Amino Acids: Creating Your Own

When someone hears the words amino acid, one of their first thoughts is biology.  Throughout high school and during my first college science class I remember discussing how amino acids are important biologically because they make up the proteins in our bodies.  In organic chemistry I am looking at amino acids in a totally new way.  Now, I do not study how they effect me biologically, but rather I have to look at there nomenclature, how they are synthesized, and how they bond together with other amino acids.

Naturally occurring amino acids have an amino group bonded to an alpha carbon of a carboxy group.  Therefore, they take on the name alpha-amino acids.  There are 20 naturally occurring amino acids that make up different proteins.  They all differ in the R group (side chain) that is bonded to the alpha carbon.  All amino acids, except glycine, have a stereogenic center on the alpha carbon.  A general alpha amino acid is shown below in Figure 1 (1).

                                                  Figure 1: Alpha-Amino Acid

There are three classifications of amino acids.  Acidic amino acids are any amino acids with an additional COOH group in the side chain.  Basic amino acids are those with an additional basic N atom on the side chain, and all other amino acids are considered neutral (1).     

For this blog, I was asked to think outside of the box.  I was asked to create an artificial amino acid that contained at least six carbons.  For me, personally, this was a hard task.  I am a very structured person so I lack creativity.  First I looked at the 20 naturally occurring amino acids to make sure I did not duplicate an already existing amino acid.  With the help of ChemSketch, I finally came up with the neutral amino shown in Figure 2.

 

(2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid

  

Figure 2: Artificial Amino Acid

My next task was to figure out a synthesis for the artificial amino acid I created.  I used my organic chemistry textbook (1) as my main resource.  It describes three different methods but states there are other various ways to prepare amino acids in a laboratory.  The method that I chose to "hypothetically" synthesize my artificial amino acid was the Strecker Synthesis.  This synthesis converts an aldehyde into an amino acid by adding one carbon atom to the aldehyde carbonyl via a two-step sequence.  The aldehyde is treated with NH4Cl and then NaCN which forms an alpha-amino nitrile.  The mechanism of this reaction is shown in Figure 3.  Then the alpha-amino nitrile is hydrolyzed in aqueous acid to the amino acid (1).  The synthesis reaction of (2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid is shown in Figure 4.  A "CN" (cyanide) should be where the "A" atom, for lack of knowledge using ChemSketch to draw the structures.  

                                           Figure 3: Mechanism of Alpha- Amino Nitrile

                              Figure 4: Synthesis of (2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid
                                                       

Peptides are larger molecules that are formed by joining amino acids together with amide bonds (1).  My last challenge was creating a pentapeptide structure with the form of CGXHA.  For those people unfamiliar with abbreviations a key is below, followed by the pentapeptide structure I created. 

Key:
C-Cysteine
G-Glycine
X-Artificial Amino Acid Created
H-Histidine
A-Alanine

   

                                            Figure 5: Pentapeptide Structure

I am sure the next time I hear the words amino acids I will have a flashback to my high school biology class.  However; I will also have deeper understanding of amino acids overall instead of just knowing they form the proteins in my body.  Even though this blog was somewhat of a challenge making me step outside of my comfort zone, I believe it was beneficial in helping me learn and grow as an individual and as a student. 

    References:

1)      Smith, J. Organic Chemistry, 3^rd ed.; McGraw-Hill: New York, 2011.

Electrophilic Aromatic Substitution: From a Biological Standpoint

          In an electrophilic aromatic substitution reaction, an electrophile attacks the aromatic ring and replaces one of the hydrogen atoms.  All reactions occur via a two-step mechanism, regardless of the electrophile.  The first step a carbocation is formed by the addition of the electrophile.  In the second step, the aromatic ring is re-formed when there is a loss of a proton.  The general mechanism is shown in Figure 1 (1). 

     



                              Figure 1

Five examples of electrophilic aromatic substitutions is shown in Figure 2 (1).
 

                   Figure 2


A substituent group affects the electrophilic aromatic substitution in two ways: the rate of the reaction and the orientation.  If a substituent activates a benzene ring, such as an alkyl group, then substitution is directed ortho and para.  If a substituent deactivates a benzene ring, such as a nitro group, then substitution is directed meta (1).     

The purpose of this blog post was to research and find out how electrophilic aromatic substitutions are used in a biological sense.  After searching the internet, it was quickly noted that many of these reactions take place in enzyme pathways.  However, they are also used in synthesis of many different drugs. 

An example of a drug synthesized using electrophilic aromatic substitution is 2-(4-isobutylphenyl)propanoic acid, most commonly known as ibuprofen (2).  Isobutylbenzene first undergoes a Friedel-Crafts acylation to produce a ketone.  The alkyl group directs the substitution to ortho and para positions; para dominates because of the size of the electrophile.  This ketone is then reduced using borohydride, which creates an alcohol.  Nucleophilic substitution then takes place using HBr, replacing the OH group with Br.  This product then reacts with NaCN in a nucleophilic substitution reaction to replace the Br with CN.  Finally, an acid-cataylized reaction using sulfuric acid hydrolyzes the nitrile group to a carboxylic acid.  Thus the final product of ibuprofen is formed.  The mechanism of this synthesis is shown in Figure 3 (3).

   















                                Figure 3


In conclusion, electrophilic aromatic substitutions are common in laboratory synthesis and within biological pathways.  They have a profound impact within everyday use, even though one might not realize it.  In the synthesis of ibuprofen, the very first step is an electrophilic aromatic substitution.  These reactions are important because they produce products that can then undergo other substitutions that will yield the desired compound.  As technology advances scientists will be able to learn even more knowledge about these type of reactions, specifically in these two areas.               

References

1) Smith, J. Organic Chemistry, 3rd ed.; McGraw-Hill: New York, 2011.

2) Sigma Aldrich. Ibuprofen. http://www.sigmaaldrich.com/catalog/product/sigma/i4883?lang=en&  
 region=US (accessed Mar 12, 2014)

3) Dewick P. Essentials of Organic Chemistry: For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry. John Wiley & Sons Ltd: West Sussex, 2006