Suppose that we take a bite out of an apple. How do you think your body digests and absorbs the nutrients in that sweet morsel? It turns out that a long series of coupled reactions extract all the nutrients available in that bite. These reactions work together to transport this energy along another long chain of reactions that metabolize the energy into useful work. Coupled reactions drive the energy force that keeps you alive.
Just think of it, coupled chemical reactions are the heart of the engine that sustains life itself. If you would like to know about this important phenomenon continue by reading the article below.
- Coupled Reactions are Defined As? - In this section, we will introduce a hypothetical coupled reaction.
- Coupling Reaction Example - In this section, we go over the iodine clock reaction.
- Cross-Coupling Reactions - Here we go over the relationship between cross-coupling reactions, free energy and ATP.
- Amine Coupling Reaction - Here we go over a diazo coupling reaction.
- Ullman Coupling Reaction - Here we go over a copper-catalyzed cross-coupling reaction.
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.
$$I+D \rightleftarrows E+F$$
Gibbs Free Energy, G - this is energy, typically in the form of heat, that a system has available to do work, such as initiate a chemical reaction at constant temperature and pressure.
Coupled Reaction - occurs when 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.
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, S2O32-. When the thiosulfate, S2O32-, 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, S2O32-, 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:
Catalyze (Enzymatic Catalysis) - the increase in the rate of a biochemical reaction that is carried out by an enzyme.
Enzyme - proteins in living systems that facilitate biochemical reactions.
Hydrolysis - the chemical breakdown of a molecule by the action of water.
Metabolism - life processes that involve biochemical reactions that sustain the living state.
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
Chemical Driving Force - the force that causes a chemical reaction. All chemical reactions involve a force that drives the system to chemical equilibrium.
Enthalpy (Enthalpy of formation) - this thermodynamic quantity is equivalent to the potential energy that is stored as heat within the chemical bonds of a compound.
Entropy - a measure of a thermodynamic system's molecular disorder.
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, Pi , 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.
Catalyst - a substance that causes a reaction to go from reactants to products faster. Catalysts increase the rate of reactions.
Organometallic Catalyst - a metal-based catalyst that contains one or more metal atoms in its center while being surrounded by organic molecules which act to hinder access to the reactive metal center.
Amine - a functional group (a fragment on a molecule that consists of either, -NH2 (primary amine), NHR (secondary amine, where the, -R group, is an alkyl group, or -NR2 (tertiary amine). Amination is the addition of an amine group, -NH2, to an organic molecule.
Functional Group - a grouping of atoms on a molecule that is responsible for the reactivity of that molecule in a given reaction.
Alkyl Group - a functional group with any combination of the following structures:
Figure 4: Alkyl functional groups.
where the R groups can be any combination of the same or different alkyl groups and, n ≥ 1.
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.
Organometallic Palladium-based Catalyst - a catalyst that contains one or more palladium atoms in its center while being surrounded by organic molecules which act to hinder access to the reactive metal center.
Aryl Halide - a molecule consisting of a six-carbon ring, containing alternating single and double bonds that can exchange with one another, which is bonded to a halogen (chlorine, bromine, iodine) atom.
Nucleophile - an atom on a molecule that reacts by sharing a pair of electrons with an electron-deficient atom on another molecule.
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.
Coupled Reactions - Key takeaways
- A coupled reaction is one in which one or more, intermediates couple together two, or more, reactions.
- A catalyst increases the rate of a reaction.
- Gibbs Free Energy - a measure of a thermodynamic system's ability to cause change within a system. This change, or useful work, can take the form of the driving force of a chemical reaction, a change in phase, a change in the heat absorbed by the system, etc.
- Your body runs off of the energy released during the hydrolysis of the ATP.
- The intermediates that couple reactions are the energy carriers that act by moving from one reaction to another down a chain of reactions.
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, can then be displaced by a variety of nucleophiles.
