Fundamentals of Bioorganic Chemistry (Study Guide) - G. O. Syrova - 2018

Topic

Spatial Structure of Organic Molecules

Mutual Influence of Atoms

Relevance of the topic.

General objectives: To draw Conclusions and analyze the relationship between the Structure, configuration, and conformation of bioorganic compounds. To interpret how the Reactivity of bioorganic compounds depends on The Nature of chemical bonds and the mutual influence of atoms within the molecule.

Specific objectives

1. Determine the type of carbon atom Hybridization in bioorganic compounds, as well as the spatial orientation of bonds formed by carbon atoms in sp³, sp², and sp hybridized states.

2. Understand the Spatial Structure of rings formed by sp³-hybridized carbon atoms.

3. Explain the causes of cis-trans isomerism.

4. Be able to determine the type and sign of electronic effects in order to further predict the reactivity of Organic compounds in biochemical transformations.

Theoretical questions

1. σ-Bond: electronic and spatial structure of molecules with sp³-hybridized carbon atoms. Relative arrangement of substituents in open chains. Conformations.

2. Closed rings. «Banana bonds».

3. π-Bond, electronic structure, and main characteristics. Cis-trans isomerism.

4. Conjugated systems. Resonance (conjugation) energy. Aromaticity.

5. Electronic effects of substituents in aliphatic and Aromatic Compounds.

1. A carbon atom in the sp³-hybridized state has a tetrahedral geometry, with all its substituents positioned at an angle of 109°28'. Consequently, if a compound consists of such atoms, the molecule is not planar but three-dimensional, possessing a specific configuration. The sp-hybridized carbon atoms are bonded by a single σ-bond and are symmetrical. Rotation is possible around this bond, allowing substituents to change their spatial positions relative to one another, meaning the molecule exists in various conformational states.

Conformations, or rotational isomers (conformers), are the various geometric shapes of a molecule that interconvert by rotation around single bonds. For example, cephalin, which is abundant in the Brain, contains the aminoserving alcohol colamine (2-aminoethanol) with the structure HO-CH₂-CH₂-NH₂. The molecule contains two carbon atoms in the sp³-hybridized state. Its configuration can be represented as follows:

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Due to free rotation around the σ C₁-C₂ bond, colamine can adopt various conformational states. The resulting conformers (rotational isomers) are conventionally depicted using Newman projections, which are viewed along the C₁-C₂ bond. The carbon atom closest to the observer, C₁, and its bonds are represented by , while the more distant carbon atom, C₂, and its bonds are represented by . The relative arrangement of substituents (the -OH and -NH₂ groups in colamine) is characterized by the dihedral angle (φ) relative to each other. Depending on this angle, various conformations arise, of which there can be an infinite number. Let us examine some of them:

Rotational isomers possess a certain potential energy. When the distance between bulky substituents is small, the steric interaction between them is high, resulting in a high potential energy. The minimum spatial distance between substituents occurs in the eclipsed conformation (φ = 0), making it the least energetically favorable. In the staggered conformation, the substituents are as far apart as possible (φ = 180°), their interaction energy is low, and thus it is the most energetically favorable conformation. However, the energy difference between conformational states is small, so the transition from one conformation to another occurs readily, making it impossible to isolate them as stable isomers.

2. Compounds containing small closed rings formed by sp³-hybridized carbon atoms are characterized by The formation of so-called «banana bonds», the formation mechanism of which resembles that of a π-bond. Therefore, as we will see later, these compounds are more prone to addition reactions rather than substitution, which proceed with ring opening. Small rings include cyclopropane, cyclobutane, and cyclopentane.

Six-membered rings, which are most commonly found in the structures of BIOLOGICALLY ACTIVE SUBSTANCES, exist in the «chair» conformation, which is free from angle strain. For instance, the drug Validol, used as a vasodilator, contains menthol, which is 5-methyl-2-isopropylcyclohexan-1-ol. In the cyclohexane ring of menthol, all six carbon atoms are in the sp³-hybridized state, and therefore their chemical bonds are not coplanar.

Had the cyclohexane ring existed in a planar form, the bond angle would be 120°, meaning a planar molecule would experience angle strain. Furthermore, in a planar ring, all substituents would be in an unfavorable eclipsed conformation, which in turn causes torsional strain. Thus, due to the presence of these Two Types of strain, the cyclohexane ring should be unstable, which contradicts practical observation. In reality, the cyclohexane ring adopts spatial arrangements forming various conformations—"chair" and "boat" ("tub"). The chair conformation is the most stable because it is free of angle strain.

Each carbon atom has two types of bonds: axial (a)—oriented parallel to the axis of Symmetry, and equatorial (e)—directed away from the ring and periphery at an angle of 109°28' to the axis of symmetry. To graphically represent these bonds, the following conventions are used: axial bonds are drawn alternately pointing up and down parallel to the axis, while equatorial bonds extend outward from the ring in alternating directions. Equatorial bonds are more energetically favorable. Thus, The structure of menthol can be represented as follows:

3. The presence of a multiple bond in molecules containing an sp²-hybridized carbon atom rules out free rotation around the bond, and therefore, cis-trans isomerism occurs in this case. This type of isomerism is familiar to students from the school organic chemistry course.

4. Conjugated systems—molecules with alternating single and double bonds—are of particular interest and significance. Conjugated systems are divided into open-chain conjugation systems and closed-chain conjugation systems. The simplest aliphatic open-chain conjugated system is 1,3-butadiene:

The unhybridized p-orbitals overlap not only between carbon atoms 1 and 2, and 3 and 4, but also between 2 and 3, forming a unified system. As a result, two localized double bonds undergo conjugation to form a delocalized four-center molecular orbital. This type of conjugation is called π,π-conjugation, since the orbitals of the π-bonds participate in the interaction.

Another type of conjugation is p,π-conjugation, in which the p-orbital of heteroatoms such as O, N, S, etc., possessing a lone pair of electrons, interacts with the orbitals of a π-bond.

Conjugation is an energetically favorable process because delocalization releases energy, known as the conjugation energy, which leads to molecular stabilization. It is important to note that as the length of the conjugated chain increases, the delocalization of π-electrons enhances, alongside an increase in conjugation energy and the thermodynamic Stability of the compound.

This fact can be illustrated using the Examples of β-carotene, retinal, and retinol:

The thermodynamic stability of the discussed compounds is attributed to the π,π-conjugation of multiple bonds and increases in the series: retinol → retinal → β-carotene.

Closed-chain conjugated systems exhibit higher thermodynamic stability than open-chain conjugated systems due to the cyclic delocalization of π-electrons. Such systems are referred to as aromatic. A compound is aromatic if it possesses a planar closed ring and a single unified π-electron system spanning all atoms of the ring and containing 4n + 2 π-electrons (Hückel's rule), where n is an integer 1, 2, 3, etc.

The simplest representatives of aromatic Hydrocarbons (arenes) is benzene:

Benzene is characterized by high thermodynamic stability. METABOLISM/2.html">THE CONCEPT OF aromaticity is also applicable to compounds with fused benzene rings (naphthalene, anthracene, phenanthrene). The replacement of -CH= with -N= in benzene leads to the formation of a heterocyclic system—the pyridine molecule:

Applying the criteria of aromaticity confirms that pyridine is an aromatic compound. It should be emphasized that the orbital with the free lone pair of electrons determines the Basic Properties of pyridine. This electronic state of the nitrogen atom is commonly called the pyridine nitrogen type. It is characteristic of heterocyclic compounds containing the -N= fragment (pyridine, imidazole, pyrimidine, purine).

Pyridine nitrogen attracts the unified π-electron cloud toward itself, overall reducing the electron density of the aromatic ring. Therefore, systems containing pyridine nitrogen are termed π-deficient. Replacing the -CH=CH- fragment in benzene with >N-H yields the five-membered heterocycle pyrrole:

In this case, nitrogen contributes its lone pair of electrons to conjugation with the π-electrons of the multiple bond. Nitrogen in this state is referred to as pyrrolic nitrogen. The six-electron π-cloud belongs to a five-center system, making pyrrole a π-excessive or superaromatic system. The presence of such a system significantly influences the reactivity of pyrrole. In natural compounds, the aromatic pyrrole ring is found in various polynuclear systems, among which the porphyrin core (Hemoglobin, chlorophyll) is of primary importance.

5. The reactivity and mechanism of a chemical reaction are largely determined by the redistribution of electron density within the molecule. The mutual influence of atoms in organic molecules is transmitted via two pathways: inductive and mesomeric. Bonds between atoms of different electronegativities are polarized. This polarization propagates along the chain of σ-bonds with gradual attenuation, giving rise to partial charges denoted by δ. This electronic shift is designated as the inductive effect (I).

A substituent that attracts a bonding electron pair exhibits a negative inductive effect (-I). Only alkyl radicals possess a positive inductive effect (+I), with the +I effect increasing as the length of the radical grows. Thus, the inductive effect is the redistribution of electron density along σ-bonds depending on the electronegativity of the atoms forming these bonds.

The manifestation of the mesomeric effect requires specific conditions. The mesomeric effect is also known as the resonance effect. This indicates that the transmission of mutual influence is associated with the presence of a conjugated system. Thus, The Influence of a substituent transmitted through a system of conjugated bonds via the redistribution of electron density is called the mesomeric effect (M-effect). Substituents that withdraw electron density from the conjugated system exhibit a negative mesomeric effect (-M) (electron-withdrawing substituents). In our case, the aldehyde group exhibits a -M effect.

In p,π-conjugation, conversely, the substituent donates p-electrons into the conjugated system, resulting in a partial positive charge on the substituent. Therefore, a substituent that shares its lone electron pair into the general conjugation exhibits a positive mesomeric effect (+M). In our case, chlorine exhibits a +M effect (electron-donating substituent). Unlike the inductive effect, the mesomeric effect is transmitted through the entire system of conjugated π-bonds without attenuation and exerts a greater influence on molecular properties.

Any substituent in the benzene ring disrupts the uniform distribution of electron density characteristic of benzene. Depending on the Nature of the substituent (electron-donating or electron-withdrawing), the electron density in the ring increases or decreases, predominantly at the ortho- and para-positions. Electronic changes also occur within the substituent itself:

Thus, the redistribution of electron density in a molecule serves as the basis for qualitative predictions of reactivity in general and provides insight into the reaction mechanism.

Complete the tasks and check your Answers against the answer keys

Task No. 1

1. Indicate the type and sign of the electronic effects of the chlorine atom in the chloroprene molecule (2-chlorobutadienes-1,3):

A. -I, +M. B. +I. C. -M. D. +M.

2. Which conformation is the most energetically favorable for cyclohexane?

A. "Boat".

B. Planar six-membered ring.

C. "Chair".

D. Staggered.

3. Indicate the type and sign of the electronic effects of functional groups in the 4-hydroxybutanoic acid molecule, which is formed during Amino acid metabolism:

A. COOH (-I) -OH (+I). B. COOH (-M, -I).

C. OH (+I) COOH (-I). D. COOH (-I) -OH (-I).

Answer keys: 1-A, 2-C, 3-D.

Task No. 2

1. Conformations are:

A. Structural isomers.

B. Cis-trans isomers.

C. Rotational isomers (rotamers).

D. Homologues.

2. Conjugation energy is:

A. Energy absorbed during the formation of conjugation.

B. Energy required to disrupt conjugation.

C. Energy released upon electron delocalization.

D. Total energy of the conjugated system.

3. In what order does the positive inductive effect of radicals increase?

A. -С₃Н₇ > -C₂H₅ > -СН₃.

B. -СзН₇ < -С₂Н₅ < -СН₃.

C. (-СН₃) = (-С₂Н₅) = ( -С₃Н₇).

D. Does not change.

Answer keys: 1-C; 2-C; 3-A.

Task № 3

1. What electronic effect does the methyl group exhibit in toluene (methylbenzene)?

А. +I. В. -I. C. +М. D. -М.

2. The presence of a conjugated system in a molecule determines its status as:

A. Thermodynamic instability.

B. Thermodynamic stability.

C. Has no effect.

D. No answer.

3. Succinic acid is formed at one of the Stages of the Krebs cycle. What is its most favorable conformation and what is it called?

А. Skewed. В. Eclipsed. С. Staggered and skewed. D. Staggered.

Answer keys: 1-A, 2-B, 3-D.