Hydrolysis of carboxylic acid derivatives (7)

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Hydrolysis of carboxylic acid derivatives (1)

Carboxylic acid derivatives

The carboxyl group (abbreviated -CO₂H or -COOH) is one of the most widely occurring functional groups in chemistry as well as biochemistry. The carboxyl group of a large family of related compounds called Acyl compounds or Carboxylic Acid Derivatives.

All the reactions and compounds covered in this section will yield Carboxylic Acids on hydrolysis, and thus are known as Carboxylic Acid Derivatives. Hydrolysis is one example of Nucleophilic Acyl Substitution, which is a very important two step mechanism that is common in all reactions that will be covered here.

The systematic IUPAC nomenclature for carboxylic acid derivatives is different for the various compounds which are in this vast category, but each is based upon the name of the carboxylic acid closest to the derivative in structure. Each type is discussed individually below.

Acyl Groups

Acyl groups are named by stripping the -ic acid of the corresponding carboxylic acid and replacing it with -yl.

EXAMPLE:
CH₃COOH = acetic acid
CH₃COO-R = acetyl-R

Acyl Halides

Simply add the name of the attached halide to the end of the acyl group.

EXAMPLE:
CH₃COOH = acetic acid
CH₃COBr = acetyl bromide

Carboxylic Acid Anhydrides

A carboxylic acid anhydride ([RC=O]O[O=CR]) is a carboxylic acid (COOH) that has an acyl group (RC=O) attached to its oxygen instead of a hydrogen. If both acyl groups are the same, then it is simply the name of the carboxylic acid with the word acid replaced with anhydride. If the acyl groups are different, then they are named in alphabetical order in the same way, with anhydride replacing acid.

EXAMPLE:
CH₃COOH = acetic acid
CH₃CO-O-OCCH₃ = Ethanoic Anhydride

Esters

Esters are created when the hydrogen on a carboxylic acid is replaced by an alkyl group. Esters are known for their pleseant, fruity smell and taste, and they are often found in both natural and artificial flavors. Esters (RCOOR¹) are named as alkyl alkanoates. The alkyl group directly attached to the oxygen is named first, followed by the acyl group, with -ate replacing -yl of the acyl group.

EXAMPLE:
CH₃COOH = acetic acid
CH₃COOCH₂CH₂CH₂CH₃ = acetyl butanoate

Amides

Amides which have an amino group (-NH₂) attached to a carbonyl group (RC=O) are named by replacing the -oic acid or -ic acid of the corresponding carboxylic acid with -amide.

EXAMPLE:
CH₃COOH = acetic acid
CH₃CONH₂ = acetamide

Nitriles

Nitriles (RCN) can be viewed a nitrogen analogue of a carbonyl and are known for their strong electron withdrawing nature and toxicity. Nitriles are named by adding the suffix -nitrile to the longest hydrocarbon chain (including the carbon of the cyano group). It can also be named by replacing the -ic acid or -oic acid of their corresponding carboxylic acids with -onitrile. Functional class IUPAC nomenclature may also be used in the form of alkyl cyanides.

EXAMPLE:
CH₃CH₂CH₂CH₂CN = butonitrile or butyl cyanide

Structure and Reactivity

Stability and reactivity have an inverse relationship, which means that the more stable a compound, generally the less reactive - and vice versa. Since acyl halides are the least stable group listed above, it makes sense that they can be chemically changed to the other types. Since the amides are the most stable type listed above, it should logically follow that they cannot be easily changed into the other molecule types, and this is indeed the case.

The stability of any type of carboxylic acid derivative is generally determined by the ability of its functional group to donate electrons to the rest of the molecule. In essence, the more electronegative the atom or group attached to carbonyl group, the less stable the molecule. This readily explains the fact that the acyl halides are the most reactive, because halides are generally quite electronegative. It also explains why acid anhydrides are unstable; with two carbonyl groups so close together the oxygen in between them cannot stabilize both by resonance - it can't loan electrons to both carbonyls.

The following derivative types are ordered in decreasing reactivity (the first is the most reactive):

Acyl Halides (CO-X) > Acyl Anhydrides (-CO-O-OCR) > Acyl Thioester (-CO-SR) > Acyl Esters (-CO-OR) > Acyl Amides (-CO-NR₂)

As mentioned before, any substance in the preceding list can be readily transformed into a substance to its right; that is, the more reactive derivative types (acyl halides) can be directly transformed into less reactive derivative types (esters and amides). Every type can be made directly from carboxylic acid (hence the name of this subsection) but carboxylic acid can also be made from any of these types.

Reactions of Carboxylic Acids and Their Derivatives

Carboxylic Acids

1) As acids:

     RCO2H + NaOH ----> RCO2-Na+ + H2O      RCO2H + NaHCO3 ----> RCO2-Na+ + H2O + CO2 

2) Reduction:

     RCO2H + LiAlH4 --- (1) Et2O -- (2) H2O ---->  RCH2OH 

3) Conversion to acyl chlorides:

     RCO2H  -----SOCl2  or  PCl5 ---->  RCOCl 

4) Conversion to esters (Fischer esterfication):

     RCOOH  +  R'-OH   <--- HA --->   RCOOR'  + H2O 

5) Conversion to amides:

     RCO2H  -----SOCl2  or  PCl5 ---->  RCOCl  +  NH3  <------>  RCOO-NH4+  --- heat ---> R-CONH2 + H2O 

6) Decarboxylation: (Note: you need a doubly-bonded oxygen (carbonyl) two carbons away for this reaction to work)

     RCOCH2COOH   --- heat --->  R-COCH3  +  CO2      HOCOCH2COOH  --- heat --->  CH3COOH  +  CO2 

Acyl Chlorides

1) Conversion to acids:

     R-COCl  +  H2O  ----> R-COOH  +  HCl 

2) Conversion to anhydrides:

     R-COCl  +  R'COO-  ---->  R-CO-O-COR'  +  Cl- 

3) Conversion to esters:

     R-COCl  +  R'-OH  --- pyridine --->  R-COOR'  +  Cl-  +  pyr-H+ 

4) Conversion to amides:

     R-COCl  +  R'NHR" (excess)  ---->  R-CONR'R"  +  R'NH2R"Cl 

R' and/or R" may be H

5) Conversion to ketones:

Friedel-Crafts acylation

     R-COCl  +  C6H6  --- AlCl3 --->  C6H5-COR 

Reaction of Dialkylcuprates (also known as a Gilman reagent)

     R-COCl  +  R'2CuLi  ---->  R-CO-R' 

6) Conversion to aldehydes:

     R-COCl  +  LiAlH[OC(CH3)3]3  --- (1) Et2O   (2) H2O  --->  R-CHO 

Acid Anhydrides

1) Conversion to acids:

     (R-CO)2-O  +  H2O  ---->  2 R-COOH 

2) Conversion to esters:

     (R-CO)2-O  +  R'OH  ----> R-COOR'  +  R-COOH 

3) Conversion to amides:

     (R-CO)2-O  +  H-N-(R'R")  ----> R-CON-(R'R")  +  R-COOH 

R' and/or R" may be H.

4) Conversion to aryl ketones (Friedel-Crafts acylation):

     (R-CO)2-O  +  C6H6  --- AlCl3  C6H5-COR  + R-COOH 

Esters

1) Hydrolysis:

      R-COOR'  +  H2O  <--- HA --->   R-COOH  +  R'-OH       R-COOR'  +  OH-  ---->  RCOO- +  R'-OH 

2) Transesterification (conversion to other esters):

      R-COOR'  + R"-OH  <--- HA --->  R-COO-R"  +  R'-OH 

3) Conversion to amides:

      R-COOR'  + HN-(R"R"')  ---->  R-CON-(R"R"')  + R'-OH 

R" and/or R"' may be H

4) Reaction with Grignard reagents:

     R-COOR'  +  2 R"MgX  --- Et2O --->  R-C-R"2OMgX  +  R'OMgX  ---> H3O+   R-C-R"2OH 

The intermediate and final product is a tetrahedral carbon with two R" attached directly to the carbon along with R and OH/OMgX

X = halogen.

5) Reduction:

     R-COOR'  +  LiAlH4  --- (1) Et2O  (2) H2O --->  R-CH2OH  +  R'-OH 

Amides

1) Hydrolysis:

     R-CON(R'R")  +  H3O+   --- H2O --->  R-COOH  +  R'-N+H2R"      R-CON(R'R")  +  OH-   --- H2O --->  R-COO-  +  R'-NHR" 

R,R' and/or R" may be H.

2) Dehydration (conversion to nitriles):

     R-CONH2   --- P4O10, heat, (-H2O) --->  R-CN 

[edit] Nitriles

1) Hydrolysis:

    R-CN  --- H3O+,heat ---> RCOOH     R-CN  --- OH-,H2O,heat ---> RCOO- 

2) Reduction to aldehyde:

    R-CN  --- (1) (i-Bu)2AlH  (2) H2O  --->  R-COH 

(i-Bu)₂AlH = DIBAL-H

3) Conversion to ketone (by Grignard or organolithium reagents):

    R-CN  +  R"-M  --- (1) Et2O  (2)  H3O+ --->  R-COR" 

M = MgBr (Grignard reagent) or Li (organolithium reagent)

Mechanisms

A common motif in reactions dealing with carboxylic acid derivatives is the tetrahedral intermediate. The carbonyl group is highly polar, with the carbon having a low electron density, and the oxygen having a high electron density. With an acid catalyst, a H+ is added to the oxygen of the carbonyl group, increasing the positive charge at the carbon atom. A nucleophile can then attack the carbonyl, creating a tetrahedral intermediate.

For example, in Fischer esterification, the mechanism can be outlined thus: 1) H+ is added to carbonyl oxygen 2) Oxygen atom of the alcohol adds to the carbonyl carbon 3) Proton transfer from alcohol oxygen to carboxyl oxygen 4) Water molecule ejected from tetrahedral intermediate, double bond forms, recreating the carbonyl 5) H+ is removed from carbonyl oxygen

Homo-Lumo Interactions

A fundamental principle: all steps of all heterolytic reaction mechanisms are either Bronsted or Lewis acid-base reactions

• They involve either proton transfer (Bronsted), or unshared pair/empty orbital interactions (Lewis).

• When the interacting atomic orbitals are considered, the Bronsted reactions can be seen as simply a special case of the Lewis, in which the empty orbital is the antibonding orbital of the H-X bond.

In short, all heterolytic reactions are just examples of interactions between filled atomic or molecular orbitals and empty atomic or molecular orbitals - that is, Lewis acid-base reactions. Here is a diagram to explain this point:

The interaction of any two atomic or molecular orbitals, as you learned in general chemistry, produces two new orbitals.

• One of the new orbitals is higher in energy than the original ones (the antibonding orbital), and one is lower (the bonding orbital).

• When one of the initial orbitals is filled with a pair of electrons (a Lewis base), and the other is empty (a Lewis acid), we can place the two electrons into the lower energy of the two new orbitals.

• The "filled-empty" interaction therefore is stabilizing.

When we are dealing with interacting molecular orbitals, the two that interact are generally

• The highest energy occupied molecular orbital (HOMO) of one molecule,

• The lowest energy unoccupied molecular orbital (LUMO) of the other molecule.

• These orbitals are the pair that lie closest in energy of any pair of orbitals in the two molecules, which allows them to interact most strongly.

• These orbitals are sometimes called the frontier orbitals, because they lie at the outermost boundaries of the electrons of the molecules.

Here is the filled-empty interaction redrawn as a HOMO-LUMO interaction.

Let's look at some examples. First, a reaction that you would have categorized as a Lewis acid-base reaction when you were studying general chemistry:

NH₃ has an unshared pair on nitrogen, occupying the HOMO (it is generally true that unshared pairs occupy HOMOs). BH₃ has an empty valence orbital on B, since B is a Group II element. This is the LUMO.

Here are pictures of the two orbitals from AM1 semi-empirical molecular orbital calculations:

NH3 HOMO	BH3 LUMO

The HOMO-LUMO energy diagram above describes the formation of a bond between N and B.

Now let's try a slightly more complex case. Here's a typical Bronsted acid-base reaction:

The curly arrows track which bonds are made, and which are broken, but they do not indicate what orbitals are involved.

• Water is both a Bronsted base (capable of accepting a proton) and a Lewis base, with one of its unshared pairs (the HOMO).

• H-Cl is a Bronsted acid, capable of donating a proton, but it also is a Lewis acid, using the s* orbital of the H-Cl bond (the LUMO).

• Here are pictures of the relevant HOMO and LUMO, again from AM1 semi-empirical molecular orbital calculations:

  H2O HOMO	HCl LUMO

• The interaction stabilizes the unshared pair of the oxygen, while simultaneously breaking the H-Cl bond because the interaction is with the antibonding orbital.

Another example is the S_N2 reaction, which involves the HOMO of the nucleophile and the s* orbital of the R-X bond:

Here are the relevant orbitals:

OH- HOMO	CH3-Cl LUMO

The interaction stabilizes the unshared pair of the oxygen, while simultaneously breaking the CH₃-Cl bond because the interaction is with the antibonding orbital.

Other examples include the reaction of alkenes with H-X, where the HOMO is the p MO of the alkene and the LUMO is the H-X s* orbital:

and the capture of the carobcation in an SN1 reaction by nucleophile:

You should need no reminder that the carbocation is stabilized by a filled-empty interaction between the empty p orbital of the positive carbon and the s orbital of an adjacent C-H or C-C bond

In short, all heterolytic reactions proceed because the energy of a pair of electrons is lowered by the interaction of a filled atomic or molecular orbital with an empty one.

The same reasoning can be appllied to bimolecular pericyclic reactions like the Diels-Alder cycloaddition.

Homo and Lumo for acid and base lewis

In 1923, G. N. Lewis (yes, the Lewis structure guy) suggested a way of describing a number of reactions that did not fit the Bronsted definition of acid-base reactions, yet seemed to have some unifying structural features.

He suggested:

• A base is any species with an unshared pair of electrons; examples are:

  

• An acid is any species lacking an octet; examples are:

  

This definition allows us to write acid-base reactions like these:

• 

Several things about these reactions:

• They are charge balanced - that is the total charge of all species is the same on both sides of the equations

• The red arrows are used to show how the bond between acid and base is formed
  • The tail of the arrow rests on a pair of electrons

  • The arrow points to where those electrons will be in the product

• The product is sometimes described as a Lewis "complex"

Giles Klopman points out that:

• The acid-base nomenclature is easy to confuse with Bronsted nomenclature

• Reactions like

  

  are a little confusing viewed as the acid (FeCl₃) being a species lacking an octet - Fe³⁺ is 4s², 3d⁴; and three Cl^- add six electrons to give a neutral species.

He suggested that all of these reactions be viewed as involving the interaction of a filled atomic or molecular orbital on the base, and an empty atomic or molecular orbital on the acid, regardless of the octet rule.

• The filled orbital would be the highest energy occupied molecular orbital, the HOMO

• The empty orbital will be the lowest energy unoccupied molecular orbital, the LUMO

• Then we refer to the reaction simply as a "filled-empty" interaction, or a HOMO-LUMO interaction

Here is this idea pictured in orbital terms:

Look at the formation of a molecule of hydrogen. Here are two H atoms, each with an electron, forming a molecule:

>

Each atom brings an electron.

• The interaction of their 1s orbitals creates two molecular orbitals (MOs)

• Put the two electrons in the lower energy orbital, just like building up atomic electron configurations in GenChem.

This is absolutely general:

• When any two orbitals combine, two new orbitals are produced, one higher in energy than either of the originals, and one lower

• These new orbitals are filled with the available electrons, starting with the lowest energy one (just like the aufbau principle from GenChem)

• This is why the reaction occurs! A pair of electrons moves to lower energy.

• If both species had a pair of electrons, the higher energy new orbital would have to be filled also; this is why He₂ doesn't exist

Now suppose we bring together a proton, H⁺, with no electrons, and a hydride ion, H^-, with two electrons. The proton is a Lewis acid, and the hydride ion is a Lewis base!

Again, the process occurs because the energy of a pair of electrons is lowered.

In general, the HOMO and the LUMO will not move up or down by the same amount, and the energy diagram will look more like this:

Every step of every reaction we write can be described as a filled-empty orbital interaction! Each step proceeds because a pair of electrons moves to lower energy.

Finally, let's demonstrate that all acid base reactions are really Lewis acid-base reactions.

Here's a typical Bronsted acid-base reaction:

The curly arrows track which bonds are made, and which are broken, but they do not indicate what orbitals are involved.

• Water is both a Bronsted base (capable of accepting a proton) and a Lewis base, with one of its unshared pairs (the HOMO).

• H-Cl is a Bronsted acid, capable of donating a proton, but it also is a Lewis acid, using the s* orbital of the H-Cl bond (the LUMO).

Here are pictures of the relevant HOMO and LUMO, from AM1 semi-empirical molecular orbital calculations:

H2O HOMO	HCl LUMO (antibonding)

The interaction stabilizes the unshared pair of the oxygen, while simultaneously breaking the H-Cl bond because the interaction is with the antibonding orbital.

Enantiomer

Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light (+/−) by equal amounts but in opposite directions (although the polarized light can be considered an asymmetric medium). A mixture of equal parts of an optically active isomer and its enantiomer is termed racemic and has zero net rotation of plane-polarized light.

Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the body of living beings are enantiomers themselves, there is often a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects (unwanted side effects).

Owing to this discovery, drugs composed of only one enantiomer ("entantiopure") can be developed to enhance the pharmacological efficacy and sometimes do away with some side effects. An example of this kind of drug is eszopiclone (Lunesta), which is enantiopure and therefore is given in doses that are exactly 1/2 of the older, racemic mixture called zopiclone. In the case of eszopiclone, the S enantiomer is responsible for all the desired effects, though the other enantiomer seems to be inactive; while an individual must take 2 mg of zopiclone to get the same therapeutic benefit as they would receive from 1 mg of eszopiclone, that appears to be the only difference between the two drugs, and this may be an example of a pharmaceutical company taking advantage of laws that allow them to be issued a brand new patent for the enantiopure version of an existing drug. This leads to a great deal of profit that would otherwise be cut into by generics, as patents on zopiclone expired long ago and it is therefore available in generic form.

Diastereomer

Diastereomers (sometimes called diastereoisomers) are stereoisomers that are not enantiomers.^[1] Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter they are epimers. Each stereocenter gives rise to two different configurations and thus to two different stereoisomers.

Diastereomers differ from enantiomers in that the latter are pairs of stereoisomers which differ in all stereocenters and are therefore mirror images of one another.^[3] Enantiomers of a compound with more than one stereocenter are also diastereomers of the other stereoisomers of that compound that are not their mirror image. Diastereomers have different physical properties and different reactivity, unlike enantiomers.

Cis-trans isomerism and conformational isomerism are also forms of diastereomerism.

Diastereoselectivity is the preference for the formation of one or more than one diastereomer over the other in an organic reaction.

Example

Tartaric acid contains two asymmetric centers, but two of the "isomers" are equivalent and together are called a meso compound. This configuration is not optically active, while the remaining two isomers are D- and L- mirror images, i.e., enantiomers. The meso form is a diastereomer of the other forms.

(natural) tartaric acid L -(+)-tartaric acid dextrotartaric acid	D-(-)-tartaric acid levotartaric acid	mesotartaric acid
(1:1) DL -tartaric acid "racemic acid"

The families of 4, 5 and 6 carbon carbohydrates contain many diastereomers because of the large numbers of asymmetric centres in these molecules.