increasing nucleophilicity

higher energy HOMO lower energy HOMO
most nucleophilic H2Se > H2S > H2O least nucleophilic
increasing nucleophilicity
C N O F
Si P S Cl
Note: nucleophilicity is complicated and the above should be viewed as guidelines Ge As Se Br
Sn Sb Te I
A rule of thumb is that nucleophilicity increases going down a group
and increases in moving from right to leU in the periodic table Pb Bi Po At
the shape of the nucleophile also influences its nucleophilicity

in moving from the star%ng materials to the transi%on state the central carbon goes from 4-‐coordinate to 5-‐
coordinate hence sterically hindered nucleophiles react more slowly
MeO > O > O
fastest slowest
conversely, small linear anions such as N3-‐, NC-‐ and RC≡C-‐ are good nucleophiles
the following is the order of reac%vity of various nucleophiles with methyl iodide in methanol – all of these
anions would be considered good nucleophiles (from Chem. Rev. 1969, 69, 1-‐32) – PR3 are also excellent
nucleophiles

PhS-‐ > I-‐ > SCN-‐ ≈ CN-‐ > N3-‐ ≈ Br-‐ > Cl-‐ > OAc-‐ in polar pro%c solvents

PhS-‐ > CN-‐ > -‐OAc > Cl-‐ ≈ Br-‐ ≈ N3-‐ > I-‐ > SCN-‐ in dipolar apro%c solvents

Leaving Group ‡
Me
Me (-) (-) Me
Nu H LG Nu LG Nu H LG
Et Et
Et H
during the SN2 reac%on the bond to the leaving group is broken and the LG departs with a lone pair of electrons
i.e. becomes more nega%vely charged in the transi%on state

∴ two factors generally influence the leaving group ability:

i)  the strength of the bond to carbon

ii)  the stability of the leaving group
leaving group ability relates to pKa i.e. good LG’s are weak bases
tosylate TsO-‐
triflate TfO-‐
O O
O O S
N2 > S > I > O ≈ Br > Cl
F3C O
Me
pKa -14 -10 -3 -9 -8
rough order of LG ability – the LG ability depends on the nucleophile and the solvent and the above order can
vary; however, very weak bases are good leaving groups

iodide is a good leaving group as it forms a weak bond to carbon as well as being a stable anion

F-‐ is a very poor leaving group in SN2 reac%ons as it forms a very strong bond to carbon

HO-‐ is a very poor leaving group in SN2 reac%ons as it is a strong base (pKa H2O = 15.74) but can be made into a
good leaving group by protona%on (pKa H3O+ = -‐1.74) or conversion into a tosylate or triflate
Common leaving groups in SN2 reac%ons tend to have a pKa < 2
Nature of the substrate

SN2 reac%ons – back to the transi%on state

‡
R
R (-) (-) R
Nu R'' LG Nu LG Nu R'' LG
R' R'
R' R''
the nucleophile has to aTack carbon, hence with larger the R groups the rate of reac%on decreases

in moving from substrate to transi%on state carbon moves from being 4-‐coordinate to being 5-‐coordinate hence
as the R groups become larger the rate of the reac%on decreases
SN2 reac%ons ∴ only occur with primary and some secondary substrates – not with ter%ary substrates

rela%ve rates of the reac%on of the bromides below with chloride are (Chem. Rev. 1956, 56, 571):
methyl ethyl propyl iso-propyl neo-pentyl tert-butyl
Me Me Me
Me Br Br Me Me
Me Br Me Br
Me Br Me Me Br
relative rate 60 10 6.5 0.13 0.0003 negligible
neopentyl bromide is par%cularly unreac%ve as the nucleophile is severely hindered from aTacking the
necessary carbon atom (Note: neopentyl systems are also unreac<ve in SN1 reac<ons)
Me ‡
Me Me
Me Me Me
Me
Me (-) (-) Me
Nu LG Nu LG Nu R'' LG
H
H R'
H H
rate of SN2 reac%ons is increased with substrates which carry an adjacent sp2
(or sp) hybridized atom

at the SN2 transi%on state the central carbon is partly bonded to both the nucleophile and the leaving group

3 atoms are sharing 4 electrons i.e. there is a 3-‐centre,4-‐electron bond

the central carbon has a partly filled p-‐orbital and the electrons in this orbital can be delocalised into the adjacent π-‐
system which lowers the energy of the transi%on state and the reac%on is faster

‡ H
H H H H
H
(-) (-)
LG Nu LG Nu LG
Nu
delocalisa%on
into π-‐system
the π-‐system has to be in the correct orienta%on for efficient overlap and consequent transi%on state stabiliza%on
α-‐halo carbonyl compounds are par%cularly reac%ve under SN2 condi%ons as they contain an α sp2 hybridised
atom aTached to oxygen and the C=O π* is lower in energy than for an alkene
rela%ve rates for reac%on alkyl halides with KI in acetone at 50 °C are given below
(from Mechansim in Organic Chemistry, R. W. Alder, R. Baker, J. M. Brown, Wiley, 1971)
‡ H
H H H H
H
(-) (-)
LG Nu LG Nu LG
Nu
delocalisa%on
into π-‐system
Cl N O
Me Cl Cl Cl MeO Cl Cl
Me Cl
Ph
relative rate 1 200 79 200 920 3000 100,000
Summary of structural varia%ons and nucleophilic subs%tu%on taken from Organic Chemistry, Clayden,
Greeves and Warren, 2nd Edi%on, OUP 2012.
R X R X R
Electrophile Me X R X X
R R
R R R
methyl primary secondary ter%ary ‘neopentyl’
SN1 mechanism? ✗ ✗ ✗✓ ✓✓ ✗
SN2 mechanism? ✓✓ ✓ ✗✓ ✗ ✗
O O
X X
RO X X
Electrophile X R
R
α-‐carbonyl and
allyl benzyl α-‐alkoxy α-‐carbonyl
ter%ary
SN1 mechanism?
✓ ✓ ✓ ✗ ✗
SN2 mechanism?
✓ ✓ ✓ ✓✓ possible
✗ = bad ✓ = good, ✓✓ = excellent, ✗✓ = poor

1) Explain why the reac<on of B with iodide is several <mes faster than the reac<on of A with iodide
O O O O
O2N O2N I O2N O2N Ph
KI KI I
O acetone acetone O
OH O OH
NO2 NO2 NO2 Ph NO2
A B
O
2) For the reac<on below predict the effect on the rate of changing the: i) substrate to i-‐propyl chloride;
ii) substrate to methyl iodide; iii) nucelophile to CH3SNa; iv) solvent to DMSO
MeOH
MeCl + NaOMe CH3OCH3 + NaCl
3) Suggest reagents for the following reac<ons:
(a) Me Me Me (b)
N O
N Cl
I HO
OH H H
(c) N (d)
OH SMe
Br Br
H H
4) Explain the outcome of the following reac<ons
(a) Cl NEt2 (b)

NaOH
Et2N HO OH OH
Me Me H H
NaOH, H2O
NBn2 OH Cl
H2O OH
Cl Bn2N
Et Et
(c)
Br HBr Br HBr
OH Br OH Br
Br Br
(d)
OH OMe
MeO, MeOH O MeOH, H
OMe OH
Ph Ph Ph
5) Predict the outcome of the following reac<ons

O
Cl
MeOH, Et3N Cl
O Cl O AlCl3
EliminaTon reacTons mechanis%c con%nuum from E1→E2→E1cB
E2 – elimina<on bimolecular E1 – elimina<on unimolecular

Me EtOH
example: example: Br + HBr
R Me
EtOH Me Me Me
Br + EtO R +
H Br rate = k[substrate]
rate = k[substrate][base]
i.e. rate is independent of base (which is EtOH in the
i.e. rate dependent on both substrate and base
‡ above case)
(-)
X
(-) H
HH
B Me
Me
H
X
H B
C-H σ to C-X σ* Me
B Me
Me X
X Me
H X Me
B BH
concerted reac%on, single transi%on state

no intermediate is formed, an%periplanar stepwise reac%on, via an intermediate -‐ the 1st step
arrangement of proton and leaving group is most is rate determining (forma%on of C+), 2nd step is fast
favourable for elimina%on
favoured by 3° substrates and some 2° substrates
requires good base and leaving group
3° substrates give more elimina%on than 2° substrates requires good leaving group and solvent that stabilises
which give more elimina%on than 1° substrates carboca%ons

EliminaTon reacTons
RO O RO O
+ HO
E1cB – elimina%on from the conjugate base example:
Me Me
acid base conjugate base
variable kine%cs depending on substrate

requires a carbanion stabilising group O
RO +
Me
as the carbanion (an enolate in the above example) helps to expel the leaving group, conjuga%on
is developed in the transi%on state leading to the product, HO-‐, and RO-‐ can ∴ be leaving groups
requires a base and leaving group
SubsTtuTon versus EliminaTon

SN1 reac%ons are frequently accompanied by E1 reac%ons if there is an appropriately posi%oned proton – this is
unsurprising as both reac%ons proceed through the same intermediate

SN2 reac%ons can also be accompanied by E2 reac%ons

we need to look at factors affec%ng:
i)  SN1/E1 product ra%os
ii) SN2/E2 product ra%os

iii) change of mechanism i.e. SN1/E1 → SN2/E2

primary substrates do SN2 or E2 – SN2 is generally favoured but bulky bases (t-‐BuOK) allow E2 to occur
EtO
Br OEt
91 9
to maximise SN2 – use good nucleophile e.g. RS-‐, X-‐, N3-‐ in dipolar apro%c solvent
ter%ary substrates do SN1 / E1 or E2

with good ionising solvents and no added anionic base then SN1 / E1 will be favoured

with added base E2 will be favoured EtO
Br OEt
<0.1 >97
secondary substrates can do SN1 / E1 or SN2 / E2

with good ionising solvents and no added anionic base or nucleophile then SN1 / E1 will be favoured

EtO
with added base E2 will be favoured Br OEt

with good nucleophiles, dipolar apro%c solvents SN2 will be favoured 20 80
for all substrates moving from primary to secondary to ter%ary favours elimina%on

polar pro%c solvents and base favour E2 over SN2 [base/nucleophile is solvated so easier to aTack outside of
the molecule (i,e. remove a proton) than aTack carbon in an SN2 reac%on]

heat favours elimina%on over subs%tu%on.
EtO
Br OEt
increased branching at the β-‐posi%on favours elimina%on
40 60

A good overview can be found at:

hTp://www.masterorganicchemistry.com/2013/01/18/wrapup-‐the-‐quick-‐n-‐dirty-‐guide-‐to-‐sn1sn2e1e2/
1) Predict the major product (if any) from the following reac<ons giving mechanis<c reasoning
(a) Br EtOH
(b) Br EtONa
EtOH
(c) (d)
Br EtSNa EtONa
EtSH Br EtOH
2) The rate of hydrolysis of tBuCl in water is greatly accelerated by the addi<on of hydroxide. How will the product
distribu<on be affected?
as we have seen, allylic systems are reac%ve under SN2 (stabilisa%on of the transi%on state for subs%tu%on) and
under SN1 condi%ons

the allylic system has two posi%ons which can be aTacked leading to isomeric products – i.e. there are issues of
regioselec%vity
Nu Nu Nu
X Nu X
Nu SN2
Nu Nu
X Nu
SN2’
SN1 SN1’
sterics and electronics play a role in determining SN/SN’ reac%ons
O O O O
EtO O O
EtO OEt EtO OEt + Br
Cl
EtO PhS
EtO PhS
Cl Cl
SN2’ reac%ons are not very common

they can also be solvent dependent, I. Fleming, E. J. Thomas, Tetrahedron, 1971, 28, 4989
SPh
Cl PhS Cl Cl PhS Cl
DME MeOH
MeO Cl MeO MeO Cl MeO SPh
SN2’ SN2
SPh
Cl PhS Cl Cl PhS Cl
DME
MeO Cl MeO MeOH
MeO Cl MeO SPh
excellent control of SN2/SN2’ can achieved with organometallic reagents – most notably with copper, palladium
and iridium
10 mol% CuCN
n-BuMgBr Bu
OAc Bu
THF 0 °C 94 6
Et2O, 20°C 3 97
J. E. Bäckvall, M. Sellén, B. Grant, J. Am. Chem. Soc., 1990, 112, 6615.
For a review on copper-‐catalysed enan%oselec%ve conjugate addi%on and allylic subs%tu%on see: A. Alexakis,
J. E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez Chem. Rev. 2008, 108,2 796.
O Me and related
P N
Me
phosphoramidites
O
O
cat. [Ir(COD)Cl]2 Nu
Nu + R O OMe
additive R *
Nu = RNH2, ArO-, malonates, enamines, high yields

silylenol ethers, indoles, PhMgBr, NH3, high regioselectivity
alkenes, vinyltrifluoroborates etc. high enantiomeric excess
main names in the field: Helmchen, Alexakis, Hartwig, Carreira, You

OH O heat OH
Br
K2CO3, DMF
2) Suggest reagents and reac<on condi<ons for the following transforma<on
OH OH
AromaTcity – Electrophilic AromaTc SubsTtuTon and Nucleophilic AromaTc SubsTtuTon
“I was silng wri<ng at my textbook but the work did not progress; my
thoughts were elsewhere. I turned my chair to the fire and dozed. Again the
atoms were gambolling before my eyes. This <me the smaller groups kept
modestly in the background. My mental eye, rendered more acute by the
repeated visions of the kind, could now dis<nguish larger structures of manifold
confirma<on: long rows, some<mes more closely fiVed together all twining and
twis<ng in snake like mo<on. But look! What was that? One of the snakes had
seized hold of its own tail, and the form whirled mockingly before my eyes. As if
by a flash of lightning I awoke; and this <me also I spent the rest of the night in
working out the rest of the hypothesis.
August Kekulé
Let us learn to dream, gentlemen, then perhaps we shall find the truth... But let
us beware of publishing our dreams ‘<ll they have been tested by waking
understanding.”
typical reac%ons of alkenes
fast Br
+ Br2 Br
Me Me Me not substitution
Br
addition
typical reac%ons of benzene
FeBr3 catalyst Br Br
+ Br2 + HBr not addition
Br
substitution
retains aroma%c sextet of electrons in subs%tu%on reac%ons

does not behave like a “normal” polyene or alkene
benzene is both kine<cally and thermodynamically very stable
heats of hydrogena%on

H2/Pt catalyst H2/Pt catalyst
ΔHohydrog = -‐120 kJmol-‐1

ΔHohydrog= -‐210 k Jmol-‐1 H2/Pt catalyst ΔHohydrog= 3 x -‐120 = -‐360 kJmol-‐1
(hypothe%cal, 1,3,5-‐cyclohexatriene)
benzene ≈150 kJmol-‐1 more stable than expected – (represents stability over hypothe%cal 1,3,5-‐
cyclohextriene) – termed the empirical resonance energy (values vary enormously)
AromaTcity

Hückel’s rule holds for anions, ca%ons and neutrals

(4n +2) π-‐electrons for aroma%c compounds; 4n π-‐electrons for an%-‐aroma%c
cyclopropenium ca%on -‐ (4n +2), n = 0, 2π electrons
SbCl5 H
(Lewis acid)
Cl H SbCl6
insoluble in non-‐polar solvents; 1 signal in 1H NMR δH = 11.1 ppm -‐ aroma%c and a ca%on

compare with cyclopropyl ca%on which is subject to rearrangement to the allyl ca%on
Nu Nu
Cl
Ph Ph Ph
Ph Ph Ph Ph Ph
Ph
Ph Ph Ph Ph Ph
Ph Ph Ph
Ph
reduced barrier 6.3 D

to rotation
6π-‐aroma%c 2π-‐aroma%c
Benzene
(4n +2), n = 1, 6π electrons δH = 7.26 ppm, planar molecule; bond length = 1.39 Å C-‐C sp3-‐sp3 1.54 Å
1.40 Å C-‐C sp3-‐sp2 1.50 Å
H δ = 7.46
H
H δ = 7.01 C-‐C sp3-‐sp 1.47 Å
isoelectronic with pyridine 2.2 D
1.39 Å
C-‐C sp2-‐sp2 1.46 Å
N H δ = 8.50
1.34 Å C-‐C benzene 1.39 Å
C=C 1.34 Å
C≡C 1.21 Å
Cyclopentadienyl Anion

(4n +2), n = 1, 6π electrons
base
H
B:
CF3
F3C
H H H
F3C CF3
CF3
pKa = 16 pKa = 43 pKa < -‐2
cyclopentadienide anion is isoelectronic with furan pyrrole and thiophene

in each case the (one of the) lone pair(s) is parallel to the p-‐orbitals and part of the π-‐system
S O NH X NH
thiophene furan pyrrole pyrrolidine
0.55 D 0.66 D 1.74 D
X X X
Electrophilic AromaTc SubsTtuTon
E
E
H step 1 is usually rate determining because
E
aroma%city is lost
σ-‐complex step 2 is fast as aroma%city is regained
Wheland intermediate
arenium ion
E E
H H
Electrophilic AromaTc SubsTtuTon

(+) ‡
‡ (+) H
(+) H (+) E
step 1 E
step 2
E
E
H H
E E
σ-‐complex
Wheland intermediate activation
arenium ion energy
E E
H H
+ E
E
Hammond’s postulate: The transi%on state resembles the structure (intermediate or substrate or product)
to which it is closest in energy

(i.e. transi%on state resembles intermediate arenium ion, therefore what stabilises the arenium ion
stabilises the transi%on state.)

Mechanis%c Evidence
isola%on of intermediates
Me Me Me Me Me
EtF, BF3
- 80 °C heat
H BF
4
Me Me Me Me Me Me
stable solid
mp -15 °C
δH = 5.6
H H H H
δH = 9.7 H H H H
SbF5 / FSO3H H
SbF6
-120 °C in SO2FCl
H δH = 8.6
H
δH = 9.3
Subs%tuent Effects
subs%tuent Y affects both the rate and regiochemistry of the reac%on
Y Y Y Y
E E
E
E
ortho meta para
(1,2-‐disubs%tuted) (1,3-‐disubs%tuted) (1,4-‐disubs%tuted)
Y Y Y Y
E E
E
E
electron dona%ng groups ac%vate the aroma%c ring (i.e. substrate reacts faster than benzene) and are ortho and
para direc%ng
ACTIVATING group means that the reac%on of the subs%tuted benzene is faster than that of benzene itself
O O
Typical ac%va%ng groups include: OH, O-‐, O R
, HN
R ,OR, NH2, NR2, alkyl, Ph
OMe OMe OMe

Br2, AcOH Br
kanisole / kbenzene = 109
Br 98 2
electron withdrawing groups deac%vate the aroma%c ring (i.e. substrate reacts slowed than benzene) and are
meta direc%ng
DEACTIVATING group means that the reac%on of the subs%tuted benzene is slower than that of benzene itself
O O O
Typical deac%va%ng groups include: R3N+, CF3, NO2, SO3H, CN, O-‐, R , OR
, NR2

halogens are mildly deac%va%ng and direct ortho and para

orienta%on of aTack when ring carries an electron dona%ng group, X:, which carries a lone pair (e.g. OMe) ortho
and para aTack
ortho aTack
X: X: X X: X: X:
H
E E E E E E
ortho ✓✓
para aTack
X: X: X: X X: X:
E
para ✓✓
E E E HE E
meta aTack
X: X: X: X: X:
E
meta
E E E E
H
in the intermediates from ortho and para aTack the carboca%ons are stabliised by overlap with the lone pair of X

in the intermediate from meta aTack in the carboca%on is not stabilised by overlap with the lone pair from X
reac%on coordinate diagram for aTack on X-‐subs%tuted benzene (X = EDG)
TS1
TS2
meta
intermdiate
Energy
more stable intermediate(s) formed

faster ∴ ortho and para products predominate

ortho and para benzene reacts slower than these substrates as
similar energies substrates are more electron rich

X:
+ E products
reac%on coordinate
Therefore the intermediates (and hence the transi<on states which lead to those intermediates) are lower in
energy (more stabilised) for ortho and para aVack and hence the rate of these reac<ons is faster than for
meta aVack (and faster than for benzene)
orienta%on of aTack when ring carries an electron withdrawing group, Z, (e.g. NO2) meta aTack
ortho aTack
Z Z Z Z Z
H
E E E E E
ortho ✗✗
para aTack
Z Z Z Z Z
E
para ✗✗
E E HE E
meta aTack
Z Z Z Z Z
E
meta
E E E E
H
in the intermediates from ortho and para aTack the carboca%ons are destabilised as next to EWG Z

in the intermediate from meta aTack in the carboca%on is never adjacent to EWG
reac%on coordinate diagram for aTack on Z-‐subs%tuted benzene (Z = EWG)
TS1
ortho and para
similar energies TS2
intermediate
Energy
less stable intermediate(s) formed

slower ∴ meta products predominate
meta
benzene reacts faster than these
substrates as it is more electron rich
+ E
products
reac%on coordinate
The intermediates (and hence the transi<on states which lead to those intermediates) are higher in energy
(less stable) for ortho and para aVack and hence the rate of these reac<ons is slower than for meta aVack –
meta by default (all slower than for benzene as aroma<c ring is electron poor)
Halogens
mildly deac%va%ng as they are electronega%ve and withdraw electron density from the ring through the σ-‐framework
(falls off with distance)
halogens direct ortho and para as they have lone pairs in high energy orbitals which stabilise the intermediates for
ortho/para aTack
:OMe OMe :Cl Cl
1.2 D 1.6 D
O 2p –lone pair Cl 3p –lone pair

Me
good 2p -‐2p overlap poor 2p -‐3p overlap
MeO – overall electron dona%ng on benzene ring Cl – overall electron withdrawing on benzene ring
increasing electronega<vity
increasing size of p-‐orbitals

increasing electronega<vity
both oxygen and chlorine are electronega%ve
N O F
with anisole the σ-‐electon withdrawing of the oxygen is less than the π-‐ P S Cl
dona%on of the oxygen 2p lone pair and anisole is ac%vated with respect to
benzene Se Br
with chlorobenzene the σ-‐electon withdrawing of the chlorine is greater than the π-‐
dona%on of the chlorine 3p lone pair and chlorobenzene is deac%vated with respect to Te I
benzene Po At
Ques<on: Nitra%on of halobenzenes
why does fluorine react faster than than the other halobenzenes?

why does fluorine give the largest amount of the para isomer?
product distribu%on % kArX/
ortho meta para kbenzene
conc. HNO3, PhF 12 -‐ 87 0.18
X conc. H2SO4 X
PhCl 30 0.9 69 0.064
NO2 PhBr 37 1.2 62 0.060
PhI 38 1.8 60 0.12
Examples H
H +
H
CH3 CH3 CH3 CH3 O2N
H
NO2
HNO3 / H2SO4 H
+
NO2 H
H
NO2
59% <4% 37% H
NO2
Me is an electron dona%ng group and hence an ac%va%ng group

Wheland intermediate for ortho / para aTack is stabilised by hyperconjuga%on – σCH → π
what happens if there are two subs%tuents on the benzene ring?

subs%tuents can be broadly categorised into three classes
i)  STRONGLY ac%va%ng and ortho and para direc%ng (OH, OR, NH2, NR2)
ii)  mildly ac%va%ng groups such as alkyl groups (ortho and para direc%ng) and halogens (mildly deac%va%ng)
iii)  deac%va%ng meta-‐direc%ng groups

subs%tuents in group i) will dominate classes ii) and iii)

subs%tuents in group ii) will dominate class iii)
Examine the electronic effects of subs%tuents then consider sterics
Me H
H
OMe N O F3C N MeO
Me O
Me
F Me MeO
MeO: o, p AcNH: o, p Me2N: o, p MeO: o, p

F: o, p Me: o, p CF3: m CHO: m
MeO dominates AcNH dominates Me2N dominates MeO dominates
∴ para ∴ ortho ∴ para (sterics) ∴ para (sterics)
opposing -‐ if similar reac%vity will get mixtures of compounds
all other things being equal a 3rd group is least likely to enter between two groups meta to one another
Cl Cl OMe OMe
HNO3,
CO2H H SO CO2H Br2 / AcOH
2 4
OMe OMe
NO2 Br
Cl: o, p MeO: o, p

CO2H: m MeO: o, p
Cl dominates ∴ ortho / para
∴ para
OH OH Me Me Me
Me Me Cl HNO3, Ac2O Cl Cl
Br2, AcOH
O2N
Br 25 NO2 75
HO: o, p Me: o, p

Me: o, p Cl: o, p
HO dominates ∴ mixture
∴ para

Note: these are guidelines and exact ra<os of ortho / meta / para products depend on the reac<on condi<ons and the
nature of the electrophile
subs%tuent effects are important for selec%vity and efficiency when designing a synthe%c route
CO2H CO2H NO2 Me

NO2
or or
NO2
target synthe%cally we want to prepare the target material in a clean, selec%ve and efficient fashion
material
CO2H NO2 Me
Look at the star%ng materials
CO2H, deac%va%ng NO2, deac%va%ng Me, ac%va%ng

meta direc%ng meta direc%ng ortho / para direc%ng
if possible best to introduce the most deac%va%ng group(s) last in the synthe%c sequence
rela%onship of NO2 groups is ortho/para with respect to CO2H ∴ best to use toluene as star%ng material
CH3 CH3 CH3 Me CO2H

HNO3 / H2SO4 NO2 HNO3, H2SO4 NO2 KMnO NO2
4
NO2 NO2 NO2
nitro group is deac%va%ng ∴ can isolate

and separate isomers if required

Br Cl
(a) N Br (b)
O O
OH OH AlCl3, heat
OMe OMe
OMe OMe
(c) (d)
Me
SO2Cl H
2 equivalents ClSO2OH
(e) SO3H
SO3H H2SO4, 160 °C H2SO4, 80 °C
2) AVempted Friedel-‐Crabs acyla<on of benzene with tBuCOCl gives some of the expected ketone, as a
minor product, and also some tbutyl benzene, but the major product is the disubs<tuted compound C.
Explain how these compounds are formed and suggest the order in which the two subs<tuents are added
to form C.
O
O
AlCl3 + +
+ Cl
A B C O
Ipso a\ack and reversible reac%ons

electrophilic aroma%c subs%tu%on is generally an irreversible process all of the above arguments with regard to
ortho, meta and para ra%os have been based on the irreversibility of the process

i.e. the reac%ons are under kine%c control -‐ but there are some excep%ons
not all electrophilic aroma%c subs%tu%on reac%ons are under kine%c control
sulfonyl group is
sulfona%on -‐ usual reac%on condi%ons: conc. H2SO4 with SO3 electron withdrawing so we
only have mono-‐subs%tu%on
O O H O OH
S S
O O HO3S HO3S
H
at high temperatures with dilute H2SO4 – sulfona%on is reversible

aTack by an electrophile at a posi%on which already carries a non-‐hydrogen subs%tuent is termed ipso-‐subs<tu<on
OH OH
Br SO3H Br
H2SO4 we can use an SO3H group as a blocking group
SO3H OH OH OH OH
Br SO3H Br SO3H Br SO3H Br H

H
ipso aTack H
SO3H S O H H
O
OH
Friedel CraUs alkyla%on can be under kine%c or thermodynamic control
Me Me Me
tBuCl / AlCl3 tBuCl / AlCl3
thermodynamic kine%c control
control Me Me high temperature low temperature
Me Me
Me Me
Me Me
Me
Me Me Me
Me Me Me Me Me Me + H
Cl: AlCl3 Cl AlCl3
Me Me Me
H
Me Me Me Me
Me Me
Me Me Me Me
Me Me
H H H Me Me
Me Me
Me Me Me Me
Me Me
Me
thermodynamic product all groups Me Me

as far apart as they can be Me Me
Me Me
IntroducTon of FuncTonal Groups –Synthesis

Friedel CraUs Alkyla%on
polyalkyla%on and rearrangement predominate
H H
excess MeCl, Me
Me Me H Cl AlCl3 Me Me Me Me
cat. AlCl3
H
Me Me Me Me Me Me
Me Me Me Me Me
with one equivalent of alkyla%ng agent mixtures of products result as the ini%ally formed monoalkyl arene is more
reac%ve than the unalkylated arene – alkyl groups are electron dona%ng

Me
cat. AlCl3,
Me Me Me
MeCl
+
Me
more reac%ve more reac%ve more reac%ve

than benzene than toluene than toluene

Friedel CraUs Alkyla%on
polyalkyla%on and rearrangement predominate
with primary alkyl halides rearrangement occurs

Me

Me Me
Me
Br
cat. AlBr3
+ primary carboca%ons are very unstable
rearrangement to the secondary carboca%on occurs
major minor
of monoalkylated products
Br AlBr3
Br: AlBr3 H Me Me
Me Me
Me
H
1,2-‐hydride shiU Me
Me
Me

Friedel CraUs Acyla%on
requires a full equivalent of the Lewis acid
mono-‐subs%tu%on predominates as introduced group is electron-‐withdrawing and deac%vates aroma%c ring

O O
Me Me
Cl
monosubs%tu%on
1 equivalent AlCl3
AlCl3
O O O O
Me O Me Me AlCl3 Me
Cl AlCl3 Me H
carbonyl group can then be removed if required (Clemensen reduc%on, Zn/HCl; Wolf-‐Kishner reduc%on, NH2NH2
then KOH, heat; dithiane than Raney Ni) giving products of a selec%ve Friedel-‐CraUs alkyla%on
para-‐isomer generally favoured by steric hindrance

O
O O
AlCl3, toluene Me
+
Me O Me
MeO MeO
93% yield

Friedel CraUs Acyla%on
Fries rearrangement can give access to either the ortho-‐ or para-‐isomer
O O
O AlCl3 O
+ pyridine
Me O Me
HO Me O Me O
AlCl3
polar solvent
O O
H non-polar
Me workup O solvent
Me
HO O Me
O
major product in AlCl3
polar solvents e.g. PhNO2 solvent-separated
ion pair
Me Me Me O
H
O workup O O Me
Cl3Al O
HO O O
AlCl3 AlCl3
major product in
non polar solvents inside solvent cage
- tight ion pair
Friedel CraUs summary

AlkylaTon AcylaTon
AlCl3 cataly<c stoichiometric
Rearrangement possible no, but loss of CO from R-‐C≡O+ if R+ stable, e.g. Ph3C+
subs%tu%on order poly mono

IntroducTon of funcTonal groups
Blanc chloromethyla%on – related to Fiedel-‐CraUs reac%ons
OMe OMe
(CH2O)n,
conc. HCl Cl
Me Cl Me
O Me O Me
halogena%on – with ac%vated aroma%cs Lewis acid ac%va%on of the electrophile is not require, with benzene and
with deac%vated aroma%cs Lewis acid ac%va%on of the electrophile is required
NO2 NO2
Br2, FeBr3
Br
Me Me
halogena%on can frequently be best achieved using Sandmeyer reac%ons (par%cularly good for introducing I and F
as well as Cl, Br and CN)
conc. HNO3 Sn, HCl HX, NaNO2, X

conc. H2SO4 NO2 or H2Pd/C NH2 0 °C N N

diazonium salts -‐ reac%ons
heat
H2O, 100 °C
Ar N N Ar F
Ar N N Ar OH
X BF4
SN1 reac%on via carbenium ion SN1 reac%on via carbernium ion – Balz Schiemann reac%on
NaNO2, N -N
NH2 HX 0 °C N 2 v. high energy intermediate, offset by the
forma%on of N2 carbenium not stabilised
slow
by π-‐system as is orthogonal to π-‐system
empty sp2 orbital
cat. CuX,
KX KI
Ar N N Ar X Ar N N Ar X
X X = Br, Cl, CN X
radical reac%on radical reac%on
HO N Ar
H3PO2
Ar N N Ar H Ar N N HO N
X X
radical reac%on
electrophilic aroma%c subs%tu%on
O O
O O
Me OR
Ar N N Me OR
X N via enol
NHAr
Nucleophilic AromaTc SubsTtuTon

SN2: alipha%c vs aroma%c
AliphaTc remember SN2 reac%ons at sp2
nucleophile aTacks C-‐I σ* resul%ng in inversion of configura%on hybridised centres (i.e. alkenes and
‡ arenes are incredibly rare)
Me (-) Me (-) Me
Nu + H I Nu I Nu H + I
Et Et H Et
AromaTc
no possibility of nucleophile aTacking backside of C-‐LG σ* (transi%on geometry impossible) LG

Lowest Unoccupied Molecular Orbital (LUMO) is π* not σ*

aTacking electron rich arene with electron rich nucleophile

SN1: alipha%c vs aroma%c

Me Me
AliphaTc Me Nu
Me X Me Nu
carbenium stabilised by hyperconjuga%on Me
Me Me
Me
AromaTc
possible but very high energy intermediate (see Sandmeyer reaca%ons) empty sp2 orbital
X Nu Nu v. high energy intermediate, offset by the forma%on of N2

carbenium not stabilised by π-‐system as is orthogonal to
π-‐system

SNAr – Addi%on – Elimina%on Mechanism

LG LG Nu LG Nu LG Nu Nu

Nu -LG

rate determining
step Meisenheimer intermediate
nucleophile aTacks LUMO, electron withdrawing groups lower energy of LUMO and stabilise the nega%ve charge in the
intermediate
best to have electron withdrawing group(s), ortho and / or para to the leaving group

Evidence
isola%on of intermediates
Cl OMe MeO OMe O
O2N NO2 O2N NO2 O2N N
MeO K MeO K O
NO2 N N
O O O O
MeO OMe O
the nega%ve charge is delocalised O2N N
O
ortho and para to leaving group

N
O O
H. Ueda, M. Sakabe, J. Tanaka, Bull. Chem. Soc. Jpn., 1968, 41, 2866-‐2871.

SNAr – Addi%on – Elimina%on Mechanism
for halogens as leaving groups, rate of reac%on usually follows kF > kCl > kBr (c.f. rate of SN2 reac%ons kI > kBr > kCl > kF)
NO2 NO2
X OMe
X = F Cl Br I
MeO 50 °C
krel 2810 3.1 2.1 1
rate determining step is generally aTack of nucleophile on aroma%c ring therefore bond strength to leaving group
is not so important in influencing the rate

fluorine is the most electronega%ve element and enhances the electrophilicity of the carbon being aTacked
increasing the rate of aTack by the nucleophile
O O O O O O
N N N
F F Nu rate = k[substrate][nucleophile]
Nu Nu
1st step usually rate
determining
leaving group ability does depend on the nucleophile, nevertheless leaving groups can broadly be divided into three
classes: taken from Physical and Mechanis<c Organic Chemistry, R. A. Y. Jones, CUP, 1979

good: F, NO2, Me3N+, OTs, Me2S+ medium: Cl, Br, I, OR, OAr, SR, SO2R poor: NMe2, H
reac%vity is complementary to Pd-‐catalysed cross-‐coupling reac%ons of halobenzenes where regioselec%vity is
generally governed by the rate of oxida%ve addi%on into the Ar-‐X bond which depends on bond strength
General Trends in Oxida<ve Addi<on θ

R2P PR2
order of reac%vity is generally I > OTf > Br >> Cl. Pd

with bidentate phosphines rate of oxida%ve addi%on increases with decreasing bite angle.

low oxida%on state metals are electron rich (nucleophilic) therefore good donor ligands i.e. H-‐, R-‐, R3P.
promote oxida%ve addi%on

oxida%ve addi%on to alkyl halides is slow as precomplexa%on is less favourable.

bulky ligands can be good as they lead to dissocia%on and more reac%ve metal complex.

metal is oxidised and hence substrate is reduced therefore electron deficient substrates react faster than electron
rich substrates.

reac%on proceeds with reten%on of olefin geometry for sp2 electrophiles.

‡
I
I PdI MeO MeO2C
+ PdL2 PdL2
Cl Cl

the ac%va%ng group

Cl OMe
Y NO2 Me3N+ SO2Ph O=CPh CF3 H
O2N O2N
MeO krel 114000 2130 18400 2700 800 1
Y Y
Explain the outcome of the following reac<on
NO2 NH2
Me Me Me Me
NH3, MeOH
NO2 NO2
the nucleophile – typically good nucleophiles in SNAr reac%ons include: RS-‐, HO-‐, RO-‐, PO-‐, RNH2
Synthesis of fluoxe<ne ‘Prozac’ – serotonin reuptake inhibitor for treatment of depression
Predict the product of the following reac<on
F
HO NHMe NaH,
+
O
F3C Ph
Me
N Me
Me
total synthesis of vancomycin – glycopep%de an%bio%c currently the ‘last line of defence’ to treat methicillin-‐
resistant staphylococcus aureus [MRSA].
Me OH
HO HO
H2N Me
O NO2 Oallyl Oallyl
OH NO2
O FOH
O OMs O OMs
O HO Cl HO
Cl Cl
O O H O Na2CO3 H O
N H N H
N N
O H H NHBoc O H H NHBoc
HO Cl OH OH OH
H O O O O O
N H H NH NH
N N NHMe
O H H N N
H H MeHNOC MeHNOC
O O OMe OMe
NH O
OMe OMe
MeO MeO
HO2C NH2
OH
OH
HO
Na2CO3
OR
O OR
O N O OR
F
Cl O OR
F Cl
O
N
O
D. A. Evans et al. Angew. Chem. Int. Ed. Engl. 1998, 37, 2700-‐2704
total synthesis of vancomycin – glycopep%de an%bio%c currently the ‘last line of defence’ to treat methicillin-‐
resistant staphylococcus aureus [MRSA].
Me OH
HO HO NO2
H2N allylO F
Me
O O OH
OH
O
O
HO Cl OH Boc
O H O O O
Cl N H H
O O N N NMe
O H H N N
H H
HO OH O O
Cl NH O
H O O O
N H H
N N NHMe MeHNOC NHDdm
O H H N N OBn
H H OBn
O O BnO
NH O
HO2C NH2 CsF, DMSO

OH
OH
HO
allylO
Cl
O O
HO Cl OH Boc
H O O O
N H H
N N NMe
O H H N N
H H
O O
NH O
MeHNOC NHDdm
OBn
OBn
BnO
Ddm =
MeO OMe
D. A. Evans et al. Angew. Chem. Int. Ed. Engl. 1998, 37, 2700-‐2704
HeteroaromaTcs and Nucleophilic subsTtuTon

4
3 pyridine is electron deficient at C-‐2 and C-‐4 and it is prone to
2 aTack by nucleophiles
N 1 N N

HOMO of pyridine is nitrogen lone pair
pyridine undergoes electrophilic aroma%c subs%tu%on only very slowly as reac%on with electrophiles occurs on
nitrogen lone pair

E E high energy intermediate

E
N v. slow -‐ electrophile reac%ng with
N
N posi%vely charged nucleophile
E
E
c. HNO3, c. H2SO4, 300 °C, 24 h NO2
N N 6% N
H
HeteroaromaTcs and Nucleophilic subsTtuTon
pyridine is electron deficient at C-‐2 and C-‐4 and is prone to
aTack by nucleophiles
N N N

HOMO of pyridine is nitrogen lone pair
POCl3 MeO Na OMe

N O N Cl N Cl N OMe
H
compare with
nucleophilic aroma%c subs%tu%on O
MeO
O
R Cl R OMe
the leaving group needs to be posi%oned ortho or para to the pyridine nitrogen atom

below are the rela%ve rates of reac%on with MeO-‐ in MeOH at 50 °C
Cl
Cl Cl CF3 NO2
N Cl N Cl N Cl
10-‐5 1 5 3,000 82,000 700,000
reac%on of the corresponding N-‐oxides and N-‐methyl pyridinium salts is significantly faster than for the parent
chloropyridines
below are the rela%ve rates of reac%on with MeO-‐ in MeOH at 50 °C
Cl Cl Cl
N Cl N Cl N Cl N N N
O Me O Me
3,000 6 x 107 1.3 x 1012 82,000 9 x 107 4.2 x 1010

M. Liveris, J. Miller, J. Chem. Soc., 1963, 3486-‐3492
as with benzenoid aroma%cs fluoride is a beTer ac%vator (leaving group) than chloride
rela%ve rate of reac%on with EtO-‐ in EtOH
F3C
N Cl Cl N Cl N F N Cl
1 65 320 2800
M. Schlosser, T. Rausis, Helv. Chimica Acta, 2005, 88, 1240-‐1249

pyrimidines and related heterocycles are more reac%ve than 2-‐halopyridines towards nucleophilic aroma%c
subs%tu%on
increasing reac%vity toward nucleophilic aroma%c subs%tu%on
X X X
X N
N > N > > > > >
N N
N N X N N N X N N X
taken from “Heterocyclic Chemistry” 5th Edi%on, J. A. Joule and K. Mills, Wiley 2010.
O
Me Ph Bu
N Cl N Cl N N
LiHMDS, toluene O BuNH2
Ph
N Cl N Ph pTSA N
Et Et
D. S. Chekmarev, S. V. Shorshnev, A. E. Stepanov, A. N. Kasatkin, Tetrahedron 2006, 62, 9919-‐9930
there are not always ‘back of the envelope’ explana%ons of selec%vity
Cl OMe Cl
MeO
R CO2Me Cl H Ph Me OMe
N N + N
A:B 96:4 92:8 85:15 84:16 76:24 8:92
R N Cl R N Cl R N OMe
A B
Y. Goto and co-‐workers, Bull. Chem. Soc. Jpn., 1989, 37, 2892
HeteroaromaTcs
pyridine N-‐oxides – much more suscep%ble to electrophilic aTack at 2 and 4 posi%ons (and to nucleophilic
addi%on at 2 and 4 posi%ons)
4
3 H2O2, CH3CO2H promotes electrophilic
2 N N subs%tu%on at 2 and 4 posi%ons
N N N
O O O O
nitra%on of pyridine N-‐oxide

NO2
NO2 NO2
Me Me Me
HNO3, H2SO4,100 °C PCl3
+ POCl3
N N N
O O 66% yield, c.f. nitra%on of pyridine in acid (6% yield)
H NO2 NO2 NO2 NO2

Me Me Me Me
PCl3
N N N N
O O O Cl
P
Cl
Cl
HeteroaromaTcs
pyridine N-‐oxides – N-‐deoxygena%on with rearrangement
O O
Me Me
Me O Me, 100 °C
H O Me
N N
O O
Me Me
O
2
H 1
3
N O Me N
O O 1O O3
2
Me Me
pyridine N-‐oxides – conversion to chloro compounds

R O R R R
P
Cl Cl
Cl H
N N N Cl N Cl
Cl
O O O O O
P P
Cl Cl Cl Cl
HeteroaromaTcs
pyridones
O OH
N O N OH N N
H H
nitra%on
NO2
O O Cl
HNO3, H2SO4 NO2 POCl3 NO2 NaBH4 NO2
N N N N
H
H
O NaBH4
O
Cl P Cl P Cl
O O Cl O Cl
O Cl Cl
H NO2 POCl3 NO2 NO2
NO2 NO2
N N N
N N
H H
H
H
HeteroaromaTcs

pyrrole, thiophene and furan

all three have aroma%c proper%es

in each case the (one of the) lone pair(s) is parallel to the p-‐orbitals and part of the π-‐system

the aroma%c heterocycles are electron rich
α
β 2 X X X
3
S1 O NH X NH
thiophene furan pyrrole pyrrolidine pyridine is electron poor

0.55 D 0.66 D 1.74 D Nu N
order of aroma%city is: thiophene > pyrrole > furan (enol ether like)

sulfur is the largest atom and hence is beTer matched for bonding to sp2-‐hybridised carbon atoms in a 5-‐membered
ring leading to thiophene being the most aroma%c
HeteroaromaTcs
ReacTons
electrophilic subs%tu%on – kine%c reac%on at the 2-‐posi%on is favoured over reac%on at the 3-‐posi%on

more reac%ve than benzene – e.g. pyrrole similar reac%vity to aniline
E more delocalised
X H X H X H X X intermediate ∴ more
E
E E E stable ∴ 2-‐subs%tu%on
favoured
X X X X
less delocalised intermediate ∴ less
H H stable ∴ 3-‐subs%u%on disfavoured
E E E E
subs%tuents already present on the aroma%c heterocycle exert less direc%ng effect than the corresponding
subs%tuents in benzene
E H H
X EDG X EDG X EDG E X EDG with EDG at α-‐posi%on
E E α’-‐subs%tu%on favoured
X X X
EWG EWG EWG with EWG at α-‐posi%on
β’-‐subs%tu%on favoured
H
E E E
HeteroaromaTcs
ReacTons
nitra%on
O O O O
N H N H H
S Me O O S NO2 S N Me O O N NO2 N
+ +
AcOH, 0 °C AcOH, -10 °C
60% trace NO2 51% 13% NO2
O
O O N
N Me O H H
O Me O O O NO2 AcO O NO2 O NO2
AcOH,-25 °C
addi%on product
acyla%on and formyla%on
O
H H O H O
N Cl3C Cl N N
CCl3 90% HNO3, -50 °C α' CCl3
β’ > α’ or β for α-‐EWG
β'
O2N
O O
Ph Me
N H, POCl3, 35 °C O H N H, POCl3, RT H O
S S N N
Me Me
H H
then hydrolysis then hydrolysis
78% 83%
HeteroaromaTcs
indole
3β
2α
N1 N O benzofuran S
H H benzothiophene
more enamine-‐like than pyrrole

aTack of electrophiles at the β posi%on is the lowest energy pathway
E
E E minor
N N H N
H H H
H E E
E aTack at β posi%on retains
major aroma%c sextet of benzenoid ring
N N N
H H H
HeteroaromaTcs
indole
3β
2α
N1 N O benzofuran S
H H benzothiophene
if the β-‐posi%on is blocked α-‐aTack occurs

α-‐aTack can occur via β-‐aTack followed by rearrangement (● = CT2 i.e. a tri%ated methylene group)
BF3•OEt2
N OH N O H N N H N
H H F3B H H H
N N H N
H H H
direct aTack at α-‐posi%on
would give solely 1:1 mixture
N
H
Explain the outcome of the following reac<ons

H Me O Me
(a) N Cl N N N F N N
Me OH OH NaH, H O
120 °C, 15 hours
H OH O H
(b) Me
MsCl, Et3N N
NMe
CO2tBu CO2tBu
N N
H H
single enantiomer racemate
O2N
(c)
Me i) F Me
NO2
Me N Me ii) aq. NaOH Me OH
Br
(d) O N O Br
N N
iPr3Si iPr3Si
Vicarious Nucleophilic Subs%tu%on -‐ (nucleophilic subs%tu%on of hydrogen)

Reviews: M. Mąkosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282; M. Mąkosza Pure & Appl. Chem. 1997, 69, 559
H
O2N Cl SO2Ph O2N O2N
O
KOH, DMSO SO2Ph PhO2S N
H H O
mechanism
SO2Ph
O O O O
N N N N
O O O O
Cl
H
H
SO2Ph SO2Ph SO2Ph SO2Ph
HO
Cl rate determining
step
For VNS require a
rate determining step is elimina%on of H-‐X (HCl) from σ-‐adduct LG EWG
nucleophile which
carries a leaving group
LG = Cl, Br, PhO, PhS, RO-‐ etc; EWG = SO2Ph, SO2NR2, SO2OPh, POPh2, CN, CO2Et
How can we explain the following results?
NO2 MeO NO2 Cl SO2Ph NO2

69%
DMSO KOH, DMSO SO2Ph
MeO Cl Cl
Vicarious Nucleophilic Subs%tu%on

orienta%on of addi%on depends on: structure of the carbanion; structure of the arene; reac%on condi%ons
NO2 Cl SO2Ph NO2

18%
KOH, DMSO SO2Ph
F F
for aTack on nitrobenzene, as the bulk of the nucleophile increases the amount of para isomer increases
X SO2Ph
NO2 NO2 NO2
R
SO2Ph PhO2S
KOH, DMSO
X R yield / % ortho para

F H 63 74 26
Cl H 75 53 47
Cl Et 68 100
Cl Ph 93 100
M. Makosza, J. Goliński, J. Baran, J. Org. Chem., 1984, 49 1488
AromaTc organometallics
Ortho-‐directed electrophilic aroma%c subs%tu%on

ortho-‐lithia%on by lithium halogen exchange – faster then deprotona%on generally requires an organolithium

base an aryl / alkenyl bromide or iodide.
OMe
OMe OMe Bu
Br
Br Bu Li Li
+ BuBr via “ate” complex
anion in an sp3 orbital anion in an sp2 orbital
mechanism involves aTack of alkyl lithium at the halogen via an intermediate “ate” complex
reac%on is an equilibrium process which favours the more stable anion (remember, anion order is sp3>sp2>sp
– the stability of the anion is in the order of the pKa of the corresponding hydrocarbon)

in the above example an sp3 anion (butyl lithium) gives an sp2 anion
D. E. Applequist, D. F. O’Brien, J. Am. Chem. Soc., 1963, 85, 743.


LDA and other amide bases are good for deprotona%on but NOT for halogen lithium exchange
lithium halogen exchange with LDA would lead

OMe N OMe to the forma%on of a very weak halogen-‐
X
Br Li Li nitrogen bond – reac%on is thermodynamically
+ N
Br in the wrong direc%on
I I Me
LDA, I2 tBuLi, MeI
I
N N N
SO2Ph SO2Ph SO2Ph
Mark G. Saulnier and Gordon W. Gribble J. Org. Chem. 1982, 47, 757
O Br Bu Li O Li R X O R


in general rate of exchange I > Br >> Cl

to make aryllithiums by lithium halogen exchange – generally use n-‐butyllithium; tert-‐butyllithium may also be used

to make vinyllithiums and alkyllithiums one frequently uses tert-‐butyllithium
with primary alkyl halides it is necessary to use two equivalents of tert-‐butyllithium
Me
Me
H
Me Me Me Me Me Me Li Me
2 equiv. tert-BuLi Me Me Me
I Li + I Me Me
H
O O OTBS O O OTBS
Me Me
PMP PMP
Me Me Me
H
with one equivalent of tert-‐butyllithium protodeiodina%on is likely to occur O O OTBS
PMP
lithium halogen exchange is a very fast reac%on which can outcompete deprotona%on of OH groups and
addi%on to C=O groups
Br O O
nBuLi, THF, -78 °C O
O RHN
O
O NR
O L. Ollero, L. Castedo, D. Dominguez, Tetrahedron, 1999, 55, 4445-‐4456

synthesis of morphine – J. E. Toh, P. L. Fuchs, J. Org. Chem. 1987, 52, 473–475

Provide a mechanism for the reac<on below.
Br
OMe OH
Br OMe
2.2 equiv. BuLi, -78 °C O OH O
O morphine
OH Me N OH
H
SO2Ph H H
PhO2S
annula%on forming benzocyclobutanes – I. A. Aidhen, J. R. Ahuja, Tetrahedron LeV. 1992, 33, 5431-‐5432.
MeO I MeO O
O t-BuLi
OMe
MeO N MeO
Me
selec%ve halogen metal exchange is possible

Ar H OH
Br Br Br Li Br
n-BuLi, Et2O, -100 °C O
73%
N OMe N OMe N OMe Cl
it is also possible to make Grignard reagents by lithium halogen exchange generally using iPrMgBr or iPrMgCl

For reviews see: P. Knochel et al. Angew. Chem. Int. Ed. 2003, 42, 4302; Chem. Commun. 2006, 583; Heterocycles
2014, 88, 827.
CO2Me CO2Me CO2Me
iPrMgCl, THF, -10 °C PhCHO
I MgCl
Ph OH
Br Br O Br OH
Br iPrMgCl•LiCl, MgCl
THF -50 °C tBu H tBu
Br Br Br
O O
Br iPrMgCl•LiCl, MgCl CN iPrMgCl•LiCl, CN
S
THF -50 °C Ph CN THF -50 °C
Br N Br Br N Br Br N Br Br N MgCl
for aroma%c heterocycles metal halogen exchange shows the following selec%vity:

with 5-‐ring heterocycles the 2-‐posi%ons undergoes exchange faster than the 3 posi%on

with 6-‐ring heterocycles, the 3 posi%on undergoes exchange faster than the 2-‐posi%on

iodine metal exchange is faster than bromine metal exchange

summary 5-‐ring 2>3; 6-‐ring 3>2; I>Br
X Br R M X M Br R M M
76%
Br Br N Br N Br
O
S Br EtMgCl. THF, RT S MgCl tBuN C O S
NHtBu
49%
Br Br Br
O
S Br EtMgCl. THF, RT S Br Me2N H S Br
I MgCl O
H
l. Christophersen, M. Begtrup, S. Ebdrup, H. Petersen, P. Vedsø J. Org. Chem., 2003, 68, 9513

directed ortho-‐metalla%on reviews: V. Snieckus, Chem. Rev. 1990, 90, 879-‐933;
J. Clayden in “Organolithiums: Selec<vity for Synthesis, Pergamon, Oxford 2002.
Me Li Me O
OMe O Bu O MeO H OLi MeO H O H
H BuLi H Li H NMe2 H, H2O
NMe2 NMe2
DMF H
use amides as electrophiles: reac<ve formyl

group is not unmasked un<l the reac<on is MeO O
quenched with acid
H

the posi%on of metalla%on can depend on the reac%on condi%ons

OMe OMe BuLi, OMe
NMe2 Li
BuLi Me2N
Li
NMe2 NMe2 NMe2
various direc%ng groups can be used

Me Me Me
Me Me Me
Me
Me O N O N O N
COCl
HO NH2 BuLi Li Br R
R
then dehydrate
increasing ability to direct ortho-‐lithia%on
condi%on dependent order

Me
Me
NR2
O O
R2N O R R2N O N O
O O S O S O O O OR X
O-‐carbamates 3° amides sulfones sulfonamides oxazloines MOM ethers ethers halogens benzylic alkoxides
O
RN O O tBu RN
S N OtBu NR2 CF3
2° amides sulfoxides imines N-‐carbamates anilines trifluoromethyl
most powerful directors O NR2 NR

( )n 2
aminomethyl remote amines
-‐78 °C -‐78 °C -‐78 °C -‐78 °C -‐50 °C -‐20 °C 0 °C >0 °C >20 °C
temperature (°C) of ortho-‐lithia%on with RLi in THF or ether
Adapted from: J. Clayden in “Organolithiums: Selec<vity for Synthesis”, Pergamon, Oxford 2002.
with ortho-‐directors which are also electrophiles, the precise reac%on condi%ons including: the nature of the
base, addi%ve and order of addi%on can influence the outcome of the reac%on see: P. Beak, R. A. Brown, J. Org
Chem., 1982, 47, 34-‐46
O O NEt2 O NEt2 O NEt2
Me
Li E
n-BuLi s-BuLi, TMEDA E
Electrophile Yield (%)
D2O 88
O O MeI 77
NEt2 s-BuLi, TMEDA NEt2 EtI 70

Li B(OMe)3; H2O2 (adds an OH) 56
F F
Me3SiCl acetone 54
Me O O PhCHO 79
NEt2 s-BuLi, TMEDA NEt2 CH2=CHCH2Br 60

SiMe3 then MeI SiMe3
F F
R. J. Mills, N. J. Taylor, V. Snieckus, J. Org. Chem., 1989, 54, 4372
synthesis of Fredericamycin – T. R. Kelly, S. H. Bell, N. Ohashi, R. J. Armstrong-‐Chong, J. Am. Chem. Soc. 1988, 110,
6471-‐6480
MeO O
TBDMSO
s-BuLi
O
MeO O NEt2 O OMe NEt2 O OMe NEt2 O OMe
Li Cl NEt2 t-BuLi MeI
O O O
Li Me
TBDMSO TBDMSO TBDMSO TBDMSO
Me Me
Me N Me
OMe Li
O
O O O OMe EtO NEt2 O OMe
N
O HN EtO O
O HO
EtO
HN O TBDMSO TBDMSO
OEt
Me
fredericamycin
lithia%on of 5-‐membered heterocycles

lithia%on occurs preferen%ally α to the heteroatom due to induc%ve effect of heteroatom with, in some
instances a DOM effect
furan and thiophene can be readily metalled α to the metal
S S Li O n-BuLi O Li
n-BuLi
-10 °C, ether ether, reflux
with pyrrole itself, the N-‐deprotona%on occurs first – the more ionic the N-‐metal bond the greater
the percentage aTack at nitrogen

with a more covalent N-‐M bond C-‐aTack occurs.
Me Me Me
H
N NaNH2 N Na Me I N BuLi N Et I N Et
O
MgBr
H H O H O
N EtMgBr N H OEt N workup N
H H
with pyrroles bearing an N-‐EWG on nitrogen α-‐metalla%on occurs
O OtBu O OtBu
Me N Me
N Me Li Me N SnMe3
then Me3SnCl
SO2Ph SO2Ph
LDA, then B(OMe)3
N N B(OH) 2
then HCl, water
selec%vity can be achieved using LDA or butyllithium
iPr iPr
no lithium halogen exchange as N
S S S S
would make weak N-‐Br bond Li Li H Bu Li E
most acidic proton removed by
directed metalla%on Br Br Li E
pyridines

pyridines are electron deficient aroma%cs and pyridines which carry a direc%ng group (halogen, CN, CO2H
etc.) undergo ready metalla%on

2, and 4-‐subsistuted pyridines metallate in the 3 posi%on

3-‐subsituted pyridines generally metallate in the 4 posi%on
1 eq. BuLi, 1 eq. BuLi,

3 eq. 3 eq. CO2H
Me N Me CO2H Me N Me
Me Li Me CO2H Me Li Me CO2H
then CO2 then CO2
N CO2H N CO2H N N
1 eq. BuLi, O
CO2H O
3 eq.
Me N Me Ph
Me Li Me
then PhCHO, then H2SO4

N N
F. Mongin, F. Trécourt, G. Quéguiner, Tetrahedron LeV., 1999, 40, 5438
“Halogen dance” term introduced by BunneT for isomerisa%on reac%ons which can accompany
deprotona%on of halogenated aroma%cs J. F. BunneT, Acc. Chem. Res. 1972, 5, 139.
Br Br
PhNHK, NH3
40-‐60%
Br Br Br
Br
for halogen dance to be synthe%cally useful the isomerisa%on must be thermodynamically favourable
Br S
S Br NaNH2, NH3 S Br S Br S S S H
+
H Br Br Br
+
S Br 66-‐72%
l. Brandsma, R. L. P. de Jong, Synth. Commun. 1990, 20, 1697-‐1700
O
Li I I O
I LDA, THF - 70 °C I Li H OEt
H
70%
N Cl N Cl N Cl N Cl
F. Guillier, F. Nivoliers, A. Conchennee, A. Godard, F. Marsais, G. Queguiner Synth. Commun. 1996, 23,
4412-‐4436
reac%ons of alkenes -‐ depending on subs%tuents alkenes can be:

electron rich and hence nucleophilic
increasing nucleophilicity
OR NR2 O
E
E
E E E E
HOMO = π bond of alkene
alkene enol ether enamine enolate LUMO = σ* or π* on electrophile
electron poor and hence electrophilic

increasing electrophilicity
Nu Nu Nu Nu Nu
O O O O
N
N
O OR NR2
HOMO = lone pair on nucleophile

LUMO = π* on alkene
Overview of reacTons of (electron rich) alkenes

Br
bromina%on
Br2 Br SN2 Br
:Br Br Br
stereospecific
Br
an%
Br
build up of par%al

posi%ve charge H
2O:
SN2 / SN1
halohydrin
Me Me
Me Br2, H2O OH Me Me OH forma%on
borderline
Br
(+)
stereospecific
Br Br Br an%
long, weak bond
Me Me Me
Me OsO4 OH Me O O O O H O OH
2
Os Os
O OH O O O O OH
O N
Me Os(VIII) +
O
O N dihydroxyla%on
O O HO O
Me stereospecific
Os Os
O O HO O
syn
Os(VI)
Overview of reacTons of alkenes
Me m-CPBA Me Me O Ar Me epoxida%on
O O O stereospecific
H O syn
Me
Me
Me O , then PPh O Me O O
3 3
Me O O O
O O
O O O
Me Me
PPh3
O PPh3 O
O
ozonolysis O PPh3 + Me O O
O
O O
Overview of reacTons of alkenes
Me Me
Me BH3 Me Me H H hydrobora%on /
H oxdia%on
then H2O2, R R
OH B B H B R stereospecific
NaOH H H
R O O O migra%on with
OH
reten%on of
H2O2, Me
Me H configura%on
NaOH
OH O
BR2
Br Br
Me HBr, water Me Me Me Me
ionic reac%on
with HBr
H Br
H
Me H2, Pd/C Me hydrogena%on
stereospecific
Me Me syn
H
1) How would you carry out the following transforma<ons?
OH
OH
2) Explain the following transforma<ons.
(a) O O
O O
HS EtO
OEt + OEt
S
O O
(b)
H2O2, NaOH, MeOH
O
3) Explain the following: Treatment of the enolate A with B at -‐78 °C followed by quenching the reac<on at -‐78 °C
provides C; however, if the reac<on mixture is first warmed to -‐25 °C before being quenched the ketone D is formed as
the major reac<on product
Me CO Me
2
OLi O HO O
OPh
OPh
MeO
Me Me
CO2Me
A B C D PhO
Conjugate AddiTon vs Direct AddiTon

H
O 1 O Nu HO Nu
2
Nu direct addi%on
1,2-‐addi%on
1 O Nu O Nu O conjugate addi%on
4 Nu Michael addi%on
3 2
1,4-‐addi%on
H
conjugate addi%on requires the presence of an electron-‐withdrawing group which results in the lowering
of the energy of all of the π-‐orbitals of the system and hence the alkene is less nucleophilic and more electrophilic
O O
i.e. alkene is electron poor
Evidence of delocalisa%on 118 ppm

143 ppm
O O O
1678 cm-‐1
1712 cm-‐1 1653 cm-‐1
1628 cm-‐1 133 ppm 13C NMR 133 ppm
infra red – remember ν ∝ √k/μ i.e. higher stretching frequency = stronger bond
examples of conjugate addi%on
NC O O
KCN (cat)., HCN regenerates cyanide anion – cataly%c
OMe NC OMe HCN too weak an acid to protonate carbonyl group
H ∴ need a good nucleophile, cyanide anion, to aTack
O neutral substrate
NC OMe
H
O: HCl O
H CN
Cl
HCl protonates carbonyl oxygen making the whole

system more electrophilic H H H
Cl O O O
Cl Cl
H
OH H
O O O O
NaOH cat.
NaOH H H
H
OH O O enolate generated by conjugate addi%on reacts with
H the alcohol to regenerate alkoxide for conjugate
addi%on
O
H
conjugate addi%on
the beTer the ability to stabilise the nega%ve

O Nu O Nu O
Nu charge the beTer the conjugate acceptor is
and hence the faster the reac%on. This can be
related to pKa
faster conjugate slower conjugate

addi%on increasing electrophilicity addi%on
Nu Nu Nu Nu Nu
O O O O
N
N
O OR NR2
O O O
EWG H O2N NC
R RO R2N
pKa 10 20 24 25 25
for some nucleophiles conjugate addi%on is the major pathway, for other nucleophiles direct addi%on is
the major pathway whereas for others slight varia%on in condi%ons can alter the course of the reac%on
examples of conjugate addi%on
O heat O O heat N O
+ +
Ph OEt N Ph N Ph OEt N Ph OEt
H H
irreversible reac%on but if given the choice amines do

conjugate addi%on
O BuMgBr Bu OH O BuMgBr O Bu
1 % CuCl
irreversible reac%on irreversible reac%on

1,2-‐addi%on 1,4-‐addi%on
NaCN, HCN NaCN, HCN

O NC OH O O
5-10 °C 80 °C NC
formed faster more stable

kine%c product thermodynamic product
lower ac%va%on energy
conjugate addi%on product is generally the thermodynamically more stable product with respect to the direct
addi%on product.

a rough comparison of bond energies supports the above conjecture
lost C=O gained O-‐H

overall gain
lost kJmol-‐1 gained kJmol-‐1
NaCN, HCN H kJmol-‐1
O NC O
5-10 °C C=Oπ 370 C-‐C 350
gained C-‐C 90
O-‐H 460
lost C=C
NaCN, HCN
O O
C=Cπ 270 C-‐C 350
80 °C NC 130
H C-‐H 400
gained C-‐H
gained C-‐C
conjugate addi%on product is generally the thermodynamically more stable product with respect to the direct
addi%on product because it retains the strong carbonyl double bond – this is general for most α,β-‐unsaturated
systems
in the above example: the direct addi%on product is the kine%c product i.e. the fastest formed product and
hence the product formed by the pathway with the lowest ac%va%on energy
why is the direct addi%on product formed fastest?
O O O delocalisa%on indicates that the carbonyl

carbon (and one of the alkenyl carbons) bear
β α
par%al posi%ve charge
more electron deficient carbon
charged nucleophiles will aTack the carbonyl carbon faster than the β-‐carbon (Hard-‐Hard interac%on)
carbonyl carbon carries the larger posi%ve charge as it is closer to the electronega%ve oxygen atom
charged nucleophiles will aTack the β-‐carbon but more slowly
thermodynamic ac%va%on
control energy
at 80 °C cyanohydrin is reversible
kine%c control at 0 °C cyanohydrin is irreversible
lower ac%va%on
NC O energy
energy
O
at 80 °C kine%c product is s%ll formed
NC
able to reverse at 80 °C first but reverts to star%ng materials
difficult to reverse and slower conjugate addi%on occurs
O
even at 80 °C
NC OH kine%c product
NaCN + HCN
formed faster
O thermodynamic product
lower in energy if direct addi%on is reversible
NC more stable
conjugate addi%on will result
extent of reac%on
what is actually happening in the addi%on of HCl to methyl vinyl ketone
H
thermodynamically controlled reac%on
O: HCl O
most stable product is formed
Cl charged nucleophiles usually do direct addi%on

H
O HO Cl
H H H
Cl O O O
Cl Cl Cl
H
H
not all products arising from conjugate addi%on are the result of ini%al reversible direct addi%on

for certain nucleophiles conjugate addi%on is the kine%cally most favoured pathway

in these instances the kine%c product also happens to be the thermodynamic product
O O O N O
+ +
Ph OEt N Ph N Ph OEt N Ph OEt
H H
irreversible reac%on irreversible reac%on

Orbital Controlled Reac%ons (SoU-‐SoU interac%ons)
if the nucleophile has a high energy HOMO this will be close in energy to the LUMO of the α,β-‐unsaturated
system

therefore conjugate aTack will occur at the β-‐carbon – the reac%on is under orbital control

for fast reac%on we require a small HOMO / LUMO gap

Nu HOMO = Nu lone pair
O O
Nu: LUMO = π* O N O
+
Ph OEt N Ph OEt
H
for amines: uncharged, direct addi%on not favoured (lone pair of intermediate energy)

conjugate addi%on is the major pathway in the above example

the reac%on is under orbital control

1. Generally 2nd row elements (e.g. P, S) favour conjugate addi%on as they have high -‐ energy 3s/3p lone pairs
that are a good energy match for the LUMO of the substrate.
2. If the nucleophile is uncharged then conjugate addi%on oUen results.

Predict the outcome of the following reac<ons – ra<onalise your predic<ons
O O LiAlH4
PhSH, base
O BuMgBr
O BuMgBr
1% CuCl
the conjugate acceptor

the more electrophilic the carbonyl group the more likely to undergo direct addi%on – charge control dominates
O R2NH O
very reac%ve carbonyl group, charge control
Cl NR2 therefore en%rely 1,2-‐addi%on
mainly nearly always always

direct addi%on conjugate addi%on conjugate addi%on
O O O O O O
N N
Cl H OR NR2 O
sterics can influence the outcome of the reac%ons
O Me O
MeMgBr conjugate addi%on even though hard
O O Grignard reagent
Summary:
more reac%ve nucleophiles (RLi, RMgBr, LiAlH4) prefer direct addi%on

more reac%ve electrophiles prefer direct addi%on

less reac%ve nucleophiles prefer conjugate addi%on

less reac%ve electrophiles prefer conjugate addi%on

watch out for: reversible direct addi%on which leads to conjugate addi%on
i.e. kine%c versus thermodynamic control
Carbonyl Groups – difference in reacTvity towards nucleophiles

O O O O O O O O
R H R Cl R O R R Me R OMe R OH R NR2
in general there are two types of mechanism

with aldehydes and ketones addi%on occurs – frequently followed by subsequent reac%on

with esters, acids, amides etc. addi%on and subsequent elimina%on occurs
O Nu O O Nu O O
Nu: Nu:
X X Nu
Structure of the carbonyl group O O O

C-‐O σ-‐bond and C-‐O π-‐bond
π-‐bonding π*-‐an%bonding
orbital orbital
the π-‐bonding orbital is polarised towards oxygen the more electronega%ve atom
∴ the π* an%bonding orbital is polarised towards carbon i.e. the large lobe is on carbon
Nu LUMO
in the mechanism of aTack the HOMO of the nucleophile overlaps with the HOMO
LUMO (π*) of the carbonyl group
O

typical addi%ons reac%ons of aldehydes and ketones are as follows:
hydra%on – aldehydes are prone to hydra%on – ketones far less so
O HO OH
+ H2O
R H R H
Keq Keq
F3C Me
hexafluoro-‐ O 1.2 x 106 acetaldehyde O 1.06
acetone F3C H
H Me
formaldehyde O 2280 acetone O 0.001
H Me
Cl3C
chloral O 2000
H
How hydrated would you expect the following compounds to be?
O
O
O
O
in a similar manner, aldehydes and ketones react with alcohols under acid catalysis to give acetals

the mechanism of this reac%on is very frequently drawn incorrectly!
electrophilic loss of water electrophilic

H
O MeOH OH MeO OH ±H MeO OH2 OMe
H
MeOH
H
MeO OMe MeO OMe
H +
acid catalysis is required so that the intermediate in the red box can expel water –
if no acid were present HO-‐ would be the leaving group – MeO is not a good enough ‘pusher’ to kick out hydroxide
the intermediates in blue boxes are closely related – they are much more electrophilic versions of the
original carbonyl group and so are readily aTacked by MeOH which is a very weak nucleophile
the whole process is in equilibrium and the most stable product is therefore formed
the reac%on can be readily reversed using acidic water
aldehydes readily form acetals with simple alcohols O OH
HO O O

with ketones the equilibrium greatly favours the ketone – H
using diols allows efficient acetal forma%on why is this?
acetal forma%on is mechanis%cally closely related to numerous other reac%ons of carbonyl compounds
aldehydes and ketones readily react with primary amines and related nitrogen nucleophiles to give imines and
related compounds – these reac%ons are generally catalysed by acid
H H H H
O PhNH2 O N O ±H N OH H N OH2
Ph Ph Ph
acid catalysed
Ph H Ph
H + N N
Explain shape of the pH rate profile for oxime forma<on
between acetone and hydroxylamine
O
+ NH2OH
NOH rate
2 4 6 8
pH
secondary amines also react with aldehydes and ketones to give iminium ions and subsequently
enamines
Me Me Me Me
O Me Me N N
N H
H
iminium ion enamine

aldehydes and ketones are more electrophilic than the corresponding imines – oxygen is more electronega%ve
than carbon

iminium ions are more electrophilic than than the corresponding aldehyde or ketone
R' R'' R'

N O N
R H R H R H
least electrophilic more electrophilic

R' R'' R'
N O N
R R R R R R
Provide a mechanism for the following reac<on (more of this later)
O NaBH4, AcOH, NaOAc HN

NH2 +
Carboxylic acids and related groups

mul%ple types of delocalisa%on are possible O O
Me
O O R Me OEt Me N
C O Me
R X R X X
X p-‐type lone pair → C-‐O π* 1743 cm-‐1 1646 cm-‐1

most important for esters (X= OR) and amides (X = NR2)

O and N have 2p orbitals which are a good size and energy match for C=O π* orbital (itself made up of overlap of
two 2 p orbitals)

nitrogen is less electronega%ve than oxygen and hence with amides there is greater p-‐type lone pair → C-‐O π*
dona%on than with esters

∴ amides are less reac%ve towards nucleophiles than esters
rough order of importance NR2 > OR > Cl O

Me
evidence: esters and amides are planar i.e. there is Me N
substan%al double bond character between X and the carbonyl Me
carbon

O O O
mul%ple types of delocalisa%on are possible
Cl F
Cl F
O O O Cl F
R X R X C νmax = 1715 cm-‐1 1766 cm-‐1 1771 cm-‐1

R X
O sp2 lone pair → C-‐X σ*

implica%on is carbonyl group has par%al triple bond character and is also very electrophilic
oxygen is more electronega%ve than nitrogen and hence the C-‐O σ* is lower in energy than the C-‐N σ* and a
beTer energy match for O sp2 lone pair
rough order of importance X = F > OR > Cl > NR2
evidence from IR stretching frequencies and X-‐ray crystal structure analysis
126.4.4 °
117.4 °
O
O O CF3
Me
Me OEt Me N
1743 cm-‐1 Me
1646 cm-‐1
E. J. Corey, J. O. Link, S. Sarshar, Y. Shao, Tetrahedron LeV. 1992, 33, 7103
the balance of these effects determines the reac%vity of the system

esters predominantly exist in the (Z)-‐conforma%on
third type of delocalisa%on affects the conforma%on of esters
O
R O O O
R O Me
C R Ph O Ph O
R O Me
O sp2 lone pair → C-‐O σ*
Z-‐ester E-‐ester
A .A. Yakovenko, J. H. Gallegos, M. Yu. An%pin, A. Masunov, T. V. Timofeeva, Cryst.Growth Des. 2011, 11, 3964
in terms of reac%vity towards nucleophiles -‐ rough order of reac%vity is:
increasing electrophilicity
O O O O O O O
R Cl R O R R Me R OMe R OH R NR2
conversely in terms of reac%vity towards electrophiles – amides are the most reac%ve
E
E
O O
R NR2 R NR2
chemoselec%vity in the reduc%on of carbonyl compounds.
OH NaBH4 O H2, Pd/C O
for chemo and regioselec%ve reduc%on it is important to choose the correct reagent

OH O OH
LiAlH4 NaBH4
HO EtO EtO
CeCl3
O O
MnO2
O
HO
summary of reducing agents for carbonyl groups adapted from Organic Chemistry, Clayden, Greeves and
Warren, 2nd Edi%on, OUP 2012.
O O
R H R OH R H
reduced
aldehyde 1° alcohol aldehyde
reduced slowly
not usually reduced

BH3•NH3, via acid
DIBAL
LDA chloride
H
NR NR O O O O O
R H R H R H R R R OR R NR2 R OH
iminium ion aldehyde ketone ester amide acid
NaCNBH3
NaBH4
LiBH4
LiAlH4
BH3
OH
R NHR R OH R R R OH R NR2 R OH
amine 1° alcohol 2° alcohol 1° alcohol amine 1° alcohol

selec%vity in reduc%on

why are esters reduced with LiBH4 but only slowly with NaBH4?
Li Li
O Li BH4 O O O
R OR R OR R OR R H R OH
H
H H H H
B B
H H H H
Li+ has a higher charge/radius ra%o compared with Na+ as it is smaller

∴ Li+ is a more potent Lewis acid than Na+

Li+ serves to ac%vate the ester carbonyl for reduc%on
how can we reduce an ester to an aldehyde?
DIBAL-‐H – diisobutylaluminium hydride
H DIBAL-‐H only becomes a good reducing agent

Al H Al Al
H once it has been ac%vated by complexa%on by
a Lewis base
exists as an H-‐bridged dimer but reacts as a monomer
Al has an empty p-‐orbital, the monomer is electrophilic
DIBAL-‐H – diisobutylaluminium hydride – commercially available as solu%ons in various organic solvents

work-‐up of DIBAL-‐H reac%ons can be complicated by gela%on due to the amphoteric nature of AlIII salts

par%%oning the reac%on mixture between an organic solvent and aqueous Rochelle salt (Na+K+ tartrate) coupled
with vigorous s%rring is a useful method of solubilising these gels
addi%on of acid destroys excess

hydride and protonates tetrahedral
intermediate
R
Al H R R R
R Al Al MeOH
R H
O DIBAL-H O H O then H O O
H H
R OR R OR R OR R OR R H
H
tetrahedral intermediate ester reduced to aldehyde with
stable at low temperature (-‐78 °C) DIBAL-‐H at low temperature
at higher temperature, DIBAL-‐H reduces esters to alcohols

R aldehyde much more
Al H R R R reac%ve than ester
R Al Al
O O H O R O
DIBAL-H H DIBAL-H
tetrahedral intermediate rapid reduc%on

not stable at RT to alcohol
DIBAL-‐H – diisobutylaluminium hydride – commercially available as solu%ons in various organic solvents

O O it can be very difficult to

DIBAL-H, toluene
reduce an α,β-‐unsaturated
O N O O N
ester to an aldehyde with
O OH DIBAL-‐H
lactols are very readily prepared by reduc%on of lactones with DIBAL-‐H
H H
O DIBAL-H, -78 °C O OH
O OH O
H H H
DIBAL is also very useful for reducing nitriles to aldehydes what is the mechanism of this reac<on?
O
H N H
C DIBAL-H H
then H2O, H
H H
if we add a Grignard reagent or organolithium to an aldehyde or ketone, monoaddi%on occurs but with esters
double addi%on is the general outcome
O O R'' O O OH
R'' MgBr R'' MgBr H2O, H
R OR' or R'' Li R OR' R R" R R" R R"
R" R"
ketone more
ter%ary alcohol
electrophilic than ester
in order to obtain mono-‐addi%on use amides as the electrophile
Me Li Me O
OMe O Bu O MeO H OLi MeO H O H
H BuLi H Li H NMe2 H, H2O
NMe2 NMe2
DMF H
the most versa%le solu%on is to use Weinreb amides MeO O
Me O
O N Me O note: aluminium and magnesium
H • HCl OMe
R OMe R N amides are par<cularly nucleophilic
iPrMgCl, or AlMe3
Me towards esters
Weinreb amide
for use of iPrMgCl in the synthesis of Weinreb amides see: J. M. Williams, R. B. Jobson, N. Yasuda, G. Marchesini, U.-‐H.
Dolling,E. J. J. Grabowski, Tetrahedron LeV., 1995, 36, 5461-‐5464

Weinreb amides – a very reliable ketone synthesis. For a review see: M. Mentzel and H. M. R.
Hoffmann, J. Prakt. Chem. 1997, 339, 517-‐524.
O R' MgBr O Mg H , H2 O OH O
OMe OMe OMe
R N or R' Li R N R N R R'
Me R' Me R'
H Me
stable chelated tetrahedral intermediate
tetrahedral intermediate protonated on work up and
collapses to generate ketone
Boc Boc
N OMe N
Me ClMg
N Me OMe
O O THF, -20 °C to RT, O
O then HCl (aq) O 93%
VITAE PHARMACEUTICALS, INC. Patent: WO2007/117560 A2, 2007.

O OH O OH
MeO OTBDPS H MgBr OTBDPS
N
THF, 77%
Me Me H Me
D. A. Evans, J. T. Starr, Angew. Chem. Int. Ed., 2002, 41, 1787-‐1790
DIBAL-‐H reduc%on of esters to aldehydes can, at %mes, be difficult to control – using a Weinreb amide overcomes
this problem
O OTBDMS O OTBDMS
MeO Me Me
N H
Me Me Me
DIBAL-H, THF
Br Br
TBDMSO TBDMSO
TBDPSO TBDPSO
OTBDMS OTBDMS
Me Me
D. A. Evans, J. T. Starr, Angew. Chem. Int. Ed., 2002, 41, 1787-‐1790
enolates will also add to Weinreb amides
Me
OLi O Li
O O O
MeN O
Me OtBu CO2tBu H, H2O
N OtBu
OMe
83%
lithium aluminium hydride – LiAlH4 -‐ all four hydrides are ac%ve

powerful and frequently non-‐selec%ve reducing agent: will reduce aldehydes, ketones, esters to primary alcohols and
amides to amines

LiAlH4 both in solu%on and as a solid is highly flammable – requires anhydrous solvents

work-‐up of LiAlH4 reduc%ons can be tricky due to the amphoteric nature of AlIII salts

a useful ‘anhydrous’ work up introduced by Feiser involves, for n grams of LiAlH4 adding dropwise n mL of water, n mL
of 15% NaOH solu%on, and then 3n mL of water. In favourable cases a granular precipitate is produced which can be
filtered. L. F. Fieser, M. Fieser, M. Reagents for Organic Synthesis 1967, 581-‐595.

another safe method for neutralising excess LiAlH4 involves quenching the reac%on with EtOAc

reduc%on of esters
tetrahedral intermediate
collapses to give an aldehyde
Li Li
O Li AlH4 O O O
H
H H H H
Al Al
H H H H
reduc%on of esters tetrahedral intermediate

collapses to give an aldehyde
Li Li
O Li AlH4 O O O
H
H H H H
Al Al
H H H H
reduc%on of amides

AlH3
Li Li AlH3
O Li AlH4 O O O NR2
R NR2 R R R H R NR2
NR2 R NR2 NR2
H H
H H
Al H H
H H
tetrahedral intermediate Al
collapses to give an iminium ion H H
why this difference in reac%on outcome?

RO-‐ is a beTer leaving group then R2N-‐

lone pair of amine is higher in energy than O and hence R2N is a beTer ‘pusher’ than RO
O
H H
N Me N Me Me Me
O HO
LiAlH4, THF LiAlH4, THF
O O
O HO
H H
O O
Me Me
H H
O OH Me Me
amide reduced to amine
1,2-‐reduc%on of α,β-‐unsaturated ketone lactone (ester) reduc%on leads to diol
(hard nucleophile)
lithium borohydride – will reduce esters to primary alcohols – see above (can be prepared from cheap NaBH4 and
LiCl, LiBr or LiI)
sodium borohydride – frequently used in alcoholic solvents such as MeOH or EtOH

generally does not reduce esters, epoxides, lactones, nitriles. All four hydrides are ac%ve

NaBH4 reacts with pro%c solvents to generate alkoxy borohydrides
Explain the stereoselec<vity exhibited by the following reac<on
H H
O O HO O
NaBH4, MeOH
O Cl O Cl
H H
87%
Luche reduc%on NaBH4 is not selec%ve for 1,2-‐ versus 1,4-‐reduc%on – addi%on of CeCl3•7H2O increases the
amount of 1,2-‐reduc%on
1,2-‐reduc%on 1,4-‐reduc%on
O NaBH4 OH OH
or NaBH4, CeCl3•7H2O NaBH4, MeOH 51% 49%
+
MeOH NaBH4, CeCl3•7H2O,
99% trace
MeOH
it appears that CeCl3 accelerates the reac%on of pro%c solvents with NaBH4 to generate alkoxy borohydrides
NaBH(4-‐n)OMen which are harder reducing agents

CeCl3 acidifies the MeOH allowing it to ac%vate the carbonyl oxygen making the carbonyl carbon more posi%ve

Reagent is harder, substrate is harder, therefore 1,2-‐reduc%on -‐ A L. Gemal, J. –L. Luche, J. Am. Chem. Soc., 1981, 103,
5454-‐5459
H Me
O O OH
MeO H
B CeIII
MeO OMe
O HO
MeMe Me Me NaBH4, CeCl3•7H2O, MeOH MeMe Me Me
Me Me
58%
Givaudan Roure (Interna%onal) SA Patent: US5929291 A1, 1999

in a related manner the use of anhydrous cerium(III) chloride in the presence of Grignard reagents and
organolithium reagents allows the addi%on of organometallics to highly enolisable aldehydes and ketones
T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima, Y. Kamiya, J . Am. Chem. Soc. 1989, 111 , 4392-‐4398;
N. Takeda, T. Imamoto Org. Synth. 1999, 76, 228
methods to dry CeCl3•7H2O -‐ W. H Bunnelle, B. A. Narayanan, Org. Synth., Coll. Vol. VIII, 1993, 602.
O
HO Bu
BuM, THF
product recovered star%ng material

BuLi 26% 55%
BuLi, CeCl3 92-‐97%
BuMgBr 28% 23%
BuMgBr, CeI3 96%

other modified borohydrides: NaBH3CN, NaBH(OAc)3 reagents of choice for reduc%ve amina%on
Ph in each case, reduc%on of the intermediate

Ph CH2O, NaBH3CN O
O iminium ion is more rapid than the reduc%on of
N the corresponding aldehyde
N pH 5 Me
Me Me
H
TBDMSO TBDMSO
AcO Me NaBH(OAc)3, SnCl2
O + O O
R
N H N H
H H
R
AcO Me
this is one method to solve the problem of polyalkyla%on when aTemp%ng to alkylate amines
MeI MeI MeI

R NH2 R NHMe R NMe2 R NMe3 I
at least as nucleophilic at least as nucleophilic

as star%ng amine 1° and 2° amine polyalkyla%on occurs
borane complexed to a Lewis base, THF•BH3, Me2S•BH3 is a good reducing agent for carboxylic acids and amides
H H H :LB H H
B H H LB
H B B B B
O O H O H O H O LB
H H
R O R O R O R O R O
H
R R
R R B
work-up B H
O H O
R OH R OBR2
R H R H
HO2C Ar' BH3•THF, THF, 0 °C HO Ar'
EtO2C Ar EtO2C Ar
98%
P. C. Lobben, S. S. –W. Leung, S. Tummala, Org. Process Res. Dev. 2004, 8, 1072–1075.
H H H
B H H
H B B R R
O O H O H B NR2
H R NR2
R NR2 R NHR2 R NR2 R H
H BR2
work-up
R NR2
ReducTon examples
MeO MeO
BH3•THF
OH OH
O O
O
O. Hoshino,Y. Mizuno,M. Murakata, H. Yamaguchi Chem. Pharm. Bull., 1999, 47, 1380-‐1383
O O O O
Me Me
Me Me Me Me
OH
CH2N2 HO
HO2C H MeO2C H MeO2C H
pTSA
H H H H O H H
O O
O
LiAlH4
O O
O
Me Me Me Me
HO HO
H water, pTSA H
H H O H H
O
O
D. N. Kirk, M. S. Rajagopalan, M. J. Varley, J. Chem. Soc., Perkin 1, 1983, 2225-‐2228
ReducTon examples
Me OMe Me OMe Me OMe

O O O
(COCl)2, DMF NaBH4, THF
O O O
O CO2H O Cl O
O HO
T. P. O'Sullivan, H. Zhang, L. N. Mander, Org. Biomol. Chem., 2007, 5, 2627-‐2635

Recently ChareVe reported the chemoselec<ve reduc<on of amides – explain these results
J. Am. Chem. Soc., 2008, 130, 18-‐19; J. Am. Chem. Soc., 2010, 132, 12817-‐12819;

N F
O O
Tf2O,
N H
H then Et3SiH 90%
MeO2C then acid workup MeO2C
N F
O N
Tf2O,
N H
H then Et3SiH 95%
MeO2C then basic workup MeO2C
O
Tf2O, then
Ph N Ph N
H H
EtO2C CO2Et
O O
Me N Me 86%
H
Rings and ring strain
classifica%on of rings
classifica%on small normal medium large

number atoms in ring 3, 4 5, 6 7-‐12 >12
types of ring strain

108°
H H
angle strain (Baeyer strain) – distor%on of angles from the idealised values H H
120°
Me Me H Me
111°
larger to relief of strain between
geminal methyl groups
angle strain – most important in small rings
OH Na CO , MeOH O
O 2 3 H
O
~60° 88° MeO H
torsional strain arises from devia%on from an ideal staggered arrangement
HH H
H H
HH H H H
H
H
major feature of 3 and 4-‐membered rings
H H H H
H H H H H HH
H H H H
H H H
H H H H
H H
H H
H H H
HH H H
H
H H HH
in its chair form cyclohexane the lowest energy conforma%on
has no torsional strain of cyclopentane is an envelope
which has some torsional strain
as a result of torsional strain 6-‐membered rings are generally more stable than 5-‐membered rings
H H
bond length strain – arises from devia%on of bond lengths from their ideal values C-‐H = 1.09 Å
Me Me
transannular strain– arises from proximity on non-‐bonded atoms frequently important
in medium rings C-‐C = 1.54 Å
H H
general features of ring closure
K or k
X: X
Y
if ring closure is thermodynamically controlled (K) then energy of product will be important
ΔG = ΔH -‐ TΔS
ring strain considera%ons mean K is generally only favourable for 5-‐ and 6-‐ membered ring
if ring closure is kine%cally controlled (k) then the energy of the transi%on state will be important
ΔG‡ = ΔH‡ -‐ TΔS‡ kBT -‐ΔG‡/RT

k = e
h
ΔH‡ -‐ enthalpy of ac%va%on includes bond breaking/making enthalpic considera%ons and the change in
strain energy in reaching the transi%on state

ΔS‡ -‐ reflects the difference in the levels of organisa%on between star%ng material(s) and transi%on state
rates of cyclisa%on of ω-‐bromo malonates: M. A. Casadei, C. Galli, L. Mandolini, J. Am. Chem. Soc., 1984, 106,
1051-‐1056
6 kBT -‐ΔG‡/RT
k = e
es%mated value increasing ΔS‡ h
4
CO2Et
2
Br
EtO2C ( )n
log k
0 NaH,
DMSO k
-‐2
small EtO2C CO2Et

-‐4
( )n
-‐6
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
ring size
Small rings: 3-‐membered rings are formed fast; 4-‐membered rings more slowly
ΔS‡ favourable as liTle preorganisa%on is required – the ends are already close to one another
ΔH‡ unfavourable due to developing strain
◾ rates of cyclisa%on of ω-‐bromo malonates: M. A. Casadei, C. Galli, L. Mandolini, J. Am. Chem. Soc., 1984, 106,
1051-‐1056
6 kBT -‐ΔG‡/RT
k = e
es%mated value increasing ΔS‡ h
4
CO2Et
2
Br
EtO2C ( )n
log k
0 NaH,
DMSO k
-‐2
normal medium large EtO2C CO2Et

-‐4
( )n
-‐6
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
ring size
Normal rings: 5-‐membered rings generally formed fastest
ΔS‡ is becoming less favourable as more preorganisa%on is required – the ends are less close to one another
ΔH‡ is fairly consistent – 5-‐7 membered rings are rela%vely unstrained
Medium rings:
ΔS‡ is s%ll increasing but propor%onally less as ring size increases – the ends are less close to one another
ΔH‡ becomes dominant – transannular strain reflected in TS and hence rate of cyclisa%on
Large rings:
ΔS‡ is unfavourable as the ends are unlikely to meet – similar to an intermolecular reac%on. Solu%on do reac%ons
under high dilu%on
ΔH‡ no ring strain so not important -‐ large rings are similar to acyclic compounds
correct alignment of orbitals is also key for efficient ring forma%on
LUMO C-‐Br σ* Br

O
Br
O Br
X O O
O
HOMO
enolate
good overlap O-‐alkyla%on occurs
poor overlap so no C-‐alkyla%on
similarly
O O O O O O
S S S
O O OH
CH3 NaH
S O
O
CH3
S O
O
X S O
O
CH3
H3C H3C H3C
Sir Jack Baldwin proposed a set of guidelines (Baldwin’s rules) to asses the likelihood that a given,
kine%cally controlled cyclisa%on would be feasible
Sir Jack Baldwin

“Ring-‐forming reac<ons are important and common
processes in organic chemistry. I now adumbrate a set of
simple rules which I have found useful in predic<ng the
Waynflete Professor of Organic
rela<ve facility of different ring closures. I believe these will Chemistry, Oxford 1978-‐2005
be useful to organic chemists, especially in planning
syntheses.” Baldwin’s Rules
J. E. Baldwin, Chem. Commun., 1976, 734-‐736.
Biosynthesis of penicillins

modes of cyclisa%on
Y Y
X Y X X X
Nu: Nu Nu: Nu
exo – bond being broken endo – bond being broken

is outside the ring being formed is inside the ring being formed
X X X
Nu: X Nu: X Nu:

X
Nu: Nu: Nu:
exo-‐tet exo-‐trig exo-‐dig endo-‐tet endo-‐trig endo-‐dig

sp3 hybridised sp2 hydridised sp hybridised sp3 hybridised sp2 hydridised sp hybridised
Baldwin’s rules
ring size 3 4 5 6
exo ✓ ✓ ✓ ✓
TET
endo -‐ -‐ ✗ ✗
exo ✓ ✓ ✓ ✓
TRIG
endo ✗ ✗ ✗ ✓
exo ✗ ✗ ✓ ✓
DIG
endo ✓ ✓ ✓ ✓
in general all exo-‐tet and exo-‐trig cyclisa%ons are favoured

5-‐exo-‐trig is faster than 6-‐endo trig
How would you assign this reac<on according to Baldwin’s rules? Is this likely to be an efficient transforma<on?
O O O O
O O O O O O
S NaH S
S S S
O O OH
CH3 NaH
S O
O
CH3
S O
O
X S O
O
CH3
S O
O
I
S O
O
H3C H3C
H3C H3C H3C
1) The following amine undergoes cyclisa<on – predict the product
O
H2N
OMe
2) Explain the contras<ng outcomes of the following reac<ons
HO
O H HO O H
O
HO H HO O
Me Me H
3) Explain the following reac<on
O O
NaOH, H2O Me
Me
Me
Thorpe-‐Ingold effect; M. E. Jung, G. Piizzi, Chem. Rev. 2005, 105, 1735−1766

the increased rate of cyclisa%on when puœng a geminal dialkyl group in the cyclising chain is known as the Thorpe
Ingold effect.
a good explana%on for the Thorpe Ingold effect concerns reac%ve rotamers
O O
O O
H H
R R O
O R = Me R=H O
Br O H H
Me
Me
krel 39 1 Br
major conforma%on, ends

held far apart, cyclisa%on
O O O O O O cannot occur
Me Me Me Me
Br Br
H H H H H H
Me Me
Br
reac%ve rotamers
for gem-‐dimethyl-‐subs%tuted substrate all of the staggered conforma%ons are of similar
energy and in two of the conformers cyclising groups are in close proximity
Examples
O
cat. neat 25 °C
oligomers iPr iPr
N
F3C
O Ph
F3C O Mo
O O
cat. neat 25 °C
F3C
CF3
Explain the following rates of cyclisa<on
iPr iPr
NH2 NH2 NH2 NH2 NH2

Br Br Br Br Br
krel 1 2.2 158 0.16 9190

From Corey’s synthesis of longifolene, J. Am. Chem. Soc., 1964, 86, 478.
Explain the various aspects of selec<vity in the following reac<ons
O O O O O
PPh3
OH TsOH
HO
O O
OsO4
O O O O O O
LiClO4 TsCl. pyridine
O
OH OH
TsO HO
HCl (aq)
O
Appendix
Hybridisa%on and bonding -‐ a brief recap
Hybridisa%on is a useful concept used by organic chemists to describe the bonding in organic molecules
A quick method to work our the hybridisa%on of an atom is to count the number of subs%tuents on that atom
(including lone pairs of electrons), remembering that in the bonded environment first row elements generally
have 8 electrons around them

4 subs%tuents = sp3 hybridised, 3 subs%tuents = sp2 hybridised, 2 subs%tuents = sp hybridised
z z z
y y y
x + x + x +
py px pz s
sp3 hybrid orbitals are made up from one s orbital and three p orbitals giving
four hybrid orbitals which point to the corners of a regular tetrahedron.
This is the bonding arrangement found in methane (bond angle = 109°) where the
sp3 hybrid orbitals overlap with the hydrogen 1s orbitals (not shown)
H sp3 hybrid orbitals
H
C H
H H
H
H H
Similarly, the nitrogen atom in ammonia can be viewed as sp3 hybridised as can the oxygen atom in water
although the H-‐X-‐H bond angle is slightly less than 109° due to lone pair–bond pair repulsion
lone pair in sp3 orbital

N N
H H O O
H H H H H
H H
H
N-‐atom is sp3 hybridised O-‐atom is sp3 hybridised
For sp2 hybridisa%on we mix two p-‐orbitals and one s-‐orbital to give three sp2 hybrid orbitals (and leave one p-‐orbital)
z z z
y y y
x x + x +
pz py px s
The three sp2 hybrid orbitals are arranged 120° apart

This is the bonding arrangement found in ethene with the sp2 hybrids overlapping
with the hydrogen 1s orbitals (not shown)
the remaining pz orbital(s) overlap to form the π-‐bond
H H sp2 hybrid orbitals
H H
pz orbital
H H
H H
C-‐atom is sp2 hybridised
Similarly, this is the hybridisa%on in carbonyl compounds and imines
H H
lone pair in sp2 orbital
O N
H H H
O and C-‐atoms are sp2 hybridised N and C-‐atoms are sp2 hybridised
For sp hybridisa%on we mix one p-‐orbitals and one s-‐orbital to give two sp hybrid orbitals (and leave two p-‐orbital)
z z z
y y y
x x x +
pz py px s
The two sp hybrid orbitals are arranged 180° apart

This is the bonding arrangement found in ethyne with the sp hybrids overlapping
with the hydrogen 1s orbitals (not shown)
the remaining p orbitals overlapping to form the two π-‐bonds
p orbitals lone pair in sp orbital
H H H H H N sp hybrid orbitals
in nitriles the N and C-‐atoms

C-‐atom is sp2 hybridised are sp hybridised
So to recap, in general, a quick method to work our the hybridisa%on of an atom is to count the number of
subs%tuents on that atom (including lone pairs of electrons), remembering that in the bonded environment
first row elements generally have 8 electrons around them -‐ sp3 = 4 sp2 = 3 sp = 2

What is the hybridisa%on of the red atoms in the following examples?
H H O
NH 4+ H 3O+ CO C C C CO 2
N H H O
Let’s look at the bonding in amides.

All other things being equal, amides are planar molecules and we are happy to draw the delocalisa%on of the
nitrogen lone pair as shown to indicate the par%al double bond character of the C-‐N bond
O O
R
R N R NHR 2
R
A B
Following the discussion above the hybridisa%on of the C and O atoms is sp2 but what is the hybridisa%on of the
nitrogen atom?

Again, following the above discussion, and looking at the form of the amide on the leU hand side (A),
the nitrogen atom has 4 subs%tuents, 2 x R, C=O and a lone pair and ∴ is sp3 hybridised
However, most organic chemists would say the N atom is sp2 hybridised. Why is this?
R R
O O
C O C O
R R N N
R N R NHR 2 R
R R R
A B N-‐sp2 hybridised N-‐sp3 hybridised
N-‐lone pair in p-‐orbital N-‐lone pair in sp3-‐orbital
The curly arrows above represent the overlap of the nitrogen lone pair with the C-‐O π-‐orbitals (the an%bonding π*
orbital). The best overlap therefore is if the N-‐atom is sp2 hybridised resul%ng in the N-‐lone pair being in a p-‐
orbital with excellent overlap with the p-‐orbitals of the C–O π-‐system

If the N-‐atom were sp3 hybridised then the N-‐lone pair would be in an sp3 orbital which would result in poorer
overlap with the adjacent C-‐O π-‐system –

Generally beTer overlap = greater stabilisa%on

In general if a π-‐system has an adjacent atom which carries a lone pair then most organic chemists would view the
hybridisa%on of the adjacent atom as sp2 with the lone pair in a p-‐orbital to maximise overlap with the adjoining π-‐
system.

What is the hybridisa%on of each of the heteroatoms in the following molecules?
O OMe
R OMe
R O O N
NMe 2
O
Perhaps we should not be too concerned about this as some molecules, for example anilines, are frequently not
perfectly planar and the hybridisa%on of nitrogen is somewhere between perfectly sp2 and perfectly sp3
Addi%onally we should be aware that other effects (e.g. sterics) can override electronic effects and hence the
hydridisa%on may not be as expected

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Reactivity and Control for Organic Synthesis 1

Reac%vity and Control for

︎ acidity and basicity

Brønsted (1879-­‐1947) deﬁni%on: an acid is a proton donor

acid HA is the source of a proton H+

HA + solvent solvent•H+ + A-­‐

What is the concentra<on of pure water?

pKa = -­‐log10Ka ∴ Ka = 10-­‐pKa

rewri%ng the above gives the Henderson-­‐Hasselbalch equa%on:

if [HA] = [A-­‐] then pH = pKa (remember log10 1 = 0)

pH = -­‐log10[H+] at neutral pH, 7 = -­‐log10[H+] ∴ [H+] = 10-­‐7 M

for water pH = 7 this refers to the following equilibrium

pKa = -­‐log10Ka ∴ Ka = 10-­‐pKa HA H+ + A-­‐

Calculate the pKa of H3O+

[HC≡C-­‐][H2O] [HC≡C-­‐][H3O+] [H3O+][HO-­‐]

HC≡CH + H2N-­‐ HC≡C-­‐ + NH3

pKa NH3 = 38 pKa HC≡CH = 25 ∴ Keq = 10-­‐25/10-­‐38 = 1013

some pKa values in water and DMSO

12.5 15 15.74 9.95 17

Remember: lower pKa = stronger acid; higher pKa = weaker acid

ii) eﬀect of hybridisa%on;

iii) eﬀect of conjuga%on/delocalisa%on

Two factors work to stabilise the phenoxide anion

Remember: these structures are

ii) induc%ve eﬀect

Worked example: explain the following order of acid strengths

+ H+ eq. B anion in sp2 orbital – 33% s-­‐character

HC CH HC C + H+ eq. C anion in sp orbital – 50% s-­‐character HC C

acid HA + H2O H3O+ + A-­‐ conjugate

The problem of amines

Important to know some pKa’s

compound pKa (water) compound pKa (water) compound pKa (water)

1) Explain the following pKa orders:

2) Which of the following is more basic?

(a) (b) (c) N Me

3.02, 4.38 1.92, 6.23

4) How might you carryout the following transforma<ons?

5) Explain the following transforma<ons?

Me NH2 < Me N Me < Me N Me

7) Predict the product of the following reac<on.

“When two molecules collide, three major forces operate.

Generally the case that:

Recently the HSAB theory has been disputed see:

Bases (Nucleophiles) Acids (Electrophiles)

Recently the HSAB theory has been disputed see:

Explain these two transforma<ons

SN1 reac%on enanTomers

dona%on of C-­‐H σ-­‐bond

benzyl ca%on stabilised by delocalisa%on

α-­‐heteroatom subs%tuted ca%ons stabilised by delocalisa%on

2° chloride, not that

butyl iso-propyl allyl benzyl

0.07 0.12 1.0 4.0

methallyl tert-butyl cinamyl dimethallyl

3° chloride 1° but allylic

solvent water ethanol ace%c acid DMSO DMF

Explain the rela<ve rates of solvolysis of the

Nucleophilic SubsTtuTon at a saturated carbon

H HOMO of nucleophile (nucleophile lone pair) aVacks

Me S more nucleophilic than Me SH BuLi is obviously more nucleophilic than butane

most basic least basic most basic least basic

most basic least basic

PR3 > NR3 increasing nucleophilicity

Brønsted (1879-‐1947) deﬁni%on: an acid is a proton donor

HA + solvent solvent•H+ + A-‐

pKa = -‐log10Ka ∴ Ka = 10-‐pKa

rewri%ng the above gives the Henderson-‐Hasselbalch equa%on:

if [HA] = [A-‐] then pH = pKa (remember log10 1 = 0)

pH = -‐log10[H+] at neutral pH, 7 = -‐log10[H+] ∴ [H+] = 10-‐7 M

pKa = -‐log10Ka ∴ Ka = 10-‐pKa HA H+ + A-‐

[HC≡C-‐][H2O] [HC≡C-‐][H3O+] [H3O+][HO-‐]

HC≡CH + H2N-‐ HC≡C-‐ + NH3

pKa NH3 = 38 pKa HC≡CH = 25 ∴ Keq = 10-‐25/10-‐38 = 1013

ii)  eﬀect of hybridisa%on;

iii)  eﬀect of conjuga%on/delocalisa%on

+ H+ eq. B anion in sp2 orbital – 33% s-‐character

HC CH HC C + H+ eq. C anion in sp orbital – 50% s-‐character HC C

acid HA + H2O H3O+ + A-‐ conjugate

dona%on of C-‐H σ-‐bond

α-‐heteroatom subs%tuted ca%ons stabilised by delocalisa%on

increasing size of p-‐orbitals

iii)  deac%va%ng meta-‐direc%ng groups

para-‐isomer generally favoured by steric hindrance

Blanc chloromethyla%on – related to Fiedel-‐CraUs reac%ons