1.2: Chemical Foundations

Search Fundamentals of Biochemistry

Learning Goals 

(Learning goals written by Claude, Sonnet 4.6, Anthropic)

Functional Groups and Organic Reactivity

• Identify the major functional groups found in biomolecules — including alcohols, thiols, amines, carbonyls, carboxylic acids and their derivatives, phosphates, and aromatics — and predict their characteristic reactivity based on structural features such as electronegativity, polarity, and resonance stabilization.
• Distinguish between closely related functional groups (e.g., alcohol vs. phenol, aldehyde vs. ketone, ester vs. thioester vs. amide) and explain how subtle structural differences produce significant differences in chemical behavior.
• Classify alcohols and amines as primary, secondary, or tertiary, and recognize how this classification affects their reactivity in biochemical contexts.

Macromolecules and Dehydration Synthesis

• Identify the four major classes of biological macromolecules, name their corresponding monomer units, and explain how polymer assembly via dehydration synthesis is unified by a common chemical logic — nucleophilic attack on an electrophilic center flanked by electron-withdrawing groups.
• Recognize that lipids, nucleic acids, proteins, and carbohydrates are each assembled through analogous condensation reactions involving carboxylic acids, phosphoric acids, or hemiacetals as electrophilic partners, and alcohols or amines as nucleophiles.
• Explain the role of primary metabolites in energy production, structural assembly, genetic information storage, and cellular signaling, and connect these functions to the functional groups present in the relevant molecules.

Organic Molecules

On Earth, all carbon-containing molecules have originated from biological, living organisms and are called organic compounds. Organic chemicals consist of relatively few similar parts combined in different ways. These structural similarities enable us to predict how a previously unseen compound may react, provided we understand how other molecules containing the same types of parts react.

These parts of organic molecules are called functional groups with specific bonding patterns and atoms most commonly found in organic molecules (C, H, O, N, S, and P). Identifying functional groups and predicting reactivity based on their properties is one of the cornerstones of organic chemistry. Functional groups are specific atoms, ions, or groups of atoms having consistent properties. A functional group makes up part of a larger molecule. For example, -OH, the hydroxyl group that characterizes alcohols, contains oxygen with an attached hydrogen. It could be found on any number of different molecules. Just as elements have distinctive properties, functional groups have characteristic chemistries. An -OH functional group on one molecule will tend to react similarly, although perhaps not identically, to an -OH on another molecule.

Organic reactions usually occur in the functional group, so learning about the reactivities of functional groups will prepare you to understand many other aspects of biochemistry.

Functional groups are structural units within organic compounds defined by specific bonding arrangements between specific atoms. The structure of capsaicin, the fiery compound found in hot peppers, has several functional groups, labeled in the figure below and explained throughout this section.

As we progress in biochemistry, it will become increasingly important to recognize the most common functional groups. These are the key structural elements that define how organic molecules react. Below is a brief introduction to the major organic functional groups.

Alkanes

The ‘default’ in organic chemistry (the lack of functional groups) is given the term alkane, characterized by single bonds between carbon and carbon or carbon and hydrogen. Methane, CH₄, is the natural gas you may burn in your furnace. Octane (C₈H₁₈) is a component of gasoline.

Alkenes and Alkynes

Alkenes (sometimes called olefins) have carbon-carbon double bonds, and alkynes have carbon-carbon triple bonds. Ethene, the simplest alkene example, is a gas that serves as a cellular signal in fruits to stimulate ripening. (If you want bananas to ripen quickly, put them in a paper bag along with an apple – the apple emits ethane gas (also called ethylene), setting off the bananas' ripening process). Ethyne, commonly known as acetylene, is used as a fuel in welding blowtorches.

Many alkenes can take two geometric forms: cis or trans. The cis and trans forms of a given alkene are different isomers with different physical properties because there is a very high energy barrier to rotation about a double bond. In the example below, the difference between cis and trans alkenes is readily apparent. Biochemists don't usually use the E (entgegen) and Z (zusammen) labels for groups attached to double bonds (using IUPAC priority numbering).

Alkanes, alkenes, and alkynes are all classified as hydrocarbons because they are composed solely of carbon and hydrogen atoms. Alkanes are said to be saturated hydrocarbons because the carbons are bonded to the maximum possible number of hydrogens – in other words, they are ‘saturated’ with hydrogen atoms. The double and triple-bonded carbons in alkenes and alkynes have fewer hydrogen atoms bonded to them – they are thus referred to as unsaturated hydrocarbons.

Aromatics

The aromatic group is exemplified by benzene and naphthalene, a compound with a distinctive ‘mothball’ smell. Aromatic groups are planar (flat) ring structures with conjugated pi bonding with 4n+2 pi electrons. Given the stability of aromatic groups due to the delocalization of pi electrons, these groups are abundant in nature.

Alkyl Halides

When the carbon atom of an alkane is bonded to one or more halogens, the compound is referred to as an alkyl halide, or haloalkane. Chloroform is a valuable laboratory solvent and was one of the earliest anesthetic drugs used in surgery. Chlorodifluoromethane was used as a refrigerant and in aerosol sprays until the late twentieth century. Still, its use was discontinued after it was found to have harmful effects on the ozone layer. Bromoethane is a simple alkyl halide often used in organic synthesis. Alkyl halide groups are quite rare in biomolecules.

Alcohols, Phenols, and Thiols

In the alcohol functional group, a carbon is single-bonded to an OH group (when part of a larger molecule, the OH group is referred to as a hydroxyl group). All alcohols can be classified as primary, secondary, or tertiary. In primary alcohols, the carbon bonded to the OH group is also bonded to only one other carbon. In secondary and tertiary alcohols, carbon is bonded to two or three other carbons. When the hydroxyl group is directly attached to an aromatic ring, the resulting group is called a phenol. The sulfur analog of an alcohol is called a thiol (from the Greek thio, for sulfur).

Note that the definition of a phenol states that the hydroxyl oxygen must be directly attached to one of the carbons of the aromatic ring. The compound below, therefore, is not a phenol – it is a primary alcohol.

The distinction is important because there is a significant difference in the reactivity of alcohols and phenols.

Ethers and Sulfides

In an ether functional group, oxygen is bonded to two carbons. Below is the structure of diethyl ether, a common laboratory solvent and one of the first compounds to be used as an anesthetic during operations. The sulfur analog of ether is called a thioether or sulfide.

Amines

Amines contain nitrogen atoms that are bonded to a single hydrogen atom and a carbon atom. Just as there are primary, secondary, and tertiary alcohols, there are primary, secondary, and tertiary amines. Ammonia is a special case with no carbon atoms. One of the most important properties of amines is that they are basic and are readily protonated to form ammonium cations. In the case where nitrogen has four bonds to carbon (which is somewhat unusual in biomolecules), it is referred to as a quaternary ammonium ion.

Note: Do not be confused by how the terms ‘primary’, ‘secondary’, and ‘tertiary’ are applied to alcohols and amines – the definitions are different. In alcohols, what matters is how many other carbons the alcohol carbon is bonded to, while in amines, what matters is how many carbons the nitrogen is bonded to.

Organic Phosphates

Phosphate and its derivative functional groups are ubiquitous in biomolecules. These include phosphate esters and diesters. A linkage between two phosphates with a bridging oxygen atom creates a phosphate anhydride.

Aldehydes and Ketones

Many functional groups contain a carbon-oxygen double bond, commonly called a carbonyl. Ketones and aldehydes are two closely related functional groups based on carbonyls that react similarly. In a ketone, the carbon atom of a carbonyl is bonded to two other carbons. In an aldehyde, the carbonyl carbon is bonded to a hydrogen atom on one side and to a carbon atom on the other. The exception to this definition is formaldehyde, in which the carbonyl carbon has bonds to two hydrogens.

Carboxylic Acids and Their Derivatives

When a carbonyl carbon is bonded on one side to a carbon (or hydrogen) and on the other side to an oxygen, nitrogen, or sulfur, the functional group is considered to be one of the carboxylic acid derivatives. The main member of this family is the carboxylic acid functional group, in which the carbonyl is bonded to a hydroxyl group. The carboxylate ion form has donated the H⁺ to the solution. Other derivatives are carboxylic esters(usually just called ‘esters’), thioesters, amides, acyl phosphates, acid chlorides, and acid anhydrides. Except for acid chlorides and acid anhydrides, carboxylic acid derivatives are very common in biological molecules and/or metabolic pathways and will be discussed in further detail in a later chapter.

Practice Recognizing Functional Groups in Molecules

A single compound often contains several functional groups, particularly in biological organic chemistry. For example, the six-carbon sugar molecules glucose and fructose contain aldehyde and ketone groups, respectively, containing five alcohol groups. A compound with several alcohol groups is often referred to as a ‘polyol’.

The hormones testosterone and dihydroxyacetone phosphate, as well as the amino acid phenylalanine, all contain multiple functional groups, as labeled below.

Although not exhaustive, this section covers the most important functional groups that we will encounter in biochemistry. Table 1.7 summarizes all the groups listed in this section.

Table 1.7 Common Organic Functional Groups

Exercise \(\PageIndex{1}\)

Identify the functional groups (other than alkanes) in the following organic compounds. State whether alcohols and amines are primary, secondary, or tertiary.

Exercise \(\PageIndex{2}\)

Draw one example of each compound fitting the descriptions below using line structures. Be sure to designate the location of all non-zero formal charges. All atoms should have complete octets (phosphorus may exceed the octet rule). There are many possible correct answers for these, so check your structures with your instructor or tutor.

1. a compound with molecular formula C₆H₁₁NO that includes alkene, secondary amine, and primary alcohol functional groups.
2. an ion with molecular formula C₃H₅O₆P^2- that includes aldehyde, secondary alcohol, and phosphate functional groups.
3. A compound with molecular formula C₆H₉NO that has an amide functional group and does not have an alkene group.

Primary metabolites

Primary metabolites are components of basic metabolic pathways required for life. They are associated with essential cellular functions such as nutrient assimilation, energy production, and growth/development.  Primary metabolites are the building blocks for synthesizing the four major macromolecules in the body: carbohydrates, lipids, proteins, and nucleic acids (DNA and RNA).

Large polymers are made from repeating smaller monomer units (Fig. 1.28). Nucleotides are the monomer units that make up nucleic acids, including DNA and RNA. In contrast, the monomers for proteins are amino acids, carbohydrates are composed of sugar residues, and lipids are composed of fatty acids or acetyl groups.

Figure 1.28 The Molecular building blocks of life are made from organic compounds. Modified from: Boghog

Reactions forming the Major Macromolecules

The major macromolecules are constructed by combining repeating monomer subunits through a process known as dehydration synthesis. Interestingly, the organic functional units used in the dehydration synthesis processes for each major macromolecule type have similarities. Thus, it is helpful to look at the reactions together (Figure 1.29)

Figure 1.29 Dehydration Synthesis Reactions Involved in Macromolecule Formation. The major organic reactions involved in the biosynthesis of lipids, nucleic acids (DNA/RNA), proteins, and carbohydrates are illustrated. Note that in all of these reactions, there is a functional group that contains two electron-withdrawing groups (the carboxylic acid, phosphoric acid, and the hemiacetal, each having two oxygen atoms attached to a central carbon or phosphorus atom). This forms a reactive, partially positive center atom (carbon in the case of the carboxylic acid and hemiacetal, or phosphorus in the case of the phosphoric acid) that the electronegative oxygen or nitrogen can attack from an alcohol or amine functional group. Within biological systems, many functional groups, such as carboxylic acids, require activation before they can be utilized in synthesis reactions, which will be detailed in later chapters.

Primary metabolites involved with energy production include numerous enzymes that break down food molecules, such as carbohydrates and lipids, and capture the energy released during the hydrolysis of adenosine triphosphate (ATP). Enzymes are biological catalysts that speed up chemical reactions. Typically, they are proteins composed of amino acid building blocks. Cells are also composed of primary metabolites. These include cell membranes (e.g., phospholipids), cell walls (e.g., peptidoglycan, chitin), and cytoskeletons (proteins). DNA and RNA, which store and transmit genetic information. Primary metabolites are also involved in cellular signaling, communication, and transport molecules. The structure and function of primary metabolites are key components of this text. These reactions will be detailed in the following chapters.

Summary

(Summary written by Claude, Sonnet 4.6, Anthropic)

This chapter establishes the chemical vocabulary and conceptual framework needed to understand the reactivity of biological molecules throughout the course. Its two central themes are the identification and properties of organic functional groups, and the chemical logic underlying the assembly of biological macromolecules.

All biochemical reactivity is rooted in the properties of functional groups — defined arrangements of atoms with predictable chemical behavior. Because organic reactions occur predominantly at functional groups rather than along the carbon backbone, recognizing these groups in unfamiliar molecules allows chemists to anticipate how those molecules will react. The major functional groups encountered in biochemistry include alkyl and aromatic hydrocarbons, alcohols, phenols, thiols, ethers, amines, aldehydes, ketones, carboxylic acids and their derivatives (esters, thioesters, amides, acyl phosphates, and anhydrides), and organic phosphates. Subtle structural differences among related groups — such as the direct attachment of a hydroxyl to an aromatic ring in phenols versus its placement on a saturated carbon in alcohols, or the identity of the heteroatom in esters versus thioesters — produce meaningful differences in reactivity that will recur throughout subsequent chapters. Most biological molecules contain multiple functional groups simultaneously, and the ability to identify each within complex structures is an essential skill for biochemists.

The second theme is the chemical unity underlying macromolecule biosynthesis. The four major biological macromolecules — proteins, nucleic acids, carbohydrates, and lipids — are each assembled from repeating monomer units (amino acids, nucleotides, monosaccharides, and fatty acids or acetyl groups, respectively) through dehydration synthesis reactions. Strikingly, these reactions share a common mechanistic logic: in each case, a nucleophilic oxygen or nitrogen from an alcohol or amine attacks an electrophilic carbon or phosphorus atom that is rendered partially positive by two flanking electron-withdrawing groups (as in carboxylic acids, phosphoric acids, and hemiacetals). This unified perspective reveals that the biosynthesis of chemically diverse macromolecules is governed by the same underlying principles of nucleophilicity and electrophilicity. In biological systems, many of these reactions additionally require activation of the electrophilic partner — a theme developed in detail in later chapters. Primary metabolites, the products of these pathways, underpin energy production, cellular structure, genetic information storage, and intercellular communication.