Coupling Reactions

Coupled Reactions are Defined As?

What is a coupling reaction?

Let's consider a chemical reaction, in which two reactants, A and B, combine to form two products, C and I :

$$A+B \rightleftarrows C+I$$

Notice that the reaction is reversible. This reaction can be forced to proceed on to produce other products if the species, I, which we will refer to as the intermediate, is consumed by a subsequent reaction.

$$I+D \rightleftarrows E+F$$

Now, let's form a longer reaction chain in which the product, I, now becomes an intermediate of the reaction and in turn reacts with another reactant, D, leading to the formation of products, E and F, down the reaction chain:

Figure 1: Reaction Chain

Let's say that the Gibbs free energy for the first part of the reaction is greater than zero, ΔG > 0. Then, this part of the reaction is thermodynamically unfavorable because, ΔG > 0, is positive for this reaction. What this means is that this part of the reaction is nonspontaneous, or that the reaction will move to products' side only with the input of free energy.

Notice that the intermediate, I, couples the two reactions. This is what we mean by coupling reaction - an intermediate, I, goes from being a product in a previous reaction to being a reactant in the next reaction down a chain of reactions. In many cases, coupled reactions utilize a thermodynamically favored reaction to propel an unfavorable reaction.

Coupling Reaction Example

Now, let's consider the following reaction which produces iodide, I ^-, from hydrogen peroxide, H₂O₂, and sulfuric acid, H₂SO₄. First, an aqueous solution containing hydrogen peroxide, sulfuric acid and starch are prepared. In another beaker, an aqueous solution of iodine and thiosulfate is prepared. Then the two solutions are mixed:

Figure 2: Iodine clock reaction

First, we note that sulfuric acid is the source of the two acidic protons, H ⁺, on the left-hand side of the first reaction. Also notice, in the above reaction that iodine, I₂, is an intermediate from the first reaction. In the second reaction, the intermediate is iodide, I ^-, which in turn becomes one of the reactants for the first reaction. In particular, in the second reaction, iodine is reconverted to iodide, I ^-, by thiosulfate, S₂O₃^2-. When the thiosulfate, S₂O₃^2-, is exhausted the reaction stops.

Starch is added to the reaction at the very beginning as a color indicator that turns dark blue in the presence of a sufficient amount of iodide, I ^-.

Why are these coupled reactions called iodine clock reactions? The reaction is known as a clock reaction because the concentrations of the initial ingredients affect how long it takes for the solution to turn dark blue.

When the solutions are mixed the two reactions occur simultaneously. The first reaction for the iodine clock reaction is much slower than the second reaction. As a result, the second reaction causes the iodine, I₂, to be consumed faster than it is produced. The delay experienced by thiosulfate, S₂O₃^2-, as it waits around for more iodine to be produced in the first reaction is the cause of the delay observed for the starch to turn dark blue.

Cross-Coupling Reactions

Now, let's talk about cross-coupling reactions. But, first, you need to become familiar with the following terms:

What is the role of ATP in coupled reactions?

• Adenosine Tri-Phosphate (ATP) is an important biochemical.

• Your body runs off of the energy released during the hydrolysis of the ATP.

• The synthesis of ATP is catalyzed by a variety of enzymes in your body.

• In fact, your body produces and hydrolyzes approximately your own body weight in ATP every single day in an effort to maintain life

The hydrolysis of adenosine tri-phosphate (ATP), is an example of a cross-coupling reaction.

Let's consider the Gibbs free energy change associated with the hydrolysis of ATP. The Gibbs free energy equation is applied to thermodynamic systems that are at chemical equilibrium and also at constant temperature and pressure. Mathematically:

$$G=H-TS$$

Where the Gibbs free energy is G, the enthalpy is H, the system temperature is T, and the system entropy is, S. As with the enthalpy H, the Gibbs free energy and the system entropy cannot be measured directly. It is only the difference in the Gibbs free energy that can be measured for any system:

$$\Delta{G}=\Delta{H}-T\Delta{S}$$

Where the Gibbs free energy difference is ΔG, the enthalpy difference is ΔH, the system temperature is T, and the system entropy difference is ΔS. For the details please see the article "Gibbs free energy".

Consider the hydrolysis of ATP:

$$ATP+H_2O \rightarrow ADP-OH+P_i+H^+$$

where products are adenosine di-phosphate, ADP-OH , inorganic phosphate, P_i , and a hydronium ion, H⁺. The Gibbs free energy released during this reaction is:

$$\Delta{G}=-31\frac{kJ}{mol}$$

Now you may ask, "How do energy carriers participate in coupled reactions?" The intermediates that couple reactions are the energy carriers that act by moving from one reaction to another down a chain of reactions.

Figure 3: Glycolysis coupled to protein synthesis.

As shown in the above example the thermodynamics of hydrolysis of ATP is centrally important to life itself. Thermodynamics shows that the hydrolysis of ATP releases a large amount of free energy that is used by the body to drive metabolic reactions that maintain the life.

Amine Coupling Reaction

What is an amine cross-coupling reaction? An amine cross-coupling reaction consists of a reaction between an amine and an organic molecule:

• An organic molecule is a carbon-based molecule.

• An amine is an organic molecule that contains an amino group, -NH₂.

• In organic chemistry, typical amine cross-coupling reactions involve the combination of two organic molecules usually catalyzed by an organometallic catalyst.

A widely used method to produce pharmaceutically useful starting materials uses a series of reactions based on Buchwald-Hartwig amination.

But, what is Buchwald-Hartwig amination?

• Buchwald-Hartwig amination involves two fragments coming together in an amine cross-coupling reaction.

• The two organic molecules are usually an aryl halide and an amine.

• The catalyst used in this type of amine cross-coupling reaction is usually an organometallic palladium-based catalyst.

• The Buchwald-Hartwig animation reaction uses a palladium-base catalyst to increase the rate of a cross-coupling reaction between aryl halides and amines resulting in the formation of a carbon-nitrogen (-C-N-) bond.

Now, let's consider a specific example of the Buchwald-Hartwig amination reaction, where an aryl-bromide (reactant) produces an aryl-tertiary amine (product):

Figure 5: Buchwald-Hartwig amination reaction.

Where, the various parts are:

Figure 6: Functional groups, Buchwald-Hartwig amination reaction

The overall reaction mechanism for this cross-coupling reaction, which is quite complex (we will not cover all the details), involves the following catalytic cycle:

Figure 7: Catalytic cycle, Buchwald-Hartwig amination reaction.

Let's consider only the compounds marked by colored squares. The black square corresponds to the following complex:

Figure 8: Palladium complex in Buchwald-Hartwig amination reaction

Here, we notice that the reactive palladium metal centers, Pd, are surrounded by functional groups that block access to these reactive atoms. This property of blocking pathways to reactive centers is called steric hindrance. We notice further that once this complex enters into an equilibrium, \(L_2Pd(X_2)_2PdL_2 \leftrightarrows L_2Pd \leftrightarrows LPd\), where:

Figure 9: Expanded formulas of Pd compounds in equilibrium

As we move clockwise along the catalytic cycle, see the addition of the aryl-bromide to the palldium catalyst:

Figure 10: Expanded formula of aryl-bromide

As we move further clockwise along the catalytic cycle we see the addition of the following base which acts as nucleophile that extracts a proton from the catalytic complex:

Figure 11: Expanded formula of base

Lastly, the addition of the base results in the synthesis of the final product:

Figure 12: Expanded formula of final product

Ullmann Coupling Reaction

The Ullman coupling reaction is a copper-catalyzed cross-coupling reaction between two iodobenzene molecules. An iodobenzene is a benzene ring bonded to an iodine atom. Condensation products are formed are between the iodo-benzene molecules. Thus, Iodobenzene, can react with another iodobenzene, in the presence of a copper-based catalyst, to form the condensation product, bi-phenyl.

Figure 13: An example of the Ullmann coupling reaction.