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Chemical structure
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A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together and can be represented using structural formulae and by molecular models;[1] complete electronic structure descriptions include specifying the occupation of a molecule's molecular orbitals.[2][3] Structure determination can be applied to a range of targets from very simple molecules (e.g., diatomic oxygen or nitrogen) to very complex ones (e.g., such as protein or DNA).
Background
[edit]Theories of chemical structure were first developed by August Kekulé, Archibald Scott Couper, and Aleksandr Butlerov, among others, from about 1858.[4] These theories were first to state that chemical compounds are not a random cluster of atoms and functional groups, but rather had a definite order defined by the valency of the atoms composing the molecule, giving the molecules a three dimensional structure that could be determined or solved.
Concerning chemical structure, one has to distinguish between pure connectivity of the atoms within a molecule (chemical constitution), a description of a three-dimensional arrangement (molecular configuration, includes e.g. information on chirality) and the precise determination of bond lengths, angles, and torsion angles, i.e. a full representation of the (relative) atomic coordinates.
In determining structures of chemical compounds, one generally aims to obtain, first and minimally, the pattern and degree of bonding between all atoms in the molecule; when possible, one seeks the three dimensional spatial coordinates of the atoms in the molecule (or other solid).[5]
Structural elucidation
[edit]The methods by which one can determine the structure of a molecule is called structural elucidation. These methods include:
- concerning only connectivity of the atoms: spectroscopies such as nuclear magnetic resonance (proton and carbon-13 NMR), and various methods of mass spectrometry (to give overall molecular mass, as well as fragment masses). Techniques such as absorption spectroscopy and the vibrational spectroscopies, infrared, and Raman, provide, respectively, important supporting information about the numbers and adjacencies of multiple bonds, and about the types of functional groups (whose internal bonding gives vibrational signatures); further inferential studies that give insight into the contributing electronic structure of molecules include cyclic voltammetry and X-ray photoelectron spectroscopy.
- concerning precise metric three-dimensional information: can be obtained for gases by gas electron diffraction and microwave (rotational) spectroscopy (and other rotationally resolved spectroscopy) and for the crystalline solid state by X-ray crystallography[6] or neutron diffraction. These technique can produce three-dimensional models at atomic-scale resolution, typically to a precision of 0.001 Å for distances and 0.1° for angles (in unusual cases even better).[7][6]
Additional sources of information are: When a molecule has an unpaired electron spin in a functional group of its structure, ENDOR and electron-spin resonance spectroscopes may also be performed. These latter techniques become all the more important when the molecules contain metal atoms, and when the crystals required by crystallography or the specific atom types that are required by NMR are unavailable to exploit in the structure determination. Finally, more specialized methods such as electron microscopy are also applicable in some cases.
TeX for chemical structures
[edit]See also
[edit]- ChemDraw - software for chemical structure diagrams
- Chemical graph generator
- Crystallographic database
- Pauli exclusion principle
- Structural chemistry
- Structural formula
References
[edit]- ^ Haaland, Arne (2008). Molecules and Models: The Molecular Structures of Main Group Element Compounds. Oxford: Oxford University Press. ISBN 978-0-19-923535-3. OCLC 173809048.
- ^ Weinhold, Frank; Landis, Clark R. (2005). Valency and Bonding: A Natural Bond Orbital Donor-Acceptor Perspective. Cambridge, UK: Cambridge University Press. ISBN 0-521-83128-8. OCLC 59712377.
- ^ Gillespie, Ronald J.; Popelier, Paul L. A. (2001). Chemical Bonding and Molecular Geometry: From Lewis to Electron Densities. New York: Oxford University Press. ISBN 0-19-510495-1. OCLC 43552798.
- ^ 36th congress of the German physicians and scientists 1861
- ^ Wells, A. F. (July 12, 2012). Structural inorganic chemistry (Fifth ed.). Oxford: Clarendon Press. ISBN 978-0-19-965763-6. OCLC 801026482.
- ^ a b Rankin, David W. H. (January 2, 2013). Structural methods in molecular inorganic chemistry. Morrison, Carole A., 1972-, Mitzel, Norbert W., 1966-. Chichester, West Sussex, United Kingdom: Wiley. ISBN 978-1-118-46288-1. OCLC 810442747.
- ^ Glusker, Jenny Pickworth (1994). Crystal structure analysis for chemists and biologists. Lewis, Mitchell; Rossi, Miriam. New York: VCH. ISBN 0-89573-273-4. OCLC 25412161.
- ^ "Helpful LaTeX Packages for Chemistry | Computational Chemistry Resources".
Further reading
[edit]- Gallagher, Warren (2006). "Lecture 7: Structure Determination by X-ray Crystallography". Chem 406: Biophysical Chemistry (PDF) (self-published course notes). Eau Claire, WI, USA: University of Wisconsin-Eau Claire, Department of Chemistry. Retrieved July 2, 2014.
- Ward, S. C.; Lightfoot, M. P.; Bruno, I. J.; Groom, C. R. (April 1, 2016). "The Cambridge Structural Database". Acta Crystallographica Section B. 72 (2): 171–179. Bibcode:2016AcCrB..72..171G. doi:10.1107/S2052520616003954. ISSN 2052-5206. PMC 4822653. PMID 27048719.
Chemical structure
View on Grokipediafrom Grokipedia
Chemical structure refers to the connectivity of atoms within a chemical entity and their three-dimensional spatial arrangement, including the types and positions of chemical bonds that hold them together.[1] This arrangement uniquely identifies a molecule or ion and dictates its fundamental behavior in chemical reactions and interactions.[2]
Chemical structures are represented in diverse formats to communicate this information effectively, with two-dimensional diagrams being the most common for illustrating atomic connectivity and approximate geometry.[3] Lewis structures depict all atoms, bonds (as lines or dots), and lone pairs explicitly, while skeletal or line-angle formulas simplify organic molecules by omitting hydrogen atoms and using lines to represent carbon-carbon bonds, assuming standard valences. For conveying stereochemistry and precise spatial details, three-dimensional models such as ball-and-stick (showing atoms as spheres and bonds as rods) or space-filling representations (illustrating atomic van der Waals radii) are employed, often in computational or experimental contexts like X-ray crystallography. International standards, such as those from IUPAC, ensure these diagrams are unambiguous, with guidelines for bond lengths, angles (e.g., 120° for sp²-hybridized carbons), and orientations to minimize overlap and enhance readability.[3]
Understanding chemical structure is essential across chemistry and related disciplines, as it directly influences a compound's physical properties (e.g., melting point, solubility) and chemical reactivity.[4] In organic synthesis, structural knowledge enables the design of molecules with targeted functions, while in structure-activity relationships (SAR), correlations between specific structural features and biological effects guide drug discovery and toxicology assessments.[5] For instance, subtle changes in bond arrangement or stereochemistry can alter pharmacological potency or toxicity, underscoring structure's role in advancing pharmaceuticals, materials science, and environmental chemistry.[6]
Fundamentals
Definition and Scope
Chemical structure is defined as the arrangement of atoms and the bonds connecting them in a chemical entity, encompassing both the connectivity (constitution) of atoms and their spatial geometry. According to the International Union of Pure and Applied Chemistry (IUPAC), constitution describes the identity of the atoms and their linkages, including bond multiplicities, while stereochemical configuration refers to the fixed spatial arrangements that distinguish stereoisomers, such as those arising from double bonds or chiral centers.[7][8] Conformation, another key aspect, involves variable spatial arrangements interconvertible by rotation around single bonds. In broader contexts, chemical structure may also include the distribution of electrons, particularly in quantum chemical descriptions, but it fundamentally focuses on atomic positions and interactions rather than dynamic behaviors like reactivity or spectroscopic properties.[2] The scope of chemical structure extends beyond isolated molecules to include extended systems such as polymers, crystalline solids, and surfaces. For discrete molecules, it specifies the precise bonding and three-dimensional layout that determine the compound's identity. In polymers, structure involves repeating units and their sequential connectivity, often termed primary structure, alongside higher-order folding.[9] Crystalline materials feature periodic lattices of atoms or ions, where structure defines unit cells and symmetry, while surfaces encompass two-dimensional arrangements at interfaces, such as in catalysis or materials science.[10] This scope distinctly separates structural features from emergent physical properties; for instance, while structure dictates potential reactivity, it does not encompass measured reaction rates or spectral signatures, which arise from interactions with external factors. Central concepts in chemical structure include atomic connectivity (constitution) as the foundational element, which establishes the molecular formula and bonding topology, and spatial arrangements—configuration for fixed geometry and conformation for variable forms—that refine the three-dimensional layout through angles, distances, and orientations. These elements collectively define the identity of a chemical species, ensuring that two entities with identical structures are considered the same compound, regardless of preparation method or isotopic variations unless specified. For example, the water molecule (H₂O) exhibits a bent geometry with a bond angle of approximately 104.5°, arising from the tetrahedral electron pair arrangement around oxygen, contrasting with the linear geometry of carbon dioxide (CO₂), where the O=C=O arrangement yields a 180° bond angle due to sp hybridization at carbon. Such structural distinctions underpin differences in properties like polarity and solubility, highlighting structure's role in chemical uniqueness.[7][8][11][12]Historical Background
The concept of chemical structure originated from early atomic theories that gradually incorporated ideas of bonding and spatial arrangement, transforming chemistry from empirical observations to a predictive science. In 1808, John Dalton introduced his atomic theory in A New System of Chemical Philosophy, proposing that elements consist of indivisible atoms combining in simple whole-number ratios to form compounds, though his model did not specify interatomic bonds.[13] Building on this, Jöns Jacob Berzelius developed the electrochemical theory in the 1810s, conceptualizing compounds as aggregates of electropositive and electronegative atoms and establishing the modern notation for chemical formulas, such as H₂O for water.[14] A pivotal advancement occurred in 1858 when August Kekulé formulated his structural theory for organic compounds, positing that carbon atoms are tetravalent and can link to form chains or rings, allowing chemists to represent molecular skeletons and explain isomerism.[15] In 1861, Alexander Butlerov presented his theory of chemical structure, stating that the chemical nature of a molecule is determined not only by the number and type of atoms but also by their arrangement and bonding, and he introduced the term "chemical structure."[16][17] This framework was revolutionized in 1874 by Jacobus Henricus van 't Hoff, who proposed the tetrahedral geometry of carbon atoms, introducing stereochemistry and accounting for the optical activity of chiral molecules.[18] The late 19th century saw confirmation of structural ideas in inorganic chemistry through Alfred Werner's coordination theory of 1893, which differentiated primary ionic bonds from secondary coordination bonds in metal complexes, resolving discrepancies in isomerism and valence. The 1920s brought the integration of quantum mechanics into chemical bonding, with Walter Heitler and Fritz London's 1927 work explaining covalent bonds as shared electron pairs, providing an electronic basis for structural stability.[19] Key milestones validated these concepts experimentally: in 1913, William Henry Bragg and William Lawrence Bragg determined the first crystal structure of sodium chloride using X-ray diffraction, confirming its ionic lattice arrangement.[20] A landmark application came in 1953, when James Watson and Francis Crick elucidated the double-helical structure of DNA, demonstrating how structural principles underpin biological function.[21] This evolution addressed fundamental challenges, such as the inadequacy of empirical formulas—obtained via combustion analysis, which yielded only elemental ratios without bonding details—for distinguishing isomers, prompting the adoption of structural formulas that depict atomic connectivity.[22]Structural Representations
Two-Dimensional Notations
Two-dimensional notations provide simplified, planar representations of chemical structures, focusing primarily on atomic connectivity and bonding rather than spatial arrangement. These methods use symbols, lines, and abbreviations to depict molecules on flat surfaces like paper or digital screens, making them essential for quick communication in chemistry. They evolved from early symbolic systems to standardize the illustration of valence electrons and bonds, enabling chemists to infer molecular composition without exhaustive detail.[23] Lewis structures, introduced by Gilbert N. Lewis in 1916, represent molecules by showing valence electrons as dots and covalent bonds as lines connecting atomic symbols. In these diagrams, lone pairs are depicted as pairs of dots, while shared electron pairs form single, double, or triple bonds indicated by one, two, or three lines, respectively. The octet rule guides construction, aiming for most atoms (except hydrogen, which follows the duet rule) to achieve eight valence electrons through bonding and lone pairs. For example, water (H₂O) is shown with oxygen at the center bonded to two hydrogens via single lines, and two lone pairs on oxygen.[23][24][25] To assess stability and alternative resonance forms, formal charge is calculated for each atom using the formula: \text{[formal charge](/page/Formal_charge)} = V - N - \frac{1}{2}B where is the number of valence electrons in a neutral atom, is the number of nonbonding (lone pair) electrons, and is the number of bonding electrons. Structures with minimal formal charges and adherence to the octet rule are preferred, as in the carbonate ion (CO₃²⁻), where one resonance form places a -1 charge on an oxygen atom. This approach helps predict reactivity but assumes idealized electron distribution.[24][26][27] Condensed structural formulas offer a more compact alternative by linearly arranging atomic symbols and omitting explicit bond lines between carbons or hydrogens in chains. For instance, ethanol is written as CH₃CH₂OH, implying single bonds between the carbons and the oxygen, with hydrogens attached to satisfy valences. This notation groups atoms efficiently, such as (CH₃)₂CHOH for isopropanol, but requires familiarity to reconstruct the full connectivity. It is widely used in nomenclature and reaction schemes for its brevity.[28][29] Skeletal formulas, also known as line-angle or bond-line drawings, further simplify representations in organic chemistry by implying carbon atoms at line intersections and endpoints, with hydrogens omitted unless attached to heteroatoms. Bonds are shown as straight lines, and rings like benzene are depicted as hexagons without explicit labels. For example, cyclohexane appears as a simple hexagon, assuming CH₂ groups at each vertex. This method prioritizes the carbon skeleton for rapid sketching and analysis of functional groups.[30] Despite their utility, two-dimensional notations have inherent limitations, as they neglect three-dimensional geometry and stereochemistry, potentially misleading interpretations of molecular shape and interactions. Extensions like wedges and dashes can indicate depth but are not standard in pure 2D forms. These simplifications suit connectivity-focused tasks but require complementary methods for spatial insights.[31][32][29]Three-Dimensional Models
Three-dimensional models extend the representation of chemical structures by capturing the spatial relationships among atoms, including distances, angles, and orientations that influence molecular properties and interactions. These models bridge the planar depictions of bonding in two-dimensional notations, such as Lewis structures, to the actual geometries observed in molecules. By incorporating elements like bond lengths, angles, and torsional twists, they enable better prediction of reactivity, stereochemistry, and physical behavior.[33] Physical models provide tangible ways to manipulate and study molecular architectures. Ball-and-stick models depict atoms as colored spheres connected by rods representing bonds, emphasizing connectivity and approximate skeletal geometry while allowing rotation to explore conformations. Originating in the 1860s, these models remain valuable for educational purposes due to their simplicity and ability to illustrate bond angles and lengths visually.[34][35] In contrast, space-filling models represent atoms as interlocking spheres sized according to their van der Waals radii, offering a realistic portrayal of molecular volume, surface area, and potential steric interactions. Developed in the mid-20th century by Robert Corey, Linus Pauling, and Walter Koltun—known as CPK models—these emphasize atomic overlap and packing density, which is crucial for understanding non-bonded repulsions in crowded molecules.[34][36][37] Computational visualizations enhance these concepts through software that generates dynamic, high-resolution images of molecular structures. Tools like PyMOL allow rendering in wireframe mode to highlight bond frameworks, surface modes to display solvent-accessible areas based on van der Waals envelopes, and orbital representations to visualize electron distributions around atoms. These digital approaches facilitate analysis of complex systems, such as proteins, by enabling zooming, rotation, and overlay of multiple representations.[38][39] Key geometric descriptors quantify the three-dimensional features of molecules. For instance, the standard carbon-carbon single bond length in alkanes is approximately 1.54 Å, while bond angles in tetrahedral carbon environments, as in methane, measure 109.5°. Dihedral angles, which define torsional orientations, are 60° in the staggered conformation of ethane, minimizing steric strain compared to the 0° eclipsed form. These parameters, derived from experimental and theoretical data, serve as benchmarks for model accuracy and molecular simulations.[33][40] Stereochemical notations convey three-dimensional chirality and conformations in simplified drawings. Solid wedges indicate bonds projecting toward the viewer from a chiral center, while dashed lines denote those receding, allowing depiction of tetrahedral stereocenters without full 3D models. Newman projections, viewed along a specific bond axis, illustrate relative positions of substituents; for ethane, the staggered arrangement shows groups offset by 60° dihedrals, contrasting the higher-energy eclipsed state where they align. These conventions are essential for communicating asymmetry and rotational barriers.[41][42] The Valence Shell Electron Pair Repulsion (VSEPR) theory provides a foundational framework for predicting three-dimensional shapes from electron pair arrangements around a central atom. Proposed by Ronald Gillespie and Ronald Nyholm, it posits that electron pairs repel each other, arranging to maximize separation: lone pairs occupy more space than bonding pairs. For phosphorus pentachloride (PCl₅), five bonding pairs result in a trigonal bipyramidal geometry, with equatorial angles of 120° and axial-equatorial angles of 90°. This model underpins the design of many 3D representations by forecasting ideal geometries for main-group compounds.[43]Determination Methods
Experimental Techniques
Experimental techniques for determining chemical structures rely on empirical measurements from spectroscopic and diffraction methods, providing direct evidence of atomic arrangements, bonding, and functional groups in molecules. These laboratory-based approaches capture physical interactions of matter with radiation or particles, yielding data that can be interpreted to reconstruct molecular architectures with high precision. Key methods include X-ray crystallography for solid-state structures, nuclear magnetic resonance (NMR) spectroscopy for solution-phase connectivity, mass spectrometry for molecular formulas and fragments, and infrared (IR) or Raman spectroscopy for vibrational signatures of functional groups. By integrating these techniques, chemists achieve comprehensive structural elucidation that accounts for both local and global features. X-ray crystallography determines the three-dimensional arrangement of atoms in crystalline solids by analyzing diffraction patterns produced when X-rays interact with the electron clouds of atoms. The fundamental principle is Bragg's law, which describes the constructive interference condition for diffraction: , where is an integer, is the X-ray wavelength, is the interplanar spacing in the crystal lattice, and is the incidence angle. This law enables measurement of lattice parameters and, through Fourier transformation of diffraction intensities, generation of electron density maps that reveal atomic positions with typical resolutions of approximately 1 Å for small molecules.[44] These maps display regions of high electron density corresponding to atomic nuclei, allowing refinement of bond lengths, angles, and stereochemistry in the crystal phase. NMR spectroscopy elucidates molecular connectivity and spatial arrangements in solution by exploiting the magnetic properties of atomic nuclei, such as H and C. Chemical shifts (, measured in parts per million, ppm) indicate the electronic environment around each nucleus, while scalar coupling constants (, in hertz, Hz) reveal through-bond interactions between neighboring atoms, providing evidence for skeletal frameworks.[45] Two-dimensional techniques like COSY (correlation spectroscopy) map -coupled protons to establish adjacency, and NOESY (nuclear Overhauser effect spectroscopy) detects through-space proximities via dipole-dipole interactions, aiding in stereochemical assignments.[46] For example, NOESY cross-peaks between non-adjacent protons confirm spatial orientations in complex organic molecules. Mass spectrometry identifies molecular formulas and substructures by ionizing molecules and analyzing the mass-to-charge ratios () of resulting fragments. The molecular ion peak represents the intact ionized molecule, offering its exact mass and thus empirical formula when combined with isotopic patterns. Fragmentation patterns arise from bond cleavages, revealing connectivity; for instance, in carbonyl compounds like aldehydes or ketones, the McLafferty rearrangement produces a characteristic odd-electron ion at for methyl ketones, involving -hydrogen transfer and alkene elimination.[47] This process, prominent in electron ionization spectra, helps deduce functional group positions without requiring pure crystals. IR and Raman spectroscopies probe vibrational modes of molecules, identifying functional groups through characteristic absorption or scattering frequencies. In IR, the carbonyl stretch (C=O) appears as a strong band around 1700 cm, diagnostic of ketones, aldehydes, or esters depending on the exact position and intensity.[48] Raman complements IR by detecting symmetric vibrations less active in IR, such as C=C stretches near 1650 cm, with both techniques providing complementary fingerprints for bond types and molecular symmetry in gaseous, liquid, or solid samples.[49] Integrating these techniques enhances structural accuracy by leveraging complementary strengths; for example, X-ray crystallography provides precise solid-state atomic coordinates, while NMR offers dynamic solution-phase details, and their joint refinement resolves ambiguities in multidomain systems like proteins.[50] Mass and vibrational data further corroborate functional groups and formulas, ensuring robust validation across phases. This multifaceted approach is essential for complex molecules where single methods may overlook conformational or environmental effects.Computational Approaches
Computational approaches to chemical structure prediction and refinement rely on theoretical models and algorithms to simulate molecular geometries and energies from first principles or empirical parametrizations, enabling the exploration of structures inaccessible to direct experimentation. These methods range from quantum mechanical treatments that solve the Schrödinger equation approximately to classical simulations using force fields, often implemented in specialized software for tasks like geometry optimization and dynamic behavior analysis.[51] In quantum mechanics, the Hartree-Fock (HF) method serves as a foundational approximation for multi-electron systems by assuming each electron moves in an average field created by the others, leading to a set of self-consistent field equations solved iteratively to obtain molecular orbitals and energies. This approach neglects electron correlation but provides a starting point for more accurate methods. Density functional theory (DFT), building on the HF framework, approximates the electron density rather than the wavefunction, using exchange-correlation functionals to account for interactions; for geometry optimization, DFT minimizes the total energy with respect to nuclear coordinates via gradient descent algorithms, yielding equilibrium structures with high efficiency for medium-sized molecules.[52][51] Molecular mechanics employs classical force fields to model structures by summing potential energy terms for bonded and non-bonded interactions, treating atoms as classical particles with predefined parameters. The MMFF94 force field, for instance, includes harmonic terms for bond stretching, such as , where is the force constant and the equilibrium distance, alongside angle bending, torsional rotations, and non-bonded van der Waals and electrostatic interactions, making it suitable for diverse organic and biomolecular systems. Software like Gaussian facilitates ab initio calculations, including HF and DFT, for precise static structure predictions, while molecular dynamics simulations—often using these force fields—model dynamic processes such as protein folding by propagating atomic trajectories over time under Newtonian mechanics.[53][54][55] Accuracy varies by method: semi-empirical approaches like AM1 offer computational speed for large systems by parametrizing integrals empirically, though with higher errors in energies and geometries compared to post-HF methods such as MP2, which include second-order correlation for improved precision in small molecules. DFT typically achieves bond length errors of about 0.01 Å relative to experimental values, balancing accuracy and scalability. Hybrid applications, such as molecular docking in drug design, combine these techniques to predict ligand binding geometries by sampling poses and scoring interactions within protein pockets, aiding lead optimization.[56][57][58]Advanced Concepts
Stereochemistry
Stereochemistry is the study of the three-dimensional spatial arrangement of atoms and substituents in molecules, leading to distinct stereoisomers (including enantiomers and diastereomers) with potentially different physical, chemical, and biological properties.[59] Chirality arises when a molecule lacks an internal plane of symmetry and cannot be superimposed on its mirror image, resulting in handedness analogous to left and right hands.[60] A classic example is a tetrahedral carbon atom bonded to four different substituents, known as a chiral center or stereocenter.[59] Stereoisomers resulting from chirality include enantiomers, which are nonsuperimposable mirror images of each other and exhibit identical physical properties except for their interaction with plane-polarized light.[61] Diastereomers, in contrast, are stereoisomers that are not mirror images and thus possess different physical properties, such as melting points or solubilities, even though they share the same connectivity.[61] Atropisomers represent a special class of stereoisomers arising from restricted rotation about a single bond, typically due to steric hindrance from bulky substituents, allowing isolation of stable conformers at room temperature.[62] To designate the absolute configuration at a chiral center, the Cahn-Ingold-Prelog (CIP) priority rules are employed, assigning priorities to substituents based on atomic number (higher atomic number receives higher priority), with ties resolved by comparing attached atoms in order of decreasing atomic number. The lowest-priority substituent is oriented away from the viewer, and the configuration is labeled R (rectus, clockwise) or S (sinister, counterclockwise) based on the sequence of the remaining substituents. Chiral molecules exhibit optical activity, the ability to rotate the plane of polarized light, quantified by the specific rotation , defined as: where is the observed rotation in degrees, is the concentration in g/mL, and is the path length in decimeters.[63] Enantiomers rotate plane-polarized light to an equal extent but in opposite directions, while racemic mixtures (1:1 enantiomer pairs) are optically inactive.[63] Resolution of racemic mixtures into enantiomers can be achieved through chiral chromatography, which employs a chiral stationary phase to differentially interact with each enantiomer, enabling their separation based on transient diastereomeric complexes.[64] The biological implications of stereochemistry are profound, as enantiomers can elicit vastly different responses in chiral biological environments. For instance, the (R)-enantiomer of thalidomide exhibits sedative effects, while the (S)-enantiomer is teratogenic, causing severe birth defects; this tragedy in the 1950s–1960s underscored the need for enantiopure drugs.[65]Conformations and Isomerism
In chemical structures, conformations refer to the various spatial arrangements of atoms that result from rotation around single bonds, allowing interconversion without breaking covalent bonds. These arrangements occupy local energy minima on the molecule's potential energy surface, with barriers separating them that determine the rates of interconversion. For instance, in ethane, the staggered conformation is the global minimum, separated from the eclipsed transition state by a torsional barrier of approximately 12 kJ/mol.[66] In more complex alkanes like butane, rotational isomers or rotamers include the anti (most stable) and gauche forms, with the gauche conformation higher in energy by about 3.8 kJ/mol due to steric interactions between the methyl groups.[67] Isomerism encompasses molecules with identical molecular formulas but distinct arrangements of atoms, broadly classified into constitutional isomers and stereoisomers. Constitutional isomers, also known as structural isomers, differ in the connectivity of atoms, such as n-pentane (straight chain) and isopentane (branched), both C5H12.[68] A subset of constitutional isomers are tautomers, which interconvert rapidly via proton transfer, like the keto-enol forms in β-dicarbonyl compounds. In acetylacetone, the enol tautomer predominates in solution (equilibrium constant Kenol/keto ≈ 7–8), stabilized by intramolecular hydrogen bonding, and the compound exhibits a pKa of approximately 9 for deprotonation of the enol.[69] Stereoisomers share the same connectivity but differ in the spatial orientation of atoms; they are subdivided into enantiomers, which are non-superimposable mirror images, and diastereomers, which are stereoisomers that are not mirror images.[70] This classification tree highlights how constitutional differences precede spatial variations in defining molecular diversity. The dynamics of conformations involve energy barriers to rotation or interconversion, influencing observable populations. Nuclear magnetic resonance (NMR) spectroscopy provides evidence for these dynamics by resolving separate signals for rotamers at low temperatures when barriers exceed ~20–30 kJ/mol, or by line-shape analysis for faster exchanges. The free energy difference between conformers relates to their equilibrium populations via ΔG = −RT ln(K), where K is the ratio of concentrations; for butane at room temperature, Kanti/gauche ≈ 4.6 yields ΔG ≈ −3.8 kJ/mol, favoring the anti form.[71] In cyclic systems, such as cyclohexane, the chair conformation interconverts to an equivalent chair conformation via a boat or twist-boat transition state with an activation energy of about 45 kJ/mol, occurring rapidly at ambient temperatures despite the high barrier.[72]Specialized Tools and Formats
Digital Structure Formats
Digital structure formats enable the storage, exchange, and computational processing of chemical structures in machine-readable ways, facilitating cheminformatics applications such as database querying and molecular modeling.[73] These formats encode atomic connectivity, coordinates, and optional stereochemical details, promoting interoperability across software tools and databases.[74] The Simplified Molecular Input Line Entry System (SMILES) is a compact, linear string notation for representing molecular structures without coordinates.[73] In SMILES, atoms are denoted by their elemental symbols, bonds are implied as single unless specified (e.g., = for double), branches are enclosed in parentheses, and rings are indicated by matching numbers after the connected atoms.[73] For example, the SMILES stringCC(O)CC represents 2-butanol, where the parentheses denote the hydroxyl branch on the second carbon.[73] This format supports canonicalization for unique representations and is widely used for substructure searching due to its simplicity and compactness.[73]
The International Chemical Identifier (InChI), developed by IUPAC, provides a hierarchical, non-proprietary string-based encoding that captures molecular topology in layers.[75] The standard InChI begins with "InChI=1S/" followed by the molecular formula, then layers for connectivity (/c), hydrogens (/h), stereochemistry (/t for tetrahedral, /b for double bonds), and isotopes if applicable.[74] For benzene, the InChI is InChI=1S/[C6H6](/page/C6H6)/c1-2-4-6-5-3-1/h1-6H, where the /c layer describes the ring connectivity and the /h layer specifies hydrogen positions.[74] InChI ensures uniqueness and reversibility to the original structure, making it suitable for database indexing and cross-platform exchange.[75]
MOL and SD files, originating from MDL Information Systems (now part of PerkinElmer), store chemical structures as plain-text files with explicit 2D or 3D atomic coordinates.[76] A MOL file consists of a header, a connection table with atom records (listing element, x/y/z coordinates), bond records (atom indices and bond types), and optional properties; SD files extend this to multiple structures for batch processing.[76] Atom blocks specify positions in Angstroms, enabling visualization and simulation, while these formats are prevalent in cheminformatics databases for storing conformer data.[77]
The Protein Data Bank (PDB) format is tailored for biomolecular structures, archiving atomic coordinates from experimental sources like X-ray crystallography.[78] It uses fixed-width records, with ATOM lines detailing residue name, chain identifier, atom name, and x/y/z coordinates (e.g., for a carbon alpha atom: "ATOM 1 N MET A 1 26.760 13.920 22.950 1.00 21.87 N").[78] Designed for proteins, nucleic acids, and complexes, PDB supports multiple models and includes metadata like resolution.[79] An extension, the macromolecular Crystallographic Information File (mmCIF), adopts a dictionary-based, self-documenting syntax for richer data representation, including hierarchical assemblies and experimental details, and has become the deposition standard since 2014.[80]
These formats enhance interoperability in cheminformatics workflows, as seen in toolkits like RDKit, which parses SMILES, InChI, MOL, and PDB for operations such as fingerprint generation and virtual screening.[81] They also enable efficient structure-based searches in repositories like PubChem, where users query by SMILES or InChI to retrieve millions of compounds with associated bioactivity data.[82]
Typesetting Chemical Structures
Typesetting chemical structures involves specialized techniques to visually represent molecular diagrams in documents, ensuring clarity, accuracy, and compatibility across print and digital media. These methods have evolved from manual illustrations to automated tools that integrate seamlessly with text and equations, facilitating communication in scientific publications. Key approaches include markup-based systems for static rendering and interactive libraries for web environments, each addressing the need to depict bonds, atoms, and spatial arrangements without distortion. Historically, chemical structures were rendered by hand-drawing, a labor-intensive process prone to inconsistencies and errors in depicting complex molecules. This shifted in the late 20th century with the advent of automated software; for instance, ISIS/Draw, developed by MDL Information Systems in the 1990s, introduced digital sketching capabilities that allowed users to create and export 2D diagrams for inclusion in reports and journals, marking a transition to reproducible, editable representations.[83][84] In LaTeX-based typesetting, packages like chemfig and XyMTeX enable the creation of vector-based chemical diagrams directly within documents, producing scalable output suitable for high-resolution printing. The chemfig package, for example, uses a simple syntax to draw structures, such as\chemfig{H-O-H} for water, allowing bonds to be specified with angles and lengths for precise control.[85] XyMTeX, an earlier system, focuses on structural formulas using mathematical notation extensions, generating PostScript vectors that integrate well with LaTeX equations but require more setup for organic molecules.[86][87] Pros of these vector approaches include infinite scalability without pixelation and embedding in PDFs for searchable documents; however, they can be verbose for intricate structures and may demand familiarity with TeX syntax, potentially slowing workflow compared to graphical editors.[88]
For digital and web-based rendering, SVG and HTML5 technologies support inline chemical diagrams through JavaScript libraries like ChemDoodle Web Components, which generate interactive 2D and 3D visuals from molecular data. These libraries produce SVG output that scales responsively in browsers and enhances accessibility by incorporating ARIA labels for screen readers to describe atomic connections and stereochemistry.[89][90]
Best practices for typesetting emphasize scalability to maintain line widths and bond angles across sizes, using vector formats like SVG or EPS to avoid raster artifacts in publications. Color should be applied judiciously for element differentiation—e.g., black for carbon, red for oxygen—while ensuring grayscale compatibility and avoiding overload that obscures details; integration with equations involves aligning baselines for subscripts and superscripts to match document fonts.[91][92][93]
Challenges persist in rendering complex stereochemistry, where wedges and dashes for chiral centers must convey depth without ambiguity, often requiring custom macros in LaTeX or layered SVGs that may not render consistently across devices. Font-independent symbols, such as sans-serif glyphs for atoms per IUPAC guidelines, help mitigate variability, but ensuring compatibility in legacy systems or diverse outputs remains difficult.[94][95][96]