Reactions of carboxylic acids and their salts include nucleophilic substitution and decarboxylation to leave enols, free radicals, or alkyl halides. A review of the IR spectroscopy of acid derivatives includes the use of vibrational coupling in the structure determination of anhydrides and imides. Many acid derivatives can be interconverted by substitution through a tetrahedral intermediate, and differences in acidity can be used to drive such reactions toward completion. Reduction of acid...

Painstaking studies of his “hexaphenylethane” and its reactivity convinced Gomberg that he had prepared the first trivalent carbon compound, triphenylmethyl radical, the discovery of which marked the emergence of fundamental organic chemistry in America. Isotopic labeling could decide whether protonated cyclopropane plays a role in Friedel-Crafts alkylation. C-13 NMR spectra of aldehydes and ketones show how characteristic chemical shifts are established empirically. The carbonyl group is...

The coincidentally substantial extent of ionic dissociation of water provides an example of Brønsted acidity, or nucleophilic substitution at hydrogen. Relative pKa values are insensitive enough to solvent that they provide insight on the role of energy-match, overlap, and resonance in ionic dissociation. The titration of alanine in water illustrates the experimental determination of pKa values and the phenomenon of buffering. The limited pKa scale in water can be extended dramatically by...

Discoverers of the structure and biological activity of steroid hormones won seven Nobel Prizes between 1927 and 1975. Studying the steps involved in Woodward’s 1951 “total” synthesis of cortisone provides a review of the organic reactions covered this semester. Many steps involved novel insights, others were based on lore from previous work In the area. The overall yield of such sequential syntheses is typically much lower than that of convergent syntheses. Practical syntheses of...

Modern spectroscopic tools show not only the constitution, configuration, and conformation of glucose but also how it interconverts between isomeric hemiketal pyranose rings. One of mankind’s great accomplishments was determinining its constitution and especially its configuration before such spectroscopy. By 1887 Heinrich Kiliani had established the constitution of glucose as an aldohexose, and with help from Emil Fischer, he developed a method for homologating aldoses. Fisher assembled a...

As in many synthetic procedures, an important challenge in ketone alkylation is choosing reagents and conditions that allow control of isomerism and of single vs. multiple substitution. [gr]β-Dicarbonyl compounds allow convenient alkylation and preparation of ketones and carboxylic acids. The aldol condensation, in which an [gr]a-position adds to a carbonyl group to generate a [gr]β-hydroxy- or an [gr]α,β-unsaturated carbonyl compound, can be driven to completion by removal of water. The...

When a nucleophilic atom bearing a good leaving group attacks a carbonyl group, an adjacent R group can migrate to the new atom, inserting it into the R-acyl bond. This mechanism can insert O, NH, or CH2 groups into the acyl bond with informative stereospecificity in the case of the Beckmann rearrangement of oximes. Although the migrating groups are formally anionic, relative migratory aptitudes show that they give up electron density during rearrangement. Acid dissociation of protons [gr]α...

Green chemistry needs new asymmetric reactions and safer, more environmental Mitsunobu reactions. The Mitsunobu mechanism is general and reliable, but atom inefficient, generating almost 30 times as much weight of by-products as of the water it is designed to eliminate. Admirably green processes include autoxidation of aldehydes to carboxylic acids using only O2, and oxidation of alcohols by loss of H2 using a ruthenium catalyst. Relative pKa values of carboxylic acids provide insight into...

Spectroscopic determination of bond dissociation energies is relatively straightforward for many diatomic molecules, but for polyatomic molecules it requires merging the results from a variety of challenging experiments. Professor Ellison describes how such techniques as flowing-afterglow mass spectroscopy and negative-ion photoelectron spectroscopy together with data on free-radical kinetics and heats of formation have allowed precise determination of the O-H, C-H, and C-O bonds in methanol...

A difficult exam question shows how visible and NMR spectroscopy related to long-term misassignment of the structure for the triphenylmethyl dimer. Evidence from 1970 shows that Friedel-Crafts propylation involves an SN2 mechanism, not a protonated cyclopropane. Assigning oxidation states from -4 to +4 to the carbon atoms of proposed starting material and product allows choosing whether a reagent that is oxidizing or reducing or neither is appropriate. Beyond belonging to the appropriate...

The ability of periodic acid (HIO4) to cleave the C-C bond of vicinal diols and [gr]α-hydroxycarbonyl compounds allowed structure determination of sugars and their ketals before spectroscopy was available. Reduction of carbonyl compounds by organometallic or hydride reagents provides a range of schemes for synthesizing various alcohols, where preference may be dictated by the desire to avoid competing processes. Wittig olefination allows conversion of C=O to C=C with good control over...

Imines are pervasive in chemistry and biology, playing key roles both the in artificial Strecker synthesis of amino acids and their biosynthesis by L-glutamate dehydrogenase and by transamination. Imines are also involved in Stork’s [gr]α-alkylation and acylation of ketones by way of enamine intermediates. Oxidation and reduction in organic chemistry can involve actual electron transfer, when ion-radical intermediates are involved as in the formation of Grignard reagents or in the pinacol...

This lecture aims at developing facility with devising plausible mechanisms for acid- and base-catalyzed reactions of carbonyl compounds, carboxylic acids, and their derivatives. When steric hindrance inhibits the A/D mechanism of Fischer esterification, an acid-catalyzed D/A mechanism can still occur. Substituent influence on the equilibrium constants for carbonyl hydration demonstrates four effects: bond strength, steric, electron withdrawal, and conjugation. Cyclic acetals play an...

The Friedel-Crafts reaction creates new alkyl- or acyl-aromatic bonds, with or without cation rearrangement. Designing reaction sequences, especially those involving diazonium intermediates, so as to access a wide variety of substituted benzenes provides a good introduction to the challenges of synthetic organic chemistry. Aromatic rings with strong electron withdrawal can undergo nucleophilic aromatic substitution, which plays an important role in biochemistry. The special properties of...

Proton decoupling simplifies C-13 NMR spectra. Dilute double labeling with C-13 confirmed the complex rearrangement scheme in steroid biosynthesis. Two-dimensional NMR yields correlations between NMR signals that underlie structural determination of proteins and identification of the mechanism of a rapid carbocation rearrangement. Substitution of an electrophile for a proton on an aromatic ring proceeds by a two-step association-dissociation mechanism involving a cyclohexadienyl cation...

Because spin-spin splitting depends on electron spin precisely at a nucleus, splitting by a C-13 depends on its orbital’s hybridization. “Higher-order effects” that give complex multiplets for nuclei with similar chemical shifts can be understood in terms of the mixing of wave functions of similar energy. Averaging of chemical shifts or spin-spin splitting may be used to measure the rate of rapid changes in molecular structure, such as changes in conformation or hydrogen bonding. Since the...

Through-space interaction between magnets of fixed strength and orientation averages to zero during random molecular tumbling, suggesting that the local field about a proton should be sensitive only to electrons that orbit about itself. The chemical shift can be sensitive to electrons orbiting elsewhere if the amount of orbiting varies with molecular orientation. This “diamagnetic anisotropy” is commonly used to rationalize the unusual chemical shifts of protons in acetylene and in aromatic...

Magnetic resonance imaging (MRI) requires gradients in the applied magnetic field, while chemical nuclear magnetic resonance (NMR) requires a highly uniform field. When protons in different parts of the body can be driven to broadcast different frequencies, tomography allows reconstructing a three-dimensional image showing water location. Dependence of the signal intensity on relaxation allows BOLD functional MRI that shows brain activity. When the applied magnetic field is sufficiently...

Infrared spectroscopy provides information for analyzing molecular structure and for understanding bonding and dynamics. Although the normal modes of alkanes involve complex coordinated vibration of many atoms, the unusual strengths of multiple bonds give alkenes and alkynes distinctive stretching frequencies. The intensity of characteristic out-of-plane C-H bending peaks allows assignment of alkene configuration. Characteristic carbonyl stretching peaks in various functional groups...

Time-dependent quantum mechanics shows how mixing orbitals of different energy causes electrons to vibrate. Mixing 1s with 2p causes a vibration that can absorb or generate light, while mixing 1s with 2s causes “breathing” that does not interact with light. Many natural organic chromophores involve mixing an unshared electron pair with a vacant pi orbital, whose conjugation determines color. Infrared spectra reveal atomic vibration frequencies, which are related by Hooke’s law to bond...

Cyclic conjugation that arises when p-orbitals touch one another can be as important for transition states as aromaticity is for stable molecules. It is the controlling factor in “pericyclic” reactions. Regiochemistry, stereochemistry, and kinetics show that two new sigma bonds are being formed simultaneously, if not symmetrically, in the 6-electron Diels-Alder cycloaddition. Although thermal dimerization of thymine residues in DNA is forbidden, photochemistry allows the 4-electron...

Despite the substantial change in the energy of individual orbitals, the overall pi-electron energy and orbital shape changes little upon linear conjugation of two double bonds. Conjugation energy of polyenes and allylic systems may be predicted by means of a semicircle mnemonic. The much greater stabilization in “aromatic” conjugated rings, and Hückel’s 4n+2 rule, derive from alternating stabilization and destabilization of successive orbitals when the ends of a conjugated chain overlap as...

Because of their unusual acidity very strong base makes it possible to isomerize an internal acetylene to the less stable terminal isomer. Many chemical reactions may be understood in terms of localized bonds, but the special stability of conjugated systems requires considering delocalized orbitals or “resonance.” Equilibrium constants, rates, and regiochemistry in systems involving allylic cations, anions, transition states, and free radicals demonstrate that allylic conjugation is worth...

Isoprenoid or terpene natural products, that seem to be made from isoprene (2-methylbutadiene), are formed by oligomerization of electrophilic isopentenyl pyrophosphate (IPP). Latex, the polymer of IPP, became commercially important when Charles Goodyear, a New Haven native, discovered how to vulcanize rubber. Statistical mechanics explains such curious properties of rubber as contraction upon heating when tightly stretched. Specific chemical treatment confers useful properties on a wide...

Alkenes may be oxidized to diols by permanganate or by OsO4 catalysis. Metal catalysts provide orbitals that allow simultaneous formation of two bonds from metal to alkene or H2. Coupling such oxidative additions to reductive eliminations, provides a low-energy catalytic path for addition of H2 to an alkene. Such catalytic hydrogenation is often said to involve syn stereochemistry, but the primary literature shows that addition can be anti when allylic rearrangement occurs on the catalyst. ...