Download Review for Ch. 20 21

Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 1
These two chapters cover compounds which are all at the “three bonds to more
electronegative atoms” oxidation state. They’re called carboxylic acid derivatives,
because they all have a carboxylic acid as the parent compound. If you want to make any
of them, you often have to go through the acid form first, although there are cases where
you can go directly from one derivative to another.
O
R
O
Cl
Acid chloride
O
R
O
O
R
R
Anhydride
O
OH
R
Carboxylic acid
O
OR
R
Ester
N
NR2
R
Amide
Least stable/Most reactive
Nitrile
Most stable/Least reactive
You can rank them by stability based on the size of the delta plus at the carbon. Acyl
chlorides have the biggest delta positive and nitriles have the smallest. As a side note,
cyclic esters and amides are called lactones and lactams respectively. These groups do
just the same chemistry as a normal ester or amide, though rings smaller than five or
larger than six are often too unstable to form easily.
O
O
O
O
O
O
NH
NH
Lactones
Lactams
Chapter 20 mostly just covers how to make carboxylic acids in the first place, and
how to make each of the derivatives from acids. Chapter 21 gets more into reactions you
can do with the derivatives. I’ll mostly follow the order they use to cover the topics, but I
might switch things around a bit in some places.
Making carboxylic acids
1) Oxidation of primary alcohols and aldehydes: This normally uses something like
CrO3 and pyridine, or stronger conditions. We’ve seen this in Ch. 10 and 19.
OH
CrO3
pyridine
O
O
OH
CrO3
pyridine
H
O
OH
2) Oxidation at the benzylic position: This uses an oxidizer like CrO3, but in
vigorous conditions (usually acid and heat.) This was in Ch. 17.
O
CrO3
heat, H2SO4
OH
3) Ozonolysis: This is less useful because you have to break carbon-carbon bonds to
do it. This is from Ch. 5.
O
1) O3
2) H2O2, H2O
OH
OH
O
4) Grignards attacking CO2: This is a new one in Ch. 21, but it’s similar to
something we saw before. Ch. 19 shows how to use a Grignard to attack a
carbonyl. We can do the same thing by attacking carbon dioxide, which is kind of
like a “double carbonyl”. Then, we just finish it off the same way, with an acid
workup.
R MgBr
O
C
O
O
R
O
H3O+
O
R
OH
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 2
Note that whatever R was, we’ve just added one carbon to it overall. This is a
useful way of extending chains one carbon at a time. The only limitation is that R
has to be compatible with Grignards – no alcohols or unprotected carbonyls, etc.
5) SN2 with a cyano group, followed by hydrolysis: This one doesn’t show up until
Ch. 22, but it’s a useful complement to the Grignard/CO2 reactions shown above,
and worth mentioning here. In this case, we can make a particular acid derivative
by using SN2 to replace a leaving group with a –CN. Then, we can convert the
nitrile to the parent acid compound by hydrolysis, which we’ll look at the
mechanism for shortly.
R Br
NaCN
acetone
R
O
N H2O, heat,
H+ or OH-
R
OH
Like the Grignard reaction above, this ends up extending the chain length by one
carbon. The only requirement is that R has to be SN2-capable, so primary is best.
6) Conversion from any other acid derivative: Again, this is Ch. 22 chemistry, but
you can take any of the compounds shown at the beginning of this packet and
convert them to the acid by hydrolysis. We’ll see the mechanism later. If it’s
something more reactive than acid (like anhydrides and acid chlorides), you only
need water. If it’s less reactive, you need water, heat, and either acid or base.
O
R
Cl
O
R
O
H2O
R
O
O
OH
R
R
O
H2O, heat,
+
OR H or OH R
OH
O
O
H2O, heat,
+
NR2 H or OH R
OH
R
O
H2O
O
OH
R
General idea of mechanisms
Most of the reactions in Ch. 21 and 22 involve swapping out the group beside the
carbonyl. Unlike SN2, you can’t just attack and kick out the leaving group at the same
time. You attack first and break up the carbon-oxygen double bond. This gets you to a
point where the central carbon has four total groups attached – the tetrahedral
intermediate. Then the oxygen’s lone pair comes back down and kicks out the leaving
group. The general idea looks like this.
O
R
HO X
X
O
Y
Tetrahedral
intermediate
Y
R
Y
Depending on what you’re doing and whether it’s in acidic or basic conditions, there
might be a few extra steps somewhere in there to account for protonation or
deprotonation. But the general pattern is still the same for most of the reactions in these
chapters.
Making esters from acids
Fischer esterification is the simplest way of making esters. You can react the
carboxylic acid with the alcohol and some catalytic H2SO4.
O
R
OH
ROH, heat
H2SO4
O
R
OR
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 3
The mechanism is pretty much the same as the general pattern, but you protonate the
carbonyl first since you’re in acid. You also need to protonate the OH before it will leave.
H HSO4
O
R
O
OH
R
H HSO4
H
OH
R
O
H
ROH
R
R
R
O
O
HO OH2
R
R
O
HO OH
HO OH
R
H
OR
O
R
OR
HSO4
Note that in the middle you have the neutral tetrahedral intermediate.
Another option we have is different from that general reaction pattern shown
above. Instead, we keep both the oxygens that started out in the acid, and just stick an R
group onto one of them. This is called alkylation, and you need a good leaving group on
R to do it. One way is with diazomethane, CH2N2. The leaving group here is
spectacularly good, since it’s nitrogen gas which leaves. Diazomethane also acts as its
own base first, to deprotonated the acid.
O
R
O
O H
R
O
O
R
H3C N N
H2C N N
O CH3
Note that the oxygens stay on the molecule the entire time, just one of them gets
alkylated. The other option uses a slightly less good leaving group, and you need a
different mild base to deprotonated the acid in the first step.
O
O
R
R
O H
O
O
R
KCO3
O CH3
H3 C I
Overall, these are written as:
O
R
O
CH2N2
OH
R
O
O
CH3
R
OH
CH3I
K2CO3
O
R
O
CH3
You can sometimes use different R groups instead of just CH3, but they have to be very
good at doing SN2. Benzylic positions are an okay choice. Usually, though, these
reactions are considered the best way to make methyl esters (with an OCH3 group) and
not much else.
Making amides from acids
This is not a reaction we can do easily, because if you combine an acid and an
amine they’re much more likely to do acid-base chemistry first.
O
R
O
HNR2
OH
R
H2NR2
O
You can sort of fix this by heating them up to several hundred degrees, but there are
better ways of making amides. Usually, you make them from acid chlorides instead.
Making anhydrides and chlorides from acids
For chlorides, we can use the same special reagent we used to turn alcohols into
alkyl chlorides: SOCl2 or a similar molecule, PCl5. We still don’t cover the mechanism.
O
R
OH
SOCl2 or
PCl5
O
R
Cl
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 4
To make the anhydride, we have a couple of options. The name ‘anhydride’ means it’s
had a molecule of water removed. If you take two carboxylic acid molecules, stick them
together, and remove a water, you get an anhydride. You can do this by using a very
powerful dehydrating reagent, P2O5. This takes two copies of the same acid and converts
them to the anhydride.
O
R
O
P2O5
OH
R
O
O
R
There’s another option that only works to make five- or six-membered cyclic anhydrides.
If you mix it with an acyclic anhydride, they’ll swap which one is the acid and which is
the anhydride.
O
O
O
HO
R
O
O
O
R
O
O
O
+2
OH
R
OH
Hydrolysis of derivatives
Any of the derivatives of carboxylic acids can be converted back into the acid by
using water. If it’s a more stable derivative, you also need either acid or base as a catalyst.
The more stable the derivative is, the more powerful conditions you need to make it break
up – higher temperatures and more concentrated acid/base.
The mechanism varies slightly depending on which derivative you’re hydrolyzing
and whether you’re in acid or base. Kind of like in Ch. 19, if you’re in acid you’ll
protonate the carbonyl first to make it more attackable. You’ll also protonate the leaving
group, to make it drop off more easily. The mechanism is identical for esters and amides.
H+
H+
O
Acid-catalyzed
ester hydrolysis:
O
OR
H
HO OR
O
H
OR
HO OR
H
H
HO OR
OH
O
H OH2
O
OH
OH
OH
HOH
HOH
H+
H+
Acid-catalyzed
amide hydrolysis:
O
O
NR2
H
HO NR2
HO NR2
H
O
OH
HOH
H
NR2
H
HO NR2
O
H OH2
OH
OH
HOH
O
OH
In base, you just go ahead and attack with OH-, because you can’t protonate the
carbonyl first. Since the product is a carboxylic acid, it immediately gets deprotonated by
the base. Another name for base-catalyzed ester hydrolysis is saponification, since that’s
how soap is made. There is a difference here between ester and amide mechanisms: ORis a much better leaving group than NR2- (the pKas are ~16 and ~35, respectively). This
means that even though you’re in base, you still have to protonate the NR2 group with
water to get it to leave. (The solutions manual gets this wrong in the answer to 21.10b).
Base-catalyzed
ester hydrolysis:
O
O OR
OR
OH
O
O
O H
OH
OH
O
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 5
H OH
O
Base-catalyzed
amide hydrolysis:
O NR2
H
O NR2
OH
OH
NR2
O
O
O H
O
OH
OH
If you’re hydrolyzing a nitrile, the mechanism is longer. It breaks down into three
sections: adding water to make an imidic acid, rearranging to an amide, and hydrolyzing
the amide. The first part looks a lot like addition to a carbonyl, just you’re attacking a
triple bond to N instead of a double bond to O. In acid, you have to protonate the nitrogen
first. The rearrangement steps going from the imidic acid to the amide look a lot like the
keto-enol tautomerization.
H
Acid-catalyzed
nitrile hydrolysis:
N
H
H
N
NH
O
H
HOH
N
Base-catalyzed
nitrile hydrolysis:
H OH
N
H
OH
HOH (Imidic acid)
OH
NH
NH
H
O
(Imidic acid)
OH
OH
NH2
NH
O
NH2
OH
O
O
H
HOH
NH2
(Amide)
O
H OH
NH2
(Amide)
Both of these reactions finish up by hydrolyzing the amide, via the mechanism shown above (either in acid or base)
The two reactive derivatives, acid chlorides and anhydrides, don’t need a catalyst.
They react with water on their own, within minutes. This is not something you’d do on
purpose, it’s just a warning that you have to keep water away from them.
O
O
O
H2 O
Cl
O
O
H2 O
O
OH
OH
Starting from here, I won’t show any mechanisms if they follow the same general pattern
shown above. You can figure out the exact details based on conditions.
Reactions with acid chlorides
Being the most reactive derivative, acid chlorides will easily convert to pretty
much any other derivative if you combine it with the right reagents. To make an amide,
combine it with an amine.
O
R
O
HNR2
Cl
+ HCl (reacts with another molecule of HNR2)
R
NR2
The problem is that in these reactions, you generate a molecule of HCl. This is not a
problem in most cases, but if you’re using amines then HCl will add to it, and make that
amine incapable of doing the reaction. If you use equal amounts of acid chloride and
amine, the reaction will only go halfway because half the amine gets acidified. There are
two ways around this: either use twice as much amine, or throw in one equivalent of
some sacrificial amine, usually pyridine, that can soak up HCl but won’t make an amide
itself. The overall balanced reactions that give you decent yield are:
O
R
2 HNR2
Cl
R
O
O
NR2
R
Cl
HNR2
pyridine
O
R
NR2
To make an ester from an acid chloride, you just need to react it with an alcohol.
Only one equivalent is required, but you still need to add some weak base like pyridine to
neutralize the HCl.
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 6
O
R
Cl
ROH
pyridine
O
R
OR
To make an anhydride from an acid chloride, you need to react it with the
deprotonated carboxylic acid, known as the carboxylate (usually with a sodium
counterion). The acid itself is not strong enough to attack the chloride, but the
carboxylate is. This gives NaCl as a byproduct, rather than HCl, so no base is required.
O
O
O
R'
R
O
Na
Cl
R
O
O
R'
This is a pretty useful reaction for making asymmetric anhydrides, with two different R
groups on them. The methods we saw before only give us symmetric anhydrides.
Reactions with anhydrides
Again, as a reactive derivative it’s easy to turn this into other, more stable
derivatives. You don’t even need a base like you did with acid chlorides, since you’re not
producing HCl as a byproduct.
O
O
O
O
ROH
O
O
O
HNR2
O
OR
NR2
Reactions with Esters
This is more difficult because esters are pretty stable. You can still convert them
to other compounds though. If you react an ester with an amine, you can get an amide. If
you react an ester with a different alcohol, you get a different ester – this is called
transesterification.
O
HNR2
O
O
OR
R'OH
OR
NR2
O
OR'
Reductions
Like we saw in Ch. 19, you can reduce carbonyl compounds with hydrides. You
can do the same with acid derivatives, and you usually end up going from the “three
bonds to more electronegative atoms” oxidation state to the “one bond to more
electronegative atoms” oxidation state. An important thing to point out is that NaBH4
does not work for most of these derivatives – it only works for aldehydes and ketones.
LiAlH4 is what you want to use here.
The first example shows up in Ch. 20, on the acid itself. Since it has an acidic
hydrogen, that reacts first with the AlH4-. Then the remaining AlH3 reduces the acid to
the aldehyde. Finally, the aldehyde gets reduced by LiAlH4 like in Ch. 19. Overall it
looks like this:
O
OH
1) LiAlH4
2) H3O+
OH
You can do the same thing with esters. They break up the ester group entirely, so
you end up with two alcohol molecules, one from each half of the ester.
O
1) LiAlH4
+
OR 2) H3O
OH + HOR
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 7
Amides are the odd one out in this category. Rather than reducing to an alcohol,
they actually choose to drop the carbonyl oxygen entirely and keep the nitrogen. The
book explains this part pretty well on pg. 1024. The overall reaction looks like this:
O
1) LiAlH4
+
NR2 2) H3O
3) OH
NR2
The OH- is necessary because otherwise you would end up with a protonated version of
the product instead.
You can also reduce nitriles to primary amines. Again, you need to finish up with
OH- so the amine is neutral.
N
1) LiAlH4
2) H3O+
3) OH-
NH2
Another exception to this general pattern is reduction of acid chlorides. In this
case, we can stop at the “two bonds to more electronegative atoms” oxidation state. You
have to use an acid chloride and hydrogenate it with a poisoned catalyst. In fact, you can
also use Lindlar catalyst here. This is called Rosenmund reduction. Alternatively, you can
use LiAlH(OC(CH3)3)3, otherwise known as lithium tri(tert-butoxy)aluminum hydride.
This is a very weak version of LiAlH4.
O
Cl
H2
Lindlar
O
O
O
LiAlH(OC(CH3)3)3
Cl
H
H
The reason you can get away with both these reactions is because unlike most of the
reductions above, acid chlorides are more reactive than the aldehydes they make. A
sufficiently weak reducing agent can react with the acid chloride but it can’t react on the
aldehyde that gets produced.
Reactions with Organometallics
There are two useful reactions that you can do with organometallics: esters plus
Grignards/organolithiums, or acid chlorides plus cuprates. Esters will react twice with
organometallics. The first time looks just like a Grignard attacking an aldehyde that we
saw in Ch. 19, but the biggest difference is that you can kick out a leaving group after this
happens. This gives you a ketone which can react with a second equivalent of
organometallic.
O
O OR
OR
R MgBr
R
O
O R H3O+ HO R
R
R
R MgBr
R
Just as we saw in the reductions section, acid chlorides are more reactive than
aldehydes or ketones. This means that if we use a weak enough organometallic, we can
add just once without risking a second addition.
O
Cl
R Cu R
O OR
R
O
R
Decarboxylation
The general idea here is that if you have a carboxylic acid two carbons away from
any type of carbonyl (ketone, aldehyde, acid, ester, etc.), then the entire CO2 unit can
drop off. The H that was part of the acid ends up attached where the CO2 used to be.
Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives
CHEM 3331, Jacquie Richardson, Fall 2010 - Page 8
O
O
R
O
OH
R
H
The mechanism for this is actually not too different from that for Diels-Alder. It helps to
keep in mind that the molecule is capable of hydrogen-bonding to itself, so it normally
looks a little different than what’s shown up there. There’s already a partial bond between
the other carbonyl and the H. To do this mechanism, you just show it going and picking
up the H fully. Everything else clicks around the ring, like in Diels-Alder. Then to finish
it up, you do a keto-enol tautomerization under acidic conditions.
O
R
H
O
O
O
R
H
O
O
- CO2
Keto-enol
O tautomerize R
H