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151 views63 pagesChemistry of The Carbonyl Group
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
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/ 63
Chemistry
of the
Carbonyl! Group
‘A Programmed Approach
to
Organic Reaction Mechanisms
STUART WARREN
Department of Organic Chemistry,
Cambridge Universiey, Camoriage
JOHN WILEY & SONS
London « New York - Sydney - Toronto Copyright © 1974 John Wiley & Sons Lid. All
Rights Reserved. No pat ofthe publication may
be reproduced, sored in a retieval system, of
transmitted, in any form or by any means, elec
tonic, mechanics, photocopying, recording Or
Dtherwise, without the peor witten permission
of the Copy ight owner
Library of Congress Catalog Card No, 74-6701
ISBN 0 471 92104 1
Made and printd in Great Britain by
Te Garden City Press Limited
Letchworth, Hertfordshire, SG6 LIS
PREFACE
This program was originally written for a
lecture course given to second year university
students. T thought that the course needed
some backing in the form of down-to-earth mat-
erial for the students to use themselves, so
that they had to translate new ideas into
their own thoughts, expressed in their own way
and reinforced by the experience of using the
ideas to solve problems, The students were
enthusiastic about the program and so I have
now rewritten it for more general use hoping
that it will be helpful to anyone taking a
university or college course, studying from a
book, revising for an exam or simply brushing
up their organic chemistry.
‘The program is an aid to learning: a
piece of support material which should help
the student in his work but does not stand by
itself, Lecturers, "advisers", and teachers
will probably fina the pages deseriping the
contents and concepts for each section useful
in assessing which part of a course the pro-
gram best supports.
I should like to thank Andrew Crompton for .
working through the program and making many
perceptive suggestions, Hilary Rhodes for
typing the printed words and Howard Jones for
his encouragement and practical help in pro-
ducing the book.
Cambridge 1974 Stuart Warren CONTENTS
Some help you may need
What do you need to know before you start?
How to use the Program
The Program
Contents of Section 1
Concepts Assumed and Concepts Introduced in
Section 1
Section 1 : Nucleophilic Addition to the
carbonyl Group (frames 1-65)
Contents of Section 2
Concepts Assumed, Introduced, and Reinforced
in Section 2
Section 2: Nucleophilie Substitution at the
carbonyl Group (frames 66-120)
Contents of Section 3
Coneepts Assumed, Introduced, ami Reinforced
in Section 3
Section 3: Nucleophilic Substitution at the
carbonyl Group with Complete Removal of
Carbonyl Oaygen (frames 121-168)
Contents of Section &
Concepts Assumed, Introduced, and Reinforced
in Section 4
Section 4: Carbanions and Bnolisation
(frames 169-216)
Concepts Assumed, Introduced, and Reinforced
in Section 5
Section 5: Building Organic Molecules from
Carbonyl Compounds (frames 217-330) SOME HELP YOU MAY NBED
This program is to help you learn about
the chemistry of the carbonyl group. I am
assuming that you are using the program as
part of a more comprehensive piece of Learning
such as a University course, You should
therefore have access to a library or at least
one reliable textbook of organic chemistry and
an "adviser"; that is someone such as a tutor
or fellow student with whom you can discuss
chemistry. You may well need both these as
you work through the program. To help you
fill in the background I'1l give references to
chapters in some of the more helpful texts?
"Cram"
J.B. Hendrickson, D.J. Cram, and G, Hammond;
organic Chemistry, 3rd ed., McGraw Hill 1970,
"Norman"
R.0.C, Norman; Principles of Organic Synthe~
sis, Methuen, 1968,
Roberts"
J.D, Roberts and M, Caserio; Basic Principles
of Organic Chemistry, Benjamin, 1964,
Nsykes"™
P. Sykes; A Guidebook to Mechanism in
Organic Chemistry, 2nd ed., Longmans, 1965.
"Pedder"
Je
Chemistry, Wiley (Vols 1-4) 1966,
. Tedder and A, Nechvatal; Basic Organic WHAT Do You 70 KNOW BEFORE YOU START? |
NEED TO KNOW BEFORE YOU STARI’
‘The program is about only a small part of
organic chemistry and I have to assume that
you know certain facts and appreciate certain
concepts. In case you feel uncertain about
any of these, here is a list of them with
appropriate remedies in each case.
I assume you cant
_ praw and recognise structures of simple
organic compounds (an aldehyde, acetone,
nebutanol...). Any organic text will tell
you about this. 4
= Write mechanisms using curly arrows (e.g. to
described the Sy? reaction between hydroxide
don and methyl iodide), If you can't do this
you should read Cram ch 9, Norman ch 4,
Roberts ch 7 sec 4, Sykes p 13-19, or Tedder
vol 1 ch 3, or consult your adviser. |
= outline the basic chemistry of alky1 halides
including nucleuphilic attack at caturated
carbon (substitution and elimination reactions
Sqls Sq2r BI and 52 mechanisms). 4 brush up
with Cram chs 10 and 14, Norman ch 4, Roberts
ch 11, Sykes chs 3 and 8, or Tedder vol 1
chs 3,4, and 5 might help.
= Explain what is meant by: the periodic
table, pK, value, anion and cation, electro-
phile and nucleophile, lone pair electrons,
tetrahedral structure, = and m-bonds, intra
molecular and reversible reactions. Again,
any text will help.
WHAT DO YOU NBED TO KNOW BEFORE YOU START
(conta.)
This 1iet applies to the whole program
but at the beginning of each section you will
find a list of “concepts assumed", This will
be a more detailed analysis of the concepts
I expect you to have grasped before you start
that section. You will find help in the
textbooks or from your adviser if you are
unsure of any of these concepts.
There are also lists of "concepts intro-
duced" and "concepts reinforced" for each
section. You may find these useful as a
check list to make sure, after you have fin-
ished the section, that you really have met
and understood these concepts. In many cases
@ concept introduced in one section will be
assumed for the next. HOW YO USE THE PROGRAM
Remember at all times that the point of
program learning is that you learn at your own
pace and that you yourself check on your own
progress. I shall give you information and
ideas in chunks called frames, each numbered
and separated by a black line. Normally each
frame includes a question which is sometimes
followed by a comment or a clue, and always
by the answer.
learning: if it is to be of any good
A program is an active form of
to you,
you must play your part by actually writing
down the answers to the questions as you go
along and checking up on points you aren't
sure about.
When you are ready to start, cover the
first page with a card and pull it down to
expose the first frame, Read and act
frame and then expose frame 2, and so
Remember to write down the answers to
questions - they are for you to check
on that
on.
the
on your
own progress and it is often only when you
commit yourself to paper that you find out
whether you really understand what you are
doing.
I hope you find the program enjoyable and
heipful.
Nucleophilic Addition, 1
CONTENTS OF SECTION I: NUCLEOPHILEC ADDITION
Frame 2
M4
47
10 THE CARBONYL GROUP
Nucleophilic addition: what it is
and how it happens.
Alcohols as nucleophiles: acetal
formation,
Some carbon-carbon bond forming
reactions with carbon nucleophiles?
cyanide ion, acetylide ion and
Grignard reagents.
Hydride ion and its derivatives
LiAlH, and NaBHs.
aldehydes and ketones.
Reduction of
Meerwein-Pondorff reduction and
Oppenauer oxidation, with a branch
program on how to draw transition
states.
‘Two general revision problems. Nucleophilic Addition, 1
Concepts Assumed
g~ and m-bonds. Inductive effects.
Polarisable bonds. pK, values.
Electrophile and
nucleophile.
Periodic table.
Transition states.
Conjugation with
qebonds and lone pairs.
Concepts Introduced
Acid catalysis.
Instability of R2,C(OR)z in acid solution,
Driving equilibria in a chosen direction by
the use of acid, solvent etc.
Stability of different carbonyl compounds,
Stability and reactivity as two sides of the
same coin.
Effect of substituents on equilibria.
Relationship between basicity and nucleo-
philicity.
Organo-magnesium compounds as nucleophiles.
Use of Grignard reagents in syntheses.
Base of dehydration of t-alcohols in acid
solution.
Sources of nucleophilic H™.
Use of Al and B compounds an anion trans-
ferring reagents.
Drawing transition states.
Stability of the six-membered ring.
Use of protecting groups (name not used).
Use of reaction mechanisms in syntheses.
Nucleophilie Addition, 1
SECTION I: NUCLBOPHILIC ADDITION TO THE
CARBONYL GROUP
Have you read the introductions explaining
what help you need, what you need to know,
and how to use the program? It's a good idea
to do this before you start.
1. The carbony1 group (2a) has an easily
yee
3
Write down the reaction (with curly arrows)
between acetone and hydroxide ion.
2. Have you actually written down the formu-
lae of the reagents and drawn the arrows?
‘The program won't be of much help to you
unless you do.
oy 0
Noo
cH; on
A nucleophile such as water uses its lone
pair electrons (+) to attack and forms a
neutral addition compound by proton transfer:
Note that only one proton is needed.
Write down the reaction between the carbonyl
compound acetaldehyde and the proton-bearing Nucleophilic Addition, 1:4
nucleophile ethanol.
4, If you find this difficult, use the lone
pair electrons on the ethanol oxygen atom to
attack the carbonyl group of acetone,
5. Answer to frame
{ i
ae
a
+ Eto
¢
es
Another approach is to add the proton first, in
acid solution, and to add the nucleophile
afterwards:
\onh
Jomd = Ye
wae es Not
XH Sa ON
In this case the proton is regenerated and this
ds an example of acid catalysis. Show how
water can be added to acetone with acid
catalysis.
6. If you are having difficulty with this,
look back at the last reaction in frame 5.
Carry out these same stops using acetone as
the carbonyl compound and water as HX.
cH, fom Hom oH om oH
Soak ee x 2 Oe
cs cus “cus” ~gH.* CHS “ow
‘one
Notice that Me,C=0H* is much more reactive
than acetone, but is still attacked at carbo:
although the positive charge is in fact on
Nueleophilic Addition, 1:5
the oxygen atom. What would happen to
R2C-OH* with water, ethanol, PhCH,SH, and
cyanide ion?
8. on pe ait pH
RA ec crepn Xo
8p
would be formed by a mechanism exactly like
the one in frame 7
When you combined R,C=0H* with ethanol you
formed an adduct (8b) which is the product of
ethanol addition to a ketone. The steps you
drew are therefore part of the acid catalysed
addition of ethanol to a ketone, Draw out
the whole of this reaction.
10. Look at the reactions in frames 7 and 9
again, Note that all the steps are reversible
and that therefore R2C-0H* may be formed from
+ R2C(OH)2, or RzC(OH)OR:
106
It is in fact a general rule that compounds of
the type R,C(OR)2, having two oxygen atoms
singly bonded to the same carbon atom, are
unstable in acid solution. A reason for this”
is that both oxygens have lone pairs of Nucleophilie Addition, 1
electrons, and so when one pair is protonated,
the lone pair on the other can form a C=0
double bond and expel the protonated atom.
Draw this in detail
Look at the reactions in frame 10 again. In
the reverse reaction we protonated and removed
the Et0- group from 10c. What happens if we
protonate and remove the HO- group?
rae
a Oh
meee ae mice neoste
Nor
This new cation, R2C=0Bt* is just as reactive
H* and can add nucleophiles in the
as RC:
same way. What happens if we add EtOH to it?
pee pre
a Rc, oR
SR
1H
OBt
This reaction sequence, added to the ones in
frames 9 and 12 gives us the addition of two
molecules of ethanol to a ketone to give
R:C(OBt),. Draw this sequence out in full
without referring back.
eee eee
th, If you have difficulty doing this, look
at frames 9, 12, and 13 without writing any-
thing down and then try.
ee eee
Nucleophilic Addition,
15. +
# on
nico a night Rcd
as \
EtOH wg
on Oa Be
Race & ace e Regge ace
ont Dore “yet
Dae
Bt
SB cde
ort
16, Does your reaction sequence exactly
follow that in frame 15? If not, try to assess
if the differences are trivial. If you are
still in doubt, consult your adviser. Tt is
important that you understand this reaction
well, This is a good place to stop if you
vant a break
17, Since this whole sequence is reversible,
it will go forwards in ethanol and backwards
an water, What do you Uiink would happen if
acetaldehyde and n-butanol were dissolved
together in a 1:3 molar ratio, and the sol-
ution refluxed for twelve hours with a cata
lytic quantity ef toluene sulphonic acid, and
the product dried and distilled?
18, This is a literature preparation of
CH, CH(OBu-n)z. Acetaldehyde is the carbonyl
component, butanol the nucleophile, and tol~
the catalyst. How
would you hydrolyse PhCH(OEt);, and what
would you get?
uene sulphonic acid i Nucleophilie Addition, 1:8
19, Reflux the PhCH(OPt), in water with a
catalytic quantity of an acid. The products
would be PhCHO and EtOH, How would you make
BtCH( OMe) 2?
20. Treat BtCHO and MeOH as in frame 17. A
glance at the reactions in frame 15 should
convince you that the mone adducts of carbonyl
compounds and nucleophiles with lone pairs are
unstable. An example is R,C(OH)OBt which is
unstable even under the conditions of its
formation, What happens to it?
—a Oe
21, ‘In ethanol it gives the acetal ReC(OEt)z,
in water the carbonyl compound R2C=0.
—oeora—eorr—esEr—
22, If we look instead at nucleophiles
without lone pairs we should find some stable
mono adducts. Which of the adducts in frame 8
should be stable?
should pe
23. The cyanide substituent has no lone pair
and so its adduct, RzC(OH)(CN) should be stable.
These compounds, cyanohydrins, are made by
adding excess NaCN and one mole of acid to the
carbonyl compound, The reaction is an equili-
rium, What is the role of the acid?
2k, To drive over the equilibrium by protona—
ting the intermediate:
a
RB 2 RC a
ang a
#8 ox
Nucleophilic Addition, 1:9
25, Since this reaction is an equilibrium,
the amount of cyanohydrin formed from any
given carbonyl compound will depend on the
relative stabilities of the carbonyl compound
itself and the product. There can be many
substituents X on a carbonyl compound R.CO.X,
such as Cl, Me, NHz, Ph, OBt, H, Some have
inductive effects, some conjugate with the
carbonyl group. Some stabilise RCOX making it
less reactive. Others activate it towards
nucleophilic attack. Arrange the compounds
RCOX, where X can be the substituents listed
above, into an order of reactivity towards a
nucleophile.
2
4
Some by lone pair conjugation:
a :
A
R
Some destabilise RCOX by inductive electron
withdrawal: Nucleophilic Additon, 1:10
27, Taking RCHO as standard, we can say that
C1 destabilises by inductive withdrawal, Me
stabilises more by 1-delocalisation, and Nia
and OBt by lone pair donation (NH; is more
effective at this: compare ammonia and water
as bases). Our order is:
CL...H...Me...Ph...OEt.. .NH2
most reactive most stable
These same factors could affect the product
as well. Arrange the same substituents in an
order for product stability.
ee
28, Since the carbonyl group has gone in
R2C(OH)CN, we would expect very little effect
from any of these substitutents. There can't
be any conjugation, and inductive effects on
the distant © atom will be small. What effect
would an inductively withdrawing substituent
have on the equilibrium for cyanohydrin form-
ation?
ae
29, It will destabilise the carbonyl compound
@ lot, and have very little effect on the
product: it will therefore push the equili-
brium over to the cyanohydrin side. Consider
cyanohydrin formation from:
a) MeCHO c) MezC=0 e) PhzC=0
b) PhcHo a) PRCO.Me £) MeCooEt
‘Two of these give no cyanohydrin at all.
Which two? One gives 100 per cent cyanohydrin
which? When equilibrium is established, ¢
forms 10,000 times as much cyanohydrin as d.
Comment .
Nucleophilic Addition, 1:11
30. we and f give no cyanohydrin at all.
~a gives all cyanohydrin,
in d there is a strong mconjugation from the
benzene ring absent in ¢ which stabilises the
carbonyl compound. These results fit in with
what we have said, if you don't see, consult
your adviser.
31. Another carbon anion you may have met is
the acetylide ion, formed by the action of
strong base on acetylene:
HeceQlu Onn, — H-Cec
It adds readily to the carbonyl group.
Draw out the reaction,
2 reelS —
TsC-H
33. The pK, of HON is 9.15, that of water is
15.7, and that of acetylene about 25. Which
anion, CNT, HO”, or acetylide ion, would add
fastest to acetone?
34, Acetylide fastest, then hydroxide, then
cyanide slowest, Remember that if HX is a
weak acid, X7 is a strong base,
35. Another type of carbon nucleophile is the
Grignard reagent RigBr made by direct metala—
tion of the organic halide with magnesium me~
tal, These compounds are nucleophilic
through carbon because the electrons in the
C-Mg bond polarise towards carbon. Draw the
attack of MeNgBr on CH Nucleophilic Addition, 1:12
oe & Ou
ages cee
nesium atom, Suggest how this might occur.
57. A possible mechanism 431
BrocngBr > Bto-Ng bit, 9Bt0-Me~Gits ed
oxk neo 2808
In any event, the product is a primary alcohol
y
and is a general route from RBr to RCH,0H.
What would be the reaction between PhCHsNgBr
and CH; CHO? ;
ee
38. dy, # Ph
Guy 1 oe
Brig OxQ He >, py Me
fF 8 Meee
Hs
CH OH ES
a RA
#20
So we can make secondary alcohols this way.
Ketones also react with Grignard reagents.
Draw the reaction between PhCH,MgBr and
39. yh Ph Ph
‘The work-up is done in acid solution, and
tertiary alcohols react easily with acid.
what further reaction might happen here?
Nucleophilic Addition, 1113
40. Protonation and loss of water leads to a
stable tertiary carbonium ion:
Ph Ph Pho Ph PI
at Pho
a MAL,
So much for carbon nucleophiles. This is a
good place to rest.
41. The simplest nucleophile of ali is the
hydride ion, H7, but as you may know, this
ion is very basic and will not add to the car-
bonyl group. Sources of H” for addition to
the
0 bond are NaBH, and LiA1Hy containing
the tetrahedral anions BHs” and AlH,”. Draw
out the structure of these ions.
he. Wyo
oH Pa
Show how Al,” my transfer HT as @ nucleo-
phile to a ketone R,C=0.
43. He oy FP ie
Sct 4b 5 ntior Hy nreneon
x7 UAT I
LiAlH,, lithium aluminium hydride is danger-
ous when damp, Can you suggest why?
Wu. It gives off hydrogen in large volumes
(7 + H.0 —9 H, + OH7) and evolves heat at
the same time. The result is usually an
impressive fire. Sodium borohydride, NaBH. Nucleophilic Addition, 1:14
4s less reactive and can be used in alkaline
aqueous solution.
What would be formed from PhOOMe and NaBHs?
4S. im
pn
ng a3 pe »
Beg wobec ey on on
HOH CH i CH3
bs
These reagents demonstrate two important pro-
perties ef boron and aluminium compounds, If
you are uncertain of the periodic table just
check to see where these two elements come.
Neutral tervalent B and Al compound are
electron deficient:
RK
Ro
only six valency
R electrons: no lone
pair.
They readily accept nucleophiles to form
stable tetravalent anions. Draw the reaction
between BF; and a fluoride ion, F
46,00 EOS BF; ——) FBP:
Also, anions can be transferred from these
tetrahedral anions to other molecules:
ppLx V v7) BB + MY
These two properties may be summarised by
saying that tervalent boron and aluminium
compounds will accept anions from one molecule
and transfer them to another,
Nucleophilic Addition, 1
technique known as the Meerwein-Pondorf?
reduction. The tervalent compound is alumin—
ium iso-propoxide, Al(OPr-i);, When a com
pound such as a ketone is added to this
reagent, it combines with it to forma tet-
vahedral anion. Draw this.
48. If you are in difficulty, remenber that
the Al atom is electrophilic and therefore
combines with nucleophiles, and think which
ond of the ketone molecule is nucleophilic.
(4 peo) sant bec —y (spr) RI -Becg™
NR
Tf ve drav this same intermediate with one of
‘the so propyl groups drawn out in full ve
can seo that the tertiary hydrogen atom in
the iso-propyi group (*) is electroniealiy
and geonetrically placed s0 that it can be
transferred to the ketone. Put arrows on the
formula te show how this happens.
Re
(4+Pr0) 11 ae (ePeD
on’
Tous
Hs
50. De
(4-Pr0) 2AL Me (s-Pr0),A1-ocHR: +
CH ===
Lf this wasn't clear, consult your adviser.
If it was clear, you ought to be able to do
the original problem so go back to frame 53.
*
in
cuts
The reason that this reaction goes so well is
that six-membered rings are very stable, and
s0 an intramolecular reaction going through a
six-membered transition state will be most
favourable.
60, The reverse reaction is known as the
Oppenauer oxidation. Here aluminium tri
tertiary butoxide and an involatile ketone
such as cyclohexanone are used to oxidise any
secondary alcohol to the corresponding ketone.
(t-Buo) a1 R2CHOH, (¢_puo) ,A10CHR:
R
o—c—R
—— (t-Bu) mae X
9
Show how a hydride transfer in this inter-
mediate leads to the oxidation of the alcohol.
Nucleophilic Addition, 1:19 |
pee
(eo) AK “ao a6) RiC=0
9
So we can reduce a ketone to an alcohol or
oxidise an alcohol to a ketone by using
Al(OPr-i); and acetone in the one case and
A1(OBu-t)3 and cyclohexanone in the other.
By their mechanism you can see that these
reactions will have no effect on other fun-
ctional groups such as C=C double bonds.
Di ee
62. This is nearly the end of the first part
of the program, so here are some general
problems.
You will remember that acetal formation
(erames 7-17) is a reversible reaction. It
turns out that the equilibrium constant for
acetal formation from a ketone is unfavour-
able: .
R,CO + R'OH — = R,C(oR')2
and poor yields are obtained. However cyclic
acetals can be made from ethylene glycol.
Draw out the mechanism for thie reaction:
o—cH
CHa
cis
+ A
x
(ort, )acx0 + wocxcHs0H Egy, o_
63. If you need some help, begin by adding
one HO group of HOCH,CH,0H to the protonated
Ketone, just as you did with ethanol in frame Nucleophilic Addition, 1:20
64.
(Hs ) 20:
He {OH
S an ).ght Soma =
(cits ) 20 (ors) ce
neuen:
4
20.
(ons) 260 }
No
Predict what happens in this reaction sequence:
=
—
o.
/
= condo)
Gg eon anlopres)s HT
castlensgcno ——) a a——3e
bu. iProH H20
G5. in the firat step the acotal from the
crienyae group but net from the ketone group
(frame 62) is formed:
CH3C0.CH2CMe2CllO ——> CH; CO .CH2CMe 2CH(OBt) 2
oniy one carbonyl group is now available for
Meerwein-Pondorff reduction (frames 61).
CH3CO.CH2CMe2CH(OBt) 2 _—
cH; CHL OK) CH, CMe 2CH(OBt) 2
finality the acetal is hydrolysed by standard
vaene, ‘The veeult of ali this is that we have
mene @ ketone in the presence of an aldehyde:
2 we Me gu Ne. Me
Avo
ox Seng eno
thus 4s the end of the first part of the
program,
NUCLEOPHILEC SUBSTITUTION, 2.1
CONTENTS OF SECTION II: NUCLEOPHILIC SUB-
Frame 66
76
80
89
ou
98
102
115
STITUTION AT THE
CARBONYL GROUP
Substitutio
how it happens.
LiAlH, reduction of esters.
Reaction of Grignard reagents with
esters.
Alkaline hydrolysis of esters.
Acid hydrolysis of amides.
Summary of acid and base catalysis.
Reaction between carboxylic acids
and thionyl chloride.
Synthesis of esters and anhydrides
from carboxylic acids.
Review questions. NUCLEOPHILEG SUBSTITUTION, 2.2
SECTION IT: NUCLBOPHILIC SUBSTITUTION AT THE
CARBONYL GROUP
Concepts assumed
Electrostatic repulsion.
Catalysis.
Heavy isotopes.
Acidity and basicity of C1”, Et0™, Nis, etc.
Concepts introduced
Relationship between nucleophilicity, leaving
group ability, and basicity.
Substitution as an extension of addition.
Position and use of electrophilic attack on
carboxylic acid derivatives.
Similarity of reaction between cyclic and
acyelic compounds.
why carboxylic acids are unreactive towards
hucleophilic substitution.
Use of 180 in establishing reaction mechanisms
Concepts reinforced
Use of acid and base catalysis and choice of
solvent in driving an equilibrium in the
chosen direction.
Advantages of the six-membered cyclic transi-
tion state.
Use of Grignard reagents in synthesis.
Ease of dehydration of tertiary alcohols.
Use of reaction mechanisms in designing
syntheses.
NUCLEOPHILIC SUBSTITUTI'
66. In the first part of the program we
considered only aldehydes and ketones. We're
now going to look at the full range of
structures including carboxylic acids, RCO.0H
acid chlorides ROO.C1, and esters ROO.OR.
Using your knowledge of nucleophilic addition,
what would be the first reaction between
hydroxide ion and benzoyl chloride PhCO.C1?
or. © °
qi i
6
Phi yo —
HO” CS
Instead of picking up a proton from the sol-
vent, this intermediate has a better reaction:
the negative charge returns to restore the
double bond expelling C17. Draw this,
6. yy °
xX. i
pn yp Now ca
on
Why did it expel C1” and not OH”?
69, Because C17 is a better leaving group
than OH”. We know this because HCl is a
stronger acid than HOH and is therefore
readier to ionise, C17 must therefore be
more stable than OH”.
Draw out the whole of the reaction.
OR Ea a ce cen eee NUCLEOPHILIC SUBSTITUTION,
Jo. @ Rs a -
pute <2 mn-fege 9 woe + oh
Ko on
his ia then a substitution reaction, O# in
the product taking the place of C1 in the
reactant.
71. What happens if aniline, PbNH2, and
penzoyl chloride react together?
°
Boe mbas i
PhNHe Phi PhNi
Peace
ci” is preferred to PhNH” as leaving group.
Which is the stronger nucleophile towards a
carbonyl group, Cl” or OH”?
earbonyl group) Ch
79. HOT because it is more basic.
it is in fact a general principle that as far
as the carbonyl group is concerned, — ol
ecules are better nucleophiles if they are
more and worse Leaving groups if they
are more -
7h, pasic fills both gaps.
Po put it another way, @ more/Less basic
nucleophile will displace a more/less basic
leaving group from a carbonyl compound.
(choose ‘more’ or ‘tess! in each case.)
75. more. less.
Which of these reactions would you expect to
work well? (See next page)
NUCLEOPHILIC SUBSTITUTIO!
+ 2S
a) C17 + CHyCONH, —) CH3CO.c1 + Nia”
b) NHs + CHjCO,OBt —) CH,CO.NH2 + EtOH
) CH3C0.07 + CH)CO.C1 —} CHyC0.0¢0.CH; + C17
76. b) and c) will work, a) won't, If you
don't see this, consult your adviser
What do you think will happen here?
RCO,OBt + LidlH, —>
_ eee os
77. If you have problems, read frames
and
43 to remind yourself that the AlHs” ion
delivers H7 as a nucleophile to the carbonyl
group.
group
78.
R 5 7 :
A ot Wl
wig — ued? —y Redon + peo
oft t
BtO™ is less basic than H” and so is dis-
placed, What will happen to the product under
the reaction conditions?
eee
79. The aldehyde is reduced to the alcohol:
z R
wymLe Pl 5 ub-c > row.0%
# #
Since the aldehyde is normally more reactive
than the ester, it is virtually impossible to
stop at the first stage and the compound is
normally treated with an excess of LiAlH, to
give the alcohol NUCLEOPHILIC SUBSTITUTION, ?.6
a0, A very important series of nucleophites
are the Grignard reagents RMgBr. What would
happen with RCO.OPt and R'NgBr? The reaction
begins like this:
R
Brie LP
obt
a1, Have you considered the possibility of
turther reaction? Frames 35 - 98 may help,
32. As before, the first reaction converts
these carbonyl compounds into reactive Prom
quets, this time ketones, An excess of
Grignard reagent therefore gives good yields
of tertiary alcohols.
R
oon SLY 4 nef Pinetree
ae So bx
— ee CLC
seg useful shorthand to indicate the to
stages of the substitution reaction. We shall
seeeet from now on, and if you are in doubt
weet ies meaning you should consult your
adviser.
wre tinai product from this reaction was &
tertiary alcohol. How might this be made into
an olefin?
83, Tertiary alcohols give carbonium sons
with great ease in acid solution (see frames
39 = 40) and the carbonium ion can either
NUCLEOPHILIC SUBSTITUTION,
2
aa
pick up a nucleophile or lose a proton to
give an olefin.
To get a good yield of
olefin you therefore want an acid with a
weakly nucleophilic anion such as H2S0« or
KHSO,, In fact this reaction often happens
during the work-up of the Grignard reaction.
CHeCHs
cHs—
on
CH: CHs
“OH.
=
#,
HCH:
facts —} cib—Esacis —> FR
cH, “cia
"Sm
cus cus
84, What product would be formed in this
reaction:
or
2, HY, HO
1. PhMgBry , _KHSOs
1 PhMgBry , KHSO y 5
85. Here we used a cyclic substituent.
¢0,0Ke
PhMgBr,
MgB:
9
Pa or
pNeBe .
eee
no
Pp
xus04
ae
Now try this reaction which has a cyclic ester
or lactone in it.
that for an ordinary ester.
Oo?
1. PhCH. MgBr,
NCH aMEBry 4
2, Ht,
#0
oH
The reaction is just like
KHSO. y y "OO 2 OCams
0 oan on
4
Ph- HH Ph
87.A Grignard reaction is probably an example
of electrophilic catalysis involving two
molecules of the Grignard reagent:
Gren
LLL ete
of v
Dhis intramolecular mechanism may remind you
of the Meerwein-Pondorff reduction (frames
49 - 59). Both have a six-membered cyclic
transition state. Draw it for this reaction
88.
SMR
“hg--- BE
4
his is a good place to rest if you want to.
89, In view of our conclusion in frame 7/4, it
may surprise you to recall that esters are
hydrolysed in alkaline solution:
a
ci —one + no” 2% cx —C—on + Brow
praw a mechanism for this.
NUCLEOPHILIC SUBSTITUTION, 2.9
90.
ow Gt ors
uo Ne no—¢-¥o" = Ho—d=0
oft ee
+ x07 = Eton
Here OH” displaces the slightly more basic
Eto”, Can you think why this happens so
easily?
91, Aclue: did you notice that the steps
are all equilibria? Think how an equilibrium
can be driven over, and perhaps compare this
reaction with the hydrolysis of acetals
(erame 17).
92. The reaction is done in water with an
excess of OH” to drive the reaction forward
by the mass action effect, There is another
reason too, Think which species will
actually be formed in aqueous alkali
93. CH3COOH will form CHsCOO™ and electro~
static repulsion will prevent attack of OT
on this so that it is effectively removed
from the equilibrating system.
94, Amides can also be hydrolysed in alkali,
but let's look at their hydrolysis in acid
solution:
CiiyCO.NH, + H20—}CHsCOOK + NHS
-
How could acid catalyse the first step of
the reaction, the formation of the tetrahedral NUCLEOPHILIC SUBSTITUTION, 2,10
intermediate?
Q
#30
R-$—M, >
95. By protonation, Note that we use the
lone pair of electrons on nitrogen, but pro-
tonate at the carbonyl group to get the most
delocalised cation:
#H20: +OH2
.
fos
ih
None of these substituents are now good
leaving groups, but in acid solution one of
‘them might be protonated. Which?
96. NH, is most basi
on . OH
2a ets
‘OH Oa
Now we have a good leaving group. Draw the
next step.
°
97. OH oH Ok
aay On + NHs
ry Sin a rho =r
iH
‘his reaction is very similar to some of the
steps in acetal formation (frames 10-12)
98, So to summarise, base can catalyse the
NUCLEOPHILIC SUBSTITUTION, 2.11
the hydrolysis of esters or amides in two
ways, State them.
heh
99. 1
equilibrium using the mass action effect.
By driving over an unfavourable
2: By capturing the carboxylic acid product
as an unreactive anion.
100, Acid catalyses the same reaction also
in two ways, State them.
ae ee
101, 1: It catalyses the addition of the
nucleophile by protonating the carbonyl group.
2: It turns what is otherwise a bad leaving
group into a good one by protonation.
102, This first catalytic function (101:1)
can be carried out by electrophiles other than
the proton. This applies particularly to
carboxylic acids. The electrophile could
attack oither oxygen ato:
°
rNdix*
Which atom do you think will actually be
attacked?
103, The carbonyl oxygen atom will be
attacked because the cation produced is
delocalised over both oxygen atoms,
No
ee 2 Rew ae
A goodexanple of thiz kind of reaction 12
the attack of thionyl chloride on carboxylic NUCLEOPHILIC SUBSTITUTION, 2.12
acids. ‘Initial attack occurs at carbonyt
Draw the products.
i
‘on Q
per oa”
We now have within the system:
a) a reactive carbonyl group. Why?
b) a good leaving group, Which?
oxygen
104.
c) a nucleophile. What?
jos. a) Because it is protonated.
b) 180s" which in fact decomposes to SOs
and C17
¢) Chloride ion.
So what do you think happens now’?
106. 9 ° 8
on ale a
RR ee +0” “Ci-yson +
cu”
the net result is that a carboxylic acid has
been converted into an seid enrOrite, _
107. You may have noticed that this i the
first example of a nucleophilic substitution
at a carboxyiie acid that we have soon, and
we find in general that, unless we attack
vuret with an electrophile, carboxylic acids
are very wireactive towards nucleophilic
‘subatitution, Can you think of a reason for
this?
NUCLEOPHILIC SUBSTITUTION, 2.19
108
These are really related reasons:
‘The carbonyl group is rather unreactive.
The leaving group would have to be HO",
notoriously one of the worst.
Perhaps the most important of the three is
that nucleophiles are bases and they there—
fore remove the acidic proton rather than
attack the carbonyl group.
Hot
do we overcome these problems by reaction
th thionyl chloride (frames 103 - 106)?
109. ‘The carbonyl group has become the
reactive C=0H".
group in C1S0.7
We have a very good leaving
The removal of a proton
has become an irrelevance since it's got to
come off anyway and because of the electro-
philic assistance we can use a very weak
nucleophile, C17
Other reagents which do the same job are
POC1; and PCls.
110, How might we convert RCO.OH to RCO.OEt?
ip oer
111, We know that EtOH will displace C1”
from the carbonyl group with base catalysis,
30 we need to make RCO.C1, and this we have
just done, The whole scheme is:
nco.os £22225 noo.c1 BE nco.o8t
In fact ve don't alvays need £0 go through
ROO.C1, a2 acid catalysed reaction betwoon
the acid and BeoH often gives the ester in
good yield, Mechanism? NUCLEOPHILEC SUBSTITUTION, 2.14
412, Protonation gives the most delocalised
cay (grame 95):
H
= Aoi 2
gt eh on
Bebe
ton
ee RNoze Se RCO.OBE + HT
qhis is another example of an equilibrium, so
we make an ethyl ester from RCO,OH, EtOH and
acid in solution in , and we hydro~
lyse an ester in with acid catalysis.
113. We make the ester in ethanol, and hydro
lyse it in water. Another useful compound is
the anhydride RCO.0CO.R, How could we make
that from RCO.OH using reactions we've dis~
cussed?
114, Again we need to displace Cl” by RCO.O"
xco.0n S944 RCo.cr
Rco.on SA#C0r4 Rco.0
‘his is practically the end of the second
section, so here are some general review
questions.
115. Arrange these compounds in order of
peactivity towards water; all reactions are to
give the carboxylic acid:
CH CO.0CO.CHs CH3CO.NHs
cH; C0.CL CH CO.OBt
ROE
NUCLEOPHILEC SUBSTITUTION, 2.15
116, Chtoride)anhyariad) ester) amide, In
fact the chloride explodes with cold water,
the annyoridereacts with cold water, the ester
reacts vith dilute seid of page but the amide
only with boiling 70% acid or 10% caustic soda.
Ask you adviser if you are in doubt about this.
ae era
117. If you hydrolysed an ester labelled with
heavy oxygen! in acid or base, would the '*0
end up in the acetic acid or
the ethanol?
118. In both acid and base 1¢ vould ond up in
the ethanol, thi 2 one of the pieces of evi-
dence used to establieh the mochantous we have
een discuseing, Tf you vant to read nore
about this see Cram p.504, Tedder vol 3, ch.6.
n ‘
a Pe
Ge Ly
cu F'o-ve = cus | Se = cHsco.on
fo
on + HIS 0nt
119, How would you carry out this multi-step
synthesis?
PhCH2CO.0H ——) PhCH2CH,0.COCH,Ph
120. Phovsco.n —BtQHy pncx.co.pe AAI y
{s0cte we PhCH. CH 20H
PhCH, CO .c1 —————> PhCH. CH0C0 .CH2Ph
There are other good routes: if you have one
discuss it with your adviser, This is the end
of the second part of the program.
ee REMOVAL OF CARBONYL OXYGEN, 3:1
yucL
STITUTION AT THE
CONTENTS OF SECTION IT:
CARBONYL GROUP WITH
COMPLETE REMOVAL OF
CARBONYL OXYGEN
Frame 121 Imine formation from aldehydes
and ketones.
127 Oxime formation and the structure
of oximes.
130 Hydrazone and semicarbazone form
ation.
197 Reduction of to CHa.
149 Conversion of C=0 to CCla+
154 DDT synthesis.
158 Chloromethylation of aromatic
compounds «
165 Review questions.
REMOVAL OF CARBONYL OXYGEN, 3.2
SECTION II.
NUCLEOPHILIC SUBSTITUTION AT THE
CARBONYL GROUP WITH COMPLETE
REMOVAL OF CARBONYL OXYGEN
Concepts Assumed
Rigidity of olefin two dimensional structure.
Geometrical isomerism.
Mechanism of the £2 reaction.
Concepts Introduced
Absence of acid chloride-like substitution in
aldehydes and ketones.
Possibility of loss of carbonyl oxygen from
tetrahedral intermediate.
Geometrical isomerism of oximes.
Usefulness of different reagents using con-
trasting conditions for the same synthetic
step.
Non-nucleophilicdty of amide nitrogen atoms.
Use of high-boiling solvents.
Medium ring compounds.
Characterising a compound as a stable crystal-
line derivative.
Concepts Reinforced :
Instability of compounds containing two atoms,
both with lone pairs, bonded to the same
carbon atom.
Incompatibility of strongly basic nucleophile
and strongly acidic conditions.
Electrophilic attack of S and P compounds on
carbonyl oxygen.
Blectrophilic substitution in the benzene ring. REMOVAL OF CARBONYL OXYGEN, 3.3
NUCLEOPHILIG SUBSTITUTION AT THE
CARBONYL GROUP LEADING TO
COMPLETE REMOVAL OF THE OXYGEN
ATOM.
SECTION ITI:
21.
jast section that aldehydes and ketones can't
You may have the impression from the
é
; 8
cHy OH + HOT —— > CHT OH + Ch
mny not?
122, The mechanism would have to be:
8 2 we
cuyHecs —) cuits) cH COaH + Cis —} OHe
Ho7 La
and Cj” As far too basic to be displaced.
ho are going to look at a new kind of sub-
ve atution reaction, Draw out the addition of
wetline, PhNiiz, to acetone to give a neutral
adducts
2. om ¢ ou
129. ; i
cartons — cu |~cws cus“ [Sons
Pha Mie a
pa Pr’
ig this addition reaction is to be extended
into a substitution, we must find a leaving
group. Neither CH, OH,nor PANH are good
leaving groups but either OH or PhNH can
REMOVAL OF CARBONYL OXYGEN, 3.4
124. By protonation (as in amide hydrolysis,
frames 94 - 97). If PhNH is protonated and
eliminated, we just reverse the reaction back
to the starting materials, but see what
happens if you protonate and eliminate OH.
Draw the reaction.
v5. on
e HT C, CHa, CHy
caf [oom = cnvNcom SO
oa ‘Seat u
pa Pi mt
Hy. 0s
=
PaO
What you have done is to make the carbonyl
oxygen atom the leaving group: the reactions
we are going to explore in this section all
involve complete removal of carbonyl oxygen
during a substitution reaction.
126. The product of this last reaction is an
imine, containing a C=N double bond, The
formation of these compounds is an equilibsium
and they are very easily hydrolysed. More
stable imines are formed from hydroxyl-amine
HONH,, Write down the complete reaction
between this compound and PhCO.Me (using the
N atom as nucleophild. REMOVAL OF CARBONYL OXYGEN, 3.5
127. es S< a <
“yu? ~ NH ‘OH
t ;
=
HO = FG
Draw out the full (two dimensional) structure
of this product.
128. Ph
ee
cus
How many isomers of this compound are there?
129, There are in fact two the C=N bond is
just as rigid as the C=C double bond, and
these compounds, oximes, are like olefins with
one substituent missing: there are "cis" and
"erans" forms?
Ph oH Ph
Ey -
oh ci ow
430, Similar reactions occur with other
amines, particularly hydrazine, NH.NHz, and
its derivatives which form good stable
crystalline imines known as hydrazones. What
compound would be formed from hydrazine and
acetone?
#
+ nM, ——>
cH
Supposing there were more acetone around,
NHe
what might happen now?
REMOVAL OF CARBONYL OXYGEN, 3.6
132. The other end of the molecule could
react to
cu, chy gt CH os
Sevens + ok LY Sexy
ous Hs cus ‘cls
193. Semicarbazide, NHzNKCONH,, also reacts
well: what product would be formed here with
acetaldehyde?
138,
Hs at
Sc-0 + Nz .NHCONH, >
This nitrogen atom is in fact the only one to
react. Why don't the other two react as well?
135. The other two nitrogen atoms have their
lone pairs conjugated to the carbonyl group:
they are in fact amide-like, It is only the
terminal nitrogen atom which is fully nucleo-
philic.
A
iP,
136. We have met the hydride ion in the gue
of NaBH, and LiALH, twice already (frames M1-
45 and 76 - 79). If we now use hydride ion >
remove the carbonyl oxygen atom altogether
we shall obviously get a hydrocarbon:
ReC=0 —) RaCHe
What could be an intermediate in this reaction REMOVAL OF CARBONYL OXYGEN, 3.7
137. ‘The obvious intermediate is found by
adding hydride ion to the carbonyl compound
in the usual way?
RH
wet — >) Son
under strongly acidic conditions this alcohol
could give a carbonium ion, Draw this.
198. ROH yt R, re R,
x i = Yu
Ro “H R H ae
ALL we have to do now is to add hydride ion to
the carbonium ion to get the hydrocarbon. You
may have been nursing a growing feeling that
all is not well with this idea, and you are
right. What is wrong?
139. If you're not sure, consider whether
there isn't something incompatible with the
nature of the hydride ion, or NaBHy or Lili,
land the conditions we have outlined for this
140, We need strong acid to protonate and
eliminate the carbonyl oxygen atom, and we
can't possibly use any of the sources of
hydride ion in acid solution: NaBH, would
react violently to give hydrogen gas, LiAlHs
or NaH would explode.
We therefore use a dissolving metal reduction
jn strong acid. This reaction, the Clemmensen
reduction, may use the principle we have out—
Lined here, but its mechanism is unknowa in
jacai. ReG=0 + Zn/lig + conc, HCL—}RsCHs
RPMOVAL OF CARBONYL OXYGEN, 3.8
11, An alternative method begins with the
formation of a hydrazone. We shall use cyclo-
hexanone here for a change, Draw the product
formed from this ketone and hydrazine (the
hydrazone)
ha. cr rh N-NHe
—=
H
‘The hydrazone has all the elements of the
product we want, cyclohexane, plus two nitro-
gen atoms. Ali(1) we have to do is to move
two hydrogen atoms from nitrogen to carbon.
This can be done in very strong base:
=
Complete the reaction mechanism to give eyclo-~
hexane
13.
The reaction is usually done at high tempera-
tures in ethylene glycol, a high-boiling polar
solvent, and is called the Wolff-Kishner reduc-
tion +
Rac
reflux in
© NHaNH, + NaoH —G2YS°L yR.cH, +Ne
200°
144, Yet another method is to make the dithio~
acetal from the ketone, say PhCO.CH2CHy, and
HSCH.CH2SH. Draw this.
——a—~x ee REMOVAL OF CARBONYL OXYGEN, 3.9
145, If you can't do this, look back at the
frames on cyclic acetal formation (62-3):
it's reaily the same reaction.
a, iframe
146. S
The dithicketal can be reduced directly to the
hydrocarbon by hydrogenation over the sulphur-
removing catalyst Raney nickel:
>< Hz, Raney Ni
oa
Ph* CH, CHa PhCH CH2CH3
147, We now have methods of reducing ketones
to hydrocarbons in acidic, alkaline, and
neutral solutions. This is useful since we
may have molecules which are sensitive to some
of these conditions. Which methods would you
use for these reactions?
a) PhCO.cMe2 .cH(OBt) ; ——}PRCH.CMesCH( OBt) »
») on CH2CHs
—
xt cont,
148. a) Wolff-Kishner. Clemmensen would
destroy the acetal.
b) Dithioketal. Either of the other methods
would do nasty things to the amide, This is
a good place to stop if you'd like a rest.
REMOVAL OF CARBONYL OXYGEN, 3.10
nucleophile to the carbonium ion, could be
extended a bit. In frames 137-8 we discussed
this idea for H7 as nucleophile, but it didn't
work out too well. Draw the sequence out for
C17 as nucleophile on a general ketone Re
150. a
OH yt ‘OHe
nacgd—9 Reel pane) me —) Rgter
cL a a cl
— ® rae
° Nor
Tt turns out that we can't do this with HC1,
we need a stronger electrophilic catalyst for
the first step than the proton, We use
instead PCls, which reacts by ionising to C1”
and PCl.*, The products are R,CC1z, and
Poci,, See if you can complete the mechanism.
151. R2C: PCL, —} Ril O-PC1 4 —) RaG-O-PCL4
cl” cL
ricer + — “O¥pc1, f81—yo-Pe1, + c17
ca” ——4 R.co1e
Draw the product you would get from PCls on
PhCO.CHtzPh
152. Ph.CCl,.CHzPh.
Supposing you now reacted this with Eto” in
BtOH. What would you get?
149, ‘The idea of adding a nucleophile to a
carbonyl compound to give an alcohol and then
dehydrating the alcohol to a carbonium ion in
acid solution, and finally adding another
153. Stuck? Bthoxide ionis very basic and
Likes to remove protons, even protons attached
to carbon atoms. We also have good leaving
groups in the molecule and that combination REMOVAL OF CARBONYL OXYGEN, 3.11 REMOVAL OF CARBONYL OXYGEN, 3.12
"a, OF CO.”
b ber,
looks like making an elimination reaction.
am
15h.
in
Ph
Pa
~
Adore —eEeEee—er 3
: ee ia:
Suggest a mechanism for this step.
155. At this point you have a choice, I want
C1
to deal with some substitutions on the benzene You nay recognise this
ring using mechanisms like that for the nitra- ~ " product as DDT, the once
tion of benzene. If you're quite familiar, ow fous, now infamous
read on. If you want to brush up on the sub- cols insecticide, Its use
ject, turn to Cramch, 16, If you know is now controversial because of the build-up
nothing about the subject, either skip to
of organic chlorocompounds in animals through
frame 165 or read Cram ch. 16 and do your best out the world,
156, With very reactive carbonyl compounds, 159, Another reactive carbonyl compound is
such as chloral C1;C.CHO, we can even add formaldehyde, Draw out the first step of its
aromatic compounds in strong acid, Draw a addition to benzene in acid solution.
mechanism for the first step, the formation
nee 160. CHa Qe H
of the alcohol: a cnt extz01
Cl, at oa
eas
GD © ence oi
Te HCL 1s used as the acid catalyst, C1”
on instead of the aromatic ring becomes the
nucleophile for the second step. Draw this.
tl 157- on
ur 161 sax 08208 cu, or
c1yc.cHo > cisc-t “ches co wt Cpt
: on 4 7
oH This is then a general reaction for adding a
cuca ClCH, group to an aromatic ring known as
cL chloromethylation, The reaction is carried out
in a single step, CHz0 and HC1 being added to
*
Now a second molecule adds ont
the aromatic compound. REMOVAL OF CARBONYL OXYGEN, 3.13
162. The catalyst used for the DDT synthesis
was H2S04, that for chloromethylation is HCL.
In the DDT synthesis we added two molecules
of aromatic hydrocarbon, but in chloromethyl-
ation the second step had C1” as nucleophile.
Comment?
Comment
163. We deliberately used #2504, an acid with
@ non-nucleophilic anion in the DDT synthesis,
and HCl, an acid with a nucleophilic anion, in
chloromethylation, We also used H,S04 for the
same reason in the dehydration of tertiary
alcohols produced by the addition of Grignard
reagents to ketones. Draw out an example of
this reaction.
164.
CH, 1. Phepr oH. 2806
‘Se=0 coPh
cH 2. WT ,H,0° CHS
CH CHa
Ph —y So-Ph
cut cH
This then is our final example of substitution
removing the carbonyl oxygen atom completely:
here you see C=0 being replaced by
165. At the end of this section, bre are two
review questions: aldehydes and ketones are
often characterised as 2,4-dinitrophenylhydra~
zones, as these are usually highly crystalline
orange compounds, Draw the formation of this
derivative from benzaldehyde giving reagent,
REMOVAL OF CARBONYL OXYGEN, 3.1%
catalyst, and the structure of the product.
ee —————ermcm
H-N=CHPh
Nos No.
SSS
167. The smallest stable cyclic acetylene is
in the nine-membered ring. If you had a
sample of @ nine-membered ring ketone, how
would you attempt to-make the cyclic acetylene
from it?
168.
cl cL
This is the end of the third section of the
program CARBANEONS AND BN
LISATION, 41
CONTENTS OF SECTION IV: CARBANIONS AND
Frame
169
172
177
189
202
208
ENOLISATION
Carbanions.
‘Tautomerism.
Equilibration and racemisation of
ketones by enolisation.
Halogenation of ketones.
Formation of bromo-acid deriva-
tives.
Organo-zine derivatives and their
use in synthesis.
Review questions.
CARBANIONS AND ENOLISATION, 4.2
SECTION IV: CARBANIONS AND ENOLISATION
Concepts Assumed
Hydrogen bonding.
Racemisation.
Polymerisation.
Concepts Introduced
Simple carbanions don't oceur.
Stability of enolate anions.
‘Tautomerisn.
Reactivity of enols and enolates at carbon.
Selectivity in reactions byt
choice of acid or base catalyst.
choice of metal in organo-metallic reagent.
Subtle arguments in rationalising difference
between acid and base catalysed halogenation
of ketones.
Concepts Reinforced
Effects of equilibria.
Drawing transition states.
Bffects of substituents on stability/reactivity,
Relationship of nucleophilic addition, sub-
stitution and enolisation.
Synthesis of acid chlorides.
Use of organo-metallic reagents in synthesis.
General relation of synthesis and mechanism. CARBANIONS AND ENOLISATION, 4.3
SECTION IV: CARBANIONS AND ENOLISATION
ee
in many simple reactions (sy) El, ete.) and
ve nave net many of them in this program.
i
are some exceptions, such as Brjc, it is a
jood general rule to say that simple carban-
sons do not occur as reactive intermediates.
tr ve want to remove a proton from a carbon
ctom to make an anion, we need somewhere to
park the negative charge and there is nothing
totter for this job than the carbonyl group.
bean arrows to show the formation of an anion
from acetone:
i is
No-H "oH ——} cH “Sous
170. @ i
ens Suton ——> on Son,
This anion, often loosely called a carbanion,
ou
is delocalised with the charge shared between
the oxygen and carbon atoms. Draw arrows to
show this.
show tess
my a
OB on Na
Now show how this anion can react with a
proton on carbon and on oxygen to give two
different products.
CARBANIONS AND ENOLISATION, 4.4%
mp i
i
on’ “udut — cus Scus A
“yt OH
i i
7 7
cu’ Son. 9 cu Non. B
These two compounds have identical structures
except for the position of one proton: this
is clearly a special case of isomerism and it
iis called tautomerism, A is called the keto
and B the enol form of acetone.
Draw out the mechanism for the conversion of
13. ye
4
e .
on Sion ton Sons = ony” Now,
This is an equilibrium, catalysed by acid as
well as by base. Show how the enol of
acetaldehyde could be formed with acid cata-
lysis
174. gn Ge on
i \ f
on ms on%
Now draw the enol form of this ketone!
cH500.cHs .CooH,«
175. There are in fact two possible enol
forms: OK oO oH oO
Which is the more stable? CARBANIONS AND ENOLISATION, 4.5
176. ‘he second: not only because the double
bond is conjugated with the carbonyl sroup
put because of intramolecular hydrogen bonding:
HO a,
‘This compound in fact exists totally as the
enol under normal conditions, in contrast to
acetone which is entirely keto. Many other
carbonyl compounds are mixtures of the two.
177. The ‘carbanions' we formed using the
carbonyl group are like enols and are called
cnolate anions. Draw the enolate anion from
°
eaPArcits
178. This time we have to remove a rather
this ketone:
distant proton, but the charge still gets to
the carbonyl group?
:
praw the arrows for the re-protonation of this
enolate to give the original compound.
179. 2g re
Now form the enolate anion from this ketone:
Ph’
CARBANIONS AND ENOLISATION, 4.6
180, You should be adept at this by now:
é ;
ce, 5 oe
Roe =
181, There's a bit of a catch here. Did you
notice that the enolate anions formed in
frames 178 and 180 are the same? Perhaps you
want to think again,
182, If the two enolates are the same, then
they must protonate to give the same ketone.
Why in fact do we form this one and not the
alternative (B)?
maps mA ody
: ;
183. Because the whole thing is an equilibrium
and the conjugated ketone (A) is the more
stable. What happens then 11 we dissolve B
in ethanol containing a small amount of Et0™?
184. Small amounts of the enolate ion will be
formed which will re-protonate to give A.
Ketone B is therefore quickly transformed into
AL ao o) wee
RS gg atm we idk
185. What happens if optically active C is
dissolved in ethanol containing a catalytic
cH,
x .
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