140C Chemistry Summer 2011 (K. Albizati)
Chapter 20 Carboxylic Acid Derivatives
We have already seen a number of carboxylic acid derivatives and how to prepare them --- esters, anhydrides, acyl halides and amides.
We have also seen that nucleophilic addition-elimination is a major reaction mode..
..and that it can be acid- or base-catalyzed.
The order of reactivity of the 4 major derivatives with a nucleophile like water (or just about any nucleophile) is quite clear:
This is due to 2 reasons:
-
Leaving group ability
Resonance of the L group with the carbonyl
Halides and carboxylates are the weakest bases and are therefore the best leaving groups under both acid and base-catalyzed conditions. Alkoxides
and amine anions are fairly strong bases and are poor leaving groups and must be catalyzed by acids and bases with a lot of heat.
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Chemistry 140C Summer 2011 (K. Albizati)
Resonance of the L group with the carbonyl depends on the ability of the atom attached to the carbonyl to bear a positive charge. That is ,
electronegativity comes into play. The more of a resonance contribution the attached atom in L makes, the greater is the electron density at carbonyl
carbon and the less reactive is the acyl group toward nucleophilic addition.
Because positive charge character is distributed to L, this atoms ability to tolerate a positive charge determines how important this resonance is.
In acyl halides, the atom is a very electronegative halogen and the resonance is not of great importance.
In esters, the atom is oxygen, which is not as electronegative so resonance contribution is greater than for acyl halides.
In anhydrides, the central oxygen can be delocalized into 2 carbonyls so there is less electron density at either carbonyl compared to an ester, thus
making anhydrides more reactive than esters.
In amides, the resonance contribution is substantial because nitrogen is the least electronegative atom of the group and can best take positive charge
character. Hence, amides have a lot of electron density at the carbonyl carbon and are the least reactive of the carboxylic acid derivatives toward
nucleophiles. This has enormous ramifications in biochemistry and molecular biology.
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Chemistry 140C Summer 2011 (K. Albizati)
Acidity of the -Hydrogens in Carboxylic Acid Derivatives
Like aldehydes and ketones the hydrogens on the carbon attached to the carbonyl group have enhanced acidity due to resonance in the enolate anion:
The relative acidities compared to a typical ketone like acetone are:
This has important ramifications to reactivity that we will see later in Chapter 23.
Basicity of Carboxylic Acid Derivatives
As you might expect, these functional groups are only weakly basic and it takes a strong acid to protonate them. Further, protonation takes place
exclusively on the carbonyl oxygen due to resonance considerations:
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Chemistry 140C Summer 2011 (K. Albizati)
We will see this protonation phenomenon repeatedly in the rest of this chapter.
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Chemistry 140C Summer 2011 (K. Albizati)
Chemistry of Acyl Halides
Acyl halides react readily with many classes of nucleophiles to give a variety of carboxylic acid derivatives:
Aldehydes
Ketones
Amides
Esters
Anhydrides
C. Acids
Acyl halides are the key intermediate compounds through which carboxylic acids are converted to a large variety of other functional groups.
Hydrolysis with Water
General Form
Example
This is not very useful because acyl halides are usually made from carboxylic acids. Proceeds via an acid-catalyzed mechanism.
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Chemistry 140C Summer 2011 (K. Albizati)
Reaction with Alcohols to Form Esters
General Form
Example
These reactions are generally promoted/catalyzed by a base, usually a tertiary amine (we will see amines in Chapter 21).
Reaction with Amines to Form Amides
General Form
Examples
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Chemistry 140C Summer 2011 (K. Albizati)
Reduction with Modified LiAlH4 to Form Aldehydes
Recall that LiAlH4 is a powerful reducing agent used to convert aldehydes and ketones to carbonyl compounds:
Also recall that all 4 hydrogens attached to aluminum are active reducing hydrogens:
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Chemistry 140C Summer 2011 (K. Albizati)
When it is determined that complete hydride transfer has occurred, the reaction is worked up by the addition of water:
The reaction of LiAlH4 with acyl halides generally provides a big mess due to the over-reactivity of LiAlH4 with this functional group. We can
modify its reactivity by first reacting LiAlH4 with 3 equivalents of an alcohol to remove 3 of the 4 reactive hydrogens in an acid-base reaction:
Soacyl chlorides can be reduced one stage to aldehydes:
General Form
Example
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Chemistry 140C Summer 2011 (K. Albizati)
Reaction with Organocuprates to Form Ketones
Recall that organocuprates (Section 18-10) are versatile organometallic reagents that possess nucleophile-like properties:
Organocuprates react with acyl halides to give ketones via replacement of the halide with an R group:
General Form
Example
This is a very useful reaction because it forms a carbon-carbon bond in a predictable and general manner. The mechanism is not known with
certainty.
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Chemistry 140C Summer 2011 (K. Albizati)
Chemistry of Anhydrides
The chemistry of anhydrides is, for the most part, analogous to acyl halides, although anhydrides are somewhat less reactive.
General Reaction with Nucleophiles
Example (with a phenol)
Only symmetrical anhydrides are used in reactions to avoid the ambiguity of where the nucleophile will react. They are usual ly used under basecatalyzed conditions with an amine base being optimal.
Chemistry of Esters
First..a little nomenclature.
Ester nomenclature is useful because so many esters are used in foodstuffs that a little knowledge of ester names will tell you a lot about what you are
eating.
Ester names have 2 parts: the esterifying alkyl group and the parent acid
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Chemistry 140C Summer 2011 (K. Albizati)
Esters are named according to the sequence: esterifying alkyl parent acid root oate suffix.
So
Hydrolysis of Esters
Esters are hydrolyzed to carboxylic acids with aqueous hydroxide ion.
General Form
Example
This reaction follows a typical base-catalyzed A-E mechanism.
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Chemistry 140C Summer 2011 (K. Albizati)
Reaction of Esters with Grignard Reagents
Recall Grignard that reagents add to aldehydes and ketones to produce alcohols:
Reaction of Grignard reagents with esters produces 3o alcohols exclusively:
General Form
Two equivalents of the Grignard add to the carbonyl.
Example
Mechanism? Think about this one.
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Chemistry 140C Summer 2011 (K. Albizati)
Reduction of Esters by Hydride Reagents
Esters are reduced by LiAlH4 down 2 stages to the alcohol:
General Form
Example
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Chemistry 140C Summer 2011 (K. Albizati)
Chemistry of Amides
First..a little about amide classes.
Seen this before.
Amide Derivatives:
Hydrolysis of Amides
Amides require strong base and heat to hydrolyze to the corresponding carboxylic acid and amine:
General Form
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Chemistry 140C Summer 2011 (K. Albizati)
Examples
The difficulty of amide hydrolysis is crucial to biochemistry. The amide functional group is very stable to aqueous environments and makes this
functional group an excellent motif for the construction of large complex molecular structures made up of repeating units.
Reduction of Amides by LiAlH4
Amides undergo an unusual reduction with LiAlH4 to give amines. Essentially the carbonyl oxygen is replaced by 2 hydrogens.
General Form
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Chemistry 140C Summer 2011 (K. Albizati)
Example
Mechanism is rather esoteric and not instructive.
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Chemistry 140C Summer 2011 (K. Albizati)
Chemistry of Nitriles
Nitriles (also known as cyanides) are similar to carboxylic acids in that they are at the same oxidation state and one can be easily converted to the
other.
Structure
Very similar structurally to alkynes sp-hybridized carbon and nitrogen with 180o C-C-N bond angle.
Hydrolysis to Carboxylic Acids
Nitriles are hydrolyzed to carboxylic acids using either strong aqueous acid or base conditions.
General Form
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Chemistry 140C Summer 2011 (K. Albizati)
Example
These reactions proceed through an intermediate amide stage. Try writing the mechanisms for these two hydrolyses for yourself.
Reaction of Nitriles with Grignard Reagents
Nitriles react with Grignard reagents to form ketones in an important C-C bond-forming reaction:
General Form
Example
This is a very versatile way to make ketones. The reaction proceeds in 2 stages nucleophilic addition followed by hydrolysis of an imine:
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Chemistry 140C Summer 2011 (K. Albizati)
Reduction of Nitriles to 1o Amines by Hydrogen
Nitriles are hydrogenated by H2 to pick up 2 molecules of H2 to produce 1o amines:
General Form
Example
This is mechanistically similar to alkene and alkyne hydrogenation.
This transformation can also be carried out by LiAlH4.
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Chemistry 140C Summer 2011 (K. Albizati)
Carboxylic Acids, Esters and Alternative Energy Sources
Arguably the most important chemical reaction in history:
Spark
Gasoline
+
CO 2 + C O + H2O
O2
+ a lot of ener gy
( a mi xture of hydr ocarbons)
What is gasoline and where does it come from?
Gasoline for use in internal combustion engines is a mixture of over 500 organic hydrocarbons of between 5 and 12 carbons.
Typical Composition of Gasoline
Examples
heptane
isooctane
cyclopentane
ethyl benzene
General Name
Aliphatic - straight chain
Aliphatic - branched
Aliphatic - cyclic
Aromatic
Percentage
30-50
20-30
20-30
Gasoline ultimately comes from petroleum which we get out of the ground. It is, therefore, not renewable. Once we run out, its gone forever.
Although we are not likely to run out for some time, it is more likely that the remaining petroleum on earth will slowly beco me increasingly more
difficult to extract from the ground and refine, making petroleum a much more expensive resource than it is now. Unfortunately, today there is no
good substitute for liquid transportation fuels. Therefore a lot of effort has gone into finding a substitute liquid transportation fuel.
Dinosaur s
and
Plant s
Mi ll ions
of
Year s
Ref i ning
(Dis til lat ion)
Smal l chai ns
methane, et hane, propane
NATURAL GAS
VERY
USEFUL
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M edium c hains
pent ane, hexane
liqui d tr ansport ation f uel s
VERY
USEFUL
Long chai ns
decane and highe r
dies el f uels
Petr oleum
(Hydrocar bons)
NOT AS
USEFUL
Chemistry 140C Summer 2011 (K. Albizati)
The Table below shows the various types of liquid transportation fuels used in the US and the carbon range for each.
Fuel Type
Carbon Number
Automotive Gasoline
C4 - C10
Kerosene and Aviation Fuel
C4 - C19
Jet-A
C5 - C13
JP-4
C4 - C16
Diesel #1
C8 - C19
Diesel #2
C9 - C21
Missile Fuel (JP-9)
3 compounds
Missile Fuel (JP-10)
C10H16 (exo-TCPD)
Fuel oil
C15 - C22
Lubricating Oil
C20 - C60
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Chemistry 140C Summer 2011 (K. Albizati)
One possible substitute for gasoline as a liquid transportation fuel is Ethanol.
Ethanol has been used as the main auto transportation fuel in Brazil for a few decades. Brazil produces a lot of cane sugar which can be fermented to
ethanol on industrial scale:
Ethanol for fuel has also been produced in the US for awhile but on much smaller scale and, up to now, it has come primarily from corn. Many
companies are now gearing up to produce much larger amounts of ethanol for use as a fuel by optimizing the fermentation process.
An issue this brings up is the Food vs. Fuel Controversy. Should we be using our valuable farmland to produce fuel or to grow food?
One solution is not to use a food crop, but to use agricultural waste material as a source of glucose which can be fermented to Ethanol:
A large number of venture-capital backed companies have been formed to try to exploit this strategy.
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Chemistry 140C Summer 2011 (K. Albizati)
Another strategy has been to find a renewable substitute for diesel fuel. (See pages 926 927 in Chapter 20)
Diesel is a fraction from petroleum consisting of carbon chains in the C8 to C20 range. We can get compounds in this range by refining used cooking
oil and other waste products. In the US over 3 billion gallons of used cooking oil are disposed of each year. This can be recycled for use as a diesel
fuel:
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Chemistry 140C Summer 2011 (K. Albizati)
Audience Participation Time!!
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Chemistry 140C Summer 2011 (K. Albizati)
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Chemistry 140C Summer 2011 (K. Albizati)
Reading: skip 20.7 (Hofmann Rearrangement)
Problem Assignment: skip 20-3, 20-4, 20-20, 20-21, 20-22, 20-23, 20-24, 20-25, 20-48, 20-58, 20-61, 20-65, 20-66, 20-67
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