Creatine Case Study

Case Study

History

Learning Goals /
Concept Map

Creatine and Related Compounds

Structure

Amino Acids

Creatine in the Body

Equilibrium

Creatine-Creatinine Equilibrium

Creatinine Test for Kidney Function

Detection

Regulation and Ethics

Laboratory Synthesis

Chemical Analysis

Creatine-Phosphocreatine Equilibrium

Uses & Side Effects



Amine and Nitrile Chemistry

Nitriles and amines are two organic functional groups containing the element nitrogen. As we will see in LABORATORY SYNTHESIS, an amine and a nitrile may be combined to make creatine in the laboratory. Let’s examine these two functional groups more closely so that we may better understand how this reaction works.

Amines

Amines, such as ethylamine, contain a nitrogen atom with a lone pair of electrons.

Nitriles

Nitriles, such as acetonitrile (systematic name: ethanenitrile), contain a functional group in which a carbon atom is connected to a nitrogen atom by a triple bond. 

To understand the chemistry of nitriles, it is useful to consider the polarity of the carbon-nitrogen bond.  We determine bond polarity by examining electronegativity values, such as those from the scale developed by Linus Pauling.


(Bruice, Organic Chemistry, 3rd ed., Prentice Hall: Upper Saddle River, NJ, 2001, p. 10)

When two atoms in a bond have similar electronegativity values (that is, when the difference in electronegativity values is 0.4 or less), the atoms in the bond share the electrons equally (or close to equally), and the bond is nonpolar covalent (also called nonpolar).  However, if one atom in the bond has a greater “pull” for the electrons, the bond is polar covalent (also called polar).  This occurs when the difference in electronegativity values falls between approximately 0.5 and 2.0.  When the electronegativity difference between the two atoms in a bond is greater than 2.0, the bond is ionic.  (Please note that the electronegativity differences used for these definitions are approximate.)

Amines v. Nitriles

If we generalize our answers to the above questions, we see that an amine—because of its lone pair of electrons—acts as a nucleophile in a polar reaction.  But why does a nitrile, which also has a lone pair of electrons, not act as a nucleophile?  It is all a matter of degrees….

We have seen that we can use pKa to determine relative acidity and basicity of two ions or molecules.  Also, because nucleophilicity roughly parallels basicity when comparing nucleophiles with the same reacting atom, we can infer the relative nucleophilicity of two nitrogen-containing molecules.  As a result, we have seen that ethylamine is a stronger nucleophile than acetonitrile.  Let’s use this information to suggest a mechanism for the reaction between ethylamine and acetonitrile.

We have seen that a nitrile—because of its polarized CºN bond—acts as an electrophile.  But why does an amine, which also has a polarized C—N bond, not act as an electrophile?  Let’s answer this question by considering the mechanism that would occur if acetonitrile were the nucleophile and ethylamine were the electrophile.

Summary

Our answers to the previous two questions show that acetonitrile, due to its available electron lone pair on nitrogen, is a potential nucleophile, and that ethylamine, due to its polarized C—N bond, is a potential electrophile.  However, the resulting reaction would require that amide ion (NH2–) be a leaving group.  NH2–, a strong base, is the conjugate base of a very weak acid (NH3) and is therefore a very poor leaving group.  So, while it is possible for acetonitrile to act as a nucleophile and ethylamine to act as an electrophile, it is much more likely for acetonitrile to be the electrophile and ethylamine to be the nucleophile, ultimately resulting in the product below.

In short, it is all a matter of degrees.  Amines can act as electrophiles, and nitriles can act as nucleophiles, but in a reaction between an amine and a nitrile, the amine is more nucleophilic, and the nitrile is more electrophilic

The last two steps of this reaction show how the final, neutral product is formed.  We will examine these steps of the mechanism in a similar system, the reaction of sarcosine and cyanamide to form creatine.  Please go to LABORATORY SYNTHESIS.

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Definitions

nucleophile:   a “nucleus-loving”, electron-rich atom or molecule containing a reactive pair of electrons that is donated to an electron-poor atom or molecule to form a new covalent bond; a Lewis base

electrophile:  an “electron-loving”, electron-poor atom or molecule that accepts a pair of electrons from an electron-rich atom or molecule to form a new covalent bond; a Lewis acid

electronegativity:   the pull of electron density between atoms in a covalent bond; the ability of an atom to attract electrons in a covalent bond

nonpolar covalent, or nonpolar:   a type of bond in which electrons are shared equally or approximately equally; occurs when the electronegativity values of the atoms in the bond are the same or similar

polar covalent, or polar:  a type of bond in which one atom has a greater pull on the electron pair than the other atom, resulting in electrons that are not shared equally between the two bonding atoms

ionic:  a type of bond in which an electron is transferred from one atom (usually a metal) to another (usually a nonmetal), resulting in two charged species, or ions