Structural Biochemistry/Organic Chemistry
The science of studying carbon-containing molecules is known as organic chemistry. One of the properties of the carbon atom that makes life possible is its ability to form four covalent bonds with other atoms, including other carbon atoms. This binding ability with comes from having four electrons in the carbon’s outer shell, causing it to need four additional electrons for its outer shell to be full.
Role of Carbon in organic chemistry
In living organisms, carbon atoms most commonly form covalent bonds with other carbons and with hydrogen, oxygen, nitrogen and sulfur atoms. Bonds between two carbon atoms, between carbon and oxygen, or between carbon and nitrogen can be single or double in organic compounds. Bonds of a higher order between these atoms can be found in inorganic compounds however. The combination of carbon with itself and with different elements and different types of bonds allows a vast number of organic compounds to be formed from only a few chemical elements. This is made all the more impressive because carbon bonds may occur in configurations that are linear, ring like, or highly branched. Such molecular shapes can produce molecules with a variety of functions. One last feature of carbon that is important in biochemistry is that carbon bonds are stable at the different temperatures associated with life. This property arises in part because the carbon atom is very small compared to most other atoms, and therefore the distance between carbon atoms forming carbon – carbon bonds is quite short. Shorter bonds tend to be stronger and more stable than longer bonds between two large atoms. Thus, carbon atoms are compatible with what we observe about life today, namely that living organisms can inhibit environments ranging from the earth’s icy poles to deep-sea vents. Aside from the simplest hydrocarbons, most organic molecules and macromolecules contain functional groups – group of atoms with special chemical features that are functionally important. Each type of functional group exhibits the same properties in all molecules in which it occurs. For example, the amino group (NH2) acts like a base. At the pH found in living organisms, amino groups readily bind H+ to become NH3+, thereby removing H+from an aqueous solution and raising the pH.
Synthesis of Carbon-Carbon Bond
The synthesis of new carbon-carbon bonds in organic reactions is an important synthetic organic technique that leads to the production of artificial chemicals such as new drugs and plastics. In the carbonyl chemistry many synthetic techniques are based on natural processes for the formation of carbon-carbon bonds in biological systems. Some examples of organic reactions forming new carbon-carbon bonds include Aldol reactions, Claisen condensation, Diels–Alder reaction, and Michael reaction.
An Aldol reaction is a powerful technique forming new carbon-carbon bonds in organic chemistry, since it unites two simple molecules into a complex one. The reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. Producsts of such reactions are called aldols, known as the product of aldehyde + alcohol. A typical Aldol reaction involve the nucleophilic addition of a ketone enolate to an aldehyde. Aldol condensation takes place when the aldol product lose a water molecule to form an α,β-unsaturated carbonyl compound. Nucleophiles that can be employed in the aldol reaction include the enols, enolates, and enol ethers of ketones, aldehydes, and other compounds carrying the carbonyl function, whereas the electrophilic reagent is usually an aldehyde or ketone. When different nucleophile and electrophile are used, the reaction is called a crossed aldol reaction. On the other hand, a reaction in which the same nucleophile and electrophile are employed is called aldol dimerization.
A Claisen condensation occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, which results in a β-keto ester or a β-diketone. In Claisen condensation, attack of an ester enolate on a carbonyl group generates a new carbon-carbon bond. The reaction mechanism involves ester enolate formation by reacting ethyl acetate with a stoichiometric amount of reagents with ester function, nucleophilic addition of another ester molecule that furnishes a ketoester, elimination of the alkoxide group, and finally the deprotonation of ketoester followed by protonation upon aqueous work-up. The overall process is endothermic and all steps before the deprotonation of ketoester are reversible. The deprotonation of ketoester drives equilibrium, since it removes the base needed to catalyze the previous steps. To prevent transesterification, both the alkoxide and ester are usually derived from the same alcohol.
In a Diels-Alder reaction, a conjugated diene adds to a substituted alkene to yield substituted cyclohexane derivatives. Such reaction is a special case of cycloaddition reactions between pi systems; four conjugated atoms containing four pi electrons reacts with a double bond containing two pi electrons. The four-carbon component is called diene and the alkene added is called dienophile. The reaction is also called a [4+2]cycloaddition. This type of reaction can still be carried out in the absence of carbon in the newly formed ring. Diels-Alder reactions that are reversible are called the retro-Diels-Alder; for example, the decomposition reaction of the cyclic system.
The Michael reaction is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. The stabilized anions derived from β-dicarbony compounds with α,β-unsaturated carbonyl compound leads to 1,4-additions. It is one of the most useful methods for the mild formation of new carbon-carbon bonds. A Michael addition is base-catalyzed and works with α,β-unsaturated ketones, aldehydes, and other carboxylic acid derivatives; they are known as Michael acceptors. A Michael donor is an electron-withdrawing group on the nucleophile such acyl and cyano. [Vollhardt] 
Isomers in organic chemistry
Organic molecules also have isomers. Isomers are molecules that contain the same number of atoms and also the same kind of atoms. However, they have different bonding arrangements. Types of isomers include constitutional (or structural) isomers, and stereoisomers.
Constitutional isomers (structural isomers) are the compounds that have the same molecular formula but differ in how the atom are arranged and connected. Chain isomers, positional isomers, and functional group isomers are constitutional isomers.
Example: Pentane and 2-Methylbutane
Example: 3-Hexanone and 2-Hexanone
Example: Ethanol and Dimethylether
Stereoisomers include conformational isomers and configurational isomers. Conformational isomers are compounds that posses the same molecular formula and atomic connectivity but differ in a rotation about a bond. In other words, conformational isomers can be interconverted by rotation about single bonds. They are not separable at room temperature. There are different kinds of conformational isomers. They are eclipsed, staggered, anti, and gauche conformations. Configurational isomers are those isomers which can only be interconverted by breaking bonds. There are two different types of configuration isomers. They are enantiomers and diastereomers. Enantiomers are non-superimposable mirror images. Diastereomers are non-superimposable non-mirror images.
Glucose and fructose, which both have the same chemical formula of C6H12O6 but a different arrangement in atoms, would be a good example of constitutional/structural isomers. Enantiomers would be a good example of a type of stereoisomer. Stereoisomers are isomers that have exact same bonding between atoms, but differ in their specific spatial arrangements. For example, enantiomers are isomers that are mirror images of each other. They can be superimposed on each other (achiral) or not (chiral), and may exhibit either R (clockwise) or S (counter-clockwise) configurations. Each mirror image of a chiral molecule expresses different properties than its counterpart. A way to determine whether a molecule is chiral or not is by looking for and identifying chiral centers. A chiral center for carbon, will have four different groups bonded to it. It must be sp3 hybridized and be tetrahedral in shape. A molecule's chiral center can also be referred to as a stereocenter.
Fullerenes are organic molecules that consist only of carbon atoms.
The role of organic synthesis research in Biochemistry
Organic synthesis is the science of constructing molecules. There are two major areas of research in organic synthesis: exploratory and target oriented. Research in both fields requires innovation, imagination, and artistic creativity.
Exploratory research involves the development of new organic reactions. Many researchers in this field focus on the optimization of previously known reactions. There are many factors when developing new organic reactions such as reactant, solvent, temperature, pH, etc. The main goals for any researcher in this field are to maximize yield of desired product, minimize side reactions/products, and be reliable for a broad spectrum of starting material. The advancement of the methodology aspect of organic synthesis expands the tools and techniques used by target oriented research.
Target oriented research involves the development of organic molecules through a series of organic reactions. Researchers in this field use preexisting reactions and commercially available materials to synthesis desired products. “Target” molecules are either natural products or designed molecules. A linear synthesis (a linear series of reactions conducted one after another) will suffice with simple molecules. Other approaches such as convergent synthesis (independent synthesis of key intermediates) are used for complex molecular structures. Methods such as solid phase synthesis are exceptionally useful in the synthesis of proteins.
“Target” molecules are biologically, medicinally, and/or theoretically interesting products. The field of bioorganic synthesis began with the synthesis of urea by Friedrich Wöhler in 1828. Natural product synthesis has been recognized with Nobel Prize in Chemistry on several occasions. Target oriented natural products are immensely useful for medical research. Cancer inhibiting molecules have been found in several natural products including marine natural products.
New reactions are constantly being developed and optimized. Many of these reactions are particularly useful in the synthesis of drugs and biomarkers. Reactions such as the palladium cross-coupling reaction, winner of the 2010 Nobel Prize in Chemistry, have been immensely useful in the synthesis of drugs, biomarkers, and other useful molecules.
The simplest Suzuki coupling reaction involves a palladium cross-coupling reaction of phenylboronic acid and bromobenzene to yield phenylbenzene.
Straying away from traditional synthetic methods has brought monumental advancements in alternate molecule building techniques in the last few decades. An example of an innovative technique is solid phase synthesis, a method in which molecular building blocks are attached to a bead and the “target” molecule is obtained with a linear series of reactant solutions. There are several advantages of solid phase synthesis compared to traditional solvent-based synthesis. Some advantages are that functional groups can be easily protected and also it is easier to extract unwanted byproducts or reactants from the desired “target” molecule. Solid phase synthesis is exceptionally useful with the synthesis of peptides, deoxyribonucleic acid (DNA), and other sequence-based molecules.
“There is excitement, adventure and challenge, and there can be great art in organic synthesis” – R.B. Woodward (Nobel Prize, 1965)
Synthetic Approach to Activated Amino Acids
The use of coupling agents in peptide synthesis is way of activating the carbonyl carbon of one amino acid, thus rendering it more reactive to the adjacent amino acid's amine group. Dicyclohexylcarbodiimide and various uronium salts are predominantly used as coupling agents in the field . Although the use of coupling agents isn't a daunting task, constructing an intrinsically activated amino acid would circumvent the use of these reagents, saving time, money, and reaction yield.
The general synthetic approach at obtaining an activated amino acid will be described herein. Reaction of a specific isocyanide with an arbitrary aldehyde yields and alpha-hydroxy indole species .
Converting the hydroxy function on this species to an amino group would yield an activated amino acid. Notice that the indole function is aromatically stabilized, acts as a great leaving group, and thus activates the carbonyl carbon. It is imperative that converted amine function is protected, so that cross reaction between monomers doesn't occur. Carrying out this task isn't easy, because many chemical syntheses require extreme conditions which aren't suitable for peptide synthesis. High temperature or pH fluctuations can easily break peptide bonds, rendering the targeted peptide destroyed. Therefore, mild conditions in carrying out this displacement are sought after.  [Gianneschi]
The ability of generating molecular modification with high selectivity is invaluable for studies of chemical and biological systems. Click chemistry is the chemical philosophy of synthesizing molecules from a core group of highly effective reactions developed by Sharpless, Finn, and Kolb in 2001. The inspiration for the development of Click chemistry came from the idea that nature tends to produce substances from smaller subunits. The logic behind click chemistry is to bind small molecular units together to produce products with reactions that proceed rapidly in high yields under ambient conditions. These reactions are required to have a high thermodynamic driving force that is orthogonal to other functional groups that may be present in biomolecules. Click chemistry reactions are effective for labeling biomolecules. They also proceed in biological conditions with high yield. An important aspect of the reactions is that they are bioorthogonal, meaning that they don’t react with functional groups in the biological systems. Some examples of Click chemistry reactions are (a) Azide-Alkyne Cycloaddition, (b) Copper-Free Azide Alkyne Cycloaddition, and (c) Staudinger Ligation shown in the schemes below.
The major goals of Click Synthesis were to simplify the methods of how molecules are synthesized and, consequently, improve the process of identifying and synthesizing molecules with biological importance. These methods have proven to be beneficial in modern drug development; particularly useful for in situ fragment-based drug design. In situ drug development via Click chemistry has been extended to the selective generation of potent inhibitors of carbonic anhydrase and HIV-1 protease. A schematic representation of the process of inhibitor development with aid of Click chemistry is shown below.
These techniques have been extremely useful in combinatorial drug development. The product of the azide-alkyne cycloaddition, triazole, is favorable in drug design because it possesses a variety of useful properties. The highly tuned properties of these reactions possessing high yields, selectivity, and ability to undergo transformation in mild (biological) environments allow the products to be directly analyzed for activity without purification (which is a significant shortcut!). Example of direct screening of click chemistry products with alpha-1,3-fucosyltransferase (fuc-T) show below.
Click chemistry designs include reactions that are opposed to the reaction with biological molecules. This is a very useful property for selectively labeling molecules to detect in biological systems. The Staudinger ligation and azide-alkyne cycloadditions have proven to be very helpful for tasks that were very challenging prior.
There are is an extensive range of applications, a brief description and example schematic depictions are presented below:
(1) Introduction of Unnatural Amino Acids Bearing Reactive Tags into Proteins.
(2) Labeling of Viral Surfaces.
(3) Incorporation of Labeled Probes onto Proteins via Post-Translational Modification.
(4) Labeling of Nucleotides for Imaging DNA and RNA.
(5) Derivatization of Lipid Probes.
(6) Activity- Based Protein Profiling.
The benefit of these methods is clear from the broad spectrum of applications in chemical biology. The scope of these reactions is quite broad and takes innovation of the researchers using these methods to maximize its potential. These methods expand to pure organic chemistry lab as well. Without constraints of biological environments, these reactions have obvious beneficial aspects with precise control of target structures. The progression of bioorthogonal chemistry (has and) continues to produce new and effect tools for the future of research. [Best]
Wöhler's Synthesis of Urea
Wöhler's synthesis is one of the examples of synthesis in which molecules are made. Carbon compounds, organic products, in this reaction are made from inorganic salt.
Pb(OCN)2 + 2 H2O + 2 NH3 -----> 2 H2N(C=O)NH2 + Pb(OH)2
Lead cyanate Water Ammonia Urea Lead hydroxide
The effect of acid on food digestion and stomach acid
The normal human stomach has about 0.02 M of HCl per day. If there's an increase of HCl in the stomach, the pH of stomach juice would falls from 2.5 to 1.0 . HCl would mess up the normal folded shapes of protein molecules in food. As a result, the acid would destroy many digestive enzymes in the stomach. Therefore, to protect itself from the increase of such acid, the cells in the stomach must work together to prevent it from happening. First, the stomach tissues are made of protein molecules with the interior covered with layers of gastric mucosa. When stimuli such as smelling and tasting activate the cells in the gastric mucosa, the signal molecule, histamine, would make the parietal cells to hide the acid juices in the stomach. As a result, there would be an increase in the acid juices production in the stomach. In order to prevent it from happening, active ingredients such as cimetidine, famotidine, and ranitidine help to reduce the acid by obstructing the histamine from helping the parietal cells. 
Vollhardt and Schore. Organic Chemistry. 6th edition. New York: W.H. Freeman and Company
Gianneschi, C. N., Rubinshtein, M., James, R.C., Kobayashi, Y., Yang, J., Young, J., Yanyan, J.M. Org. Lett., 2010, 12 (15), pp 3560–3563
Best, M.D. Biochemistry, 2009, 48 (6571), pp 6571–6584