Laboratory Synthesis

As we have seen, creatine is synthesized in the body from three amino acids—glycine, arginine, and methionine.  Creatine may also be made in the laboratory from N-methylglycine (sarcosine) and cyanamide, as shown below[1].

In fact, this reaction is a common method for the commercial preparation of the form of creatine—creatine monohydrate—used in supplements[2,3].

How does this reaction work, and what is its mechanism?  We can apply our understanding of AMINE AND NITRILE CHEMISTRY to predict the first step of this reaction.  Note that the common structural features are shown in blue.

We have just applied what we learned about the reaction between acetonitrile and ethylamine (in AMINE AND NITRILE CHEMISTRY) to predict the first step of the reaction between cyanamide and sarcosine to form creatine.  This first step results in the formation of a charged intermediate:

The remaining two steps in the synthesis of creatine are proton transfer steps that show how the neutral creatine product is formed.  Let’s see how these steps occur.

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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

Brønsted-Lowry acid: a substance that donates a hydrogen ion (proton; H+) to a base; a proton (H+) donor

Brønsted-Lowry base: a substance that accepts a hydrogen ion (proton; H+) from an acid; a proton (H+) acceptor

Lewis acid: a substance that accepts a pair of electrons from a base; an electron pair acceptor

Lewis base: a substance that donates a pair of electrons to an acid; an electron pair donor

Arrhenius acid: a substance that produces hydrogen ions (protons; H+) when dissolved in water

Arrhenius base: a substance that produces hydroxide ions (OH-) when dissolved in water

References

[1] Smith, Andri L.; Tan, Paula. “Creatine Synthesis: An Undergraduate Organic Chemistry Laboratory Experiment.” J. Chem. Educ., 2006, 83(11), 1654-1657.
[2] Williams, Melvin H.; Kreider, Richard B.; Branch, J. David. Creatine: The Power Supplement; Human Kinetics: Champaign, IL, 1999; pp 42-43.
[3] Brudnak, Mark A. “Creatine: Are the Benefits Worth the Risk?” Toxicol. Lett., 2004, 150, 123-130.
[4] Greenaway, W.; Whatley, F. R. “A Convenient Synthesis of Creatine-15N from Glycine-15N via Sarcosine-15N.” J. Labelled Compounds & Radiopharmaceuticals, 1978, 14(4), 611-615.