The two examples at the bottom are cases in which cyclobutanol formation exceeds type II cleavage. Phenyl cyclobutyl ketone yields a biradical in which the four-membered ring must undergo severe distortion to align its unpaired electron with the C–C bond that must be broken. Preferential formation of the strained bicyclo[1.1.1]pentane compound is a dramatic example of the importance of such stereoelectronic factors. In the second example, one end of the biradical is allylic, so again the odd electron in this radical system is held orthogonal to the C–C bond normally broken in a type II cleavage.
Chemistry of Vision
Many important biological processes are triggered by light signals. One such trigger, found in different species such as mammals, plants and bacteria, is the cis/trans-isomerization of a C=C bond. For example, the primary photoswitch for mammalian vision is cis-trans isomerization of retinal, derived from vitamin A, when bound to proteins known as opsins. The following diagram shows the overall event. Rhodopsin, a protonated Schiff base or imine formed from 11-cis-retinal and a lysine primary amine in opsin, is isomerized to the all-trans configuration of the chromophore. This photoisomerization induces a series of conformational changes in the chromophore and the opsin protein, resulting in an enzymatic cascade and the generation of an optic nerve impulse. The all trans-retinal is then liberated, and through a number of enzymatic reactions 11-cis-retinal is regenerated and bound to the opsin.
Time-resolved absorption experiments have shown that the cis-trans isomerization of the rhodopsin chromophore is complete in only 200 fs (a femtosecond is 10-15 second). The initial product, called photorhodopsin, is believed to be a hot, conformationally distorted form of the trans chromophore, which relaxes to bathorhodopsin in ca. 5 ps (a picosecond is 10-12 second). These events will be displayed above by clicking on the diagram. Bathorhodopsin has been studied extensively because it is the first intermediate that can be trapped at 77 ºK. Because the hydrophobic pocket holding the retinal chromophore restricts its conformational motion, the isomerization to bathorhodopsin is thought to take place by a hula-twist of the C12–H group. Resonance Raman studies of vibrational modes in rhodopsin and bathorhodopsin suggest that conformational distortion drives subsequent protein conformational changes. Later intermediates in the rhodopsin cascade have also been characterized, as shown in the redrawn diagram. Structures for many of these intermediates have yet to be determined.
Color perception in humans and primates is achieved by color receptors containing pigments with different light absorption characteristics. Trichromats, like humans, have trichromatic color vision resulting from three types of color receptors, known as cone cells. Many other mammals, including some primates, are dichromats, and have little or no color vision. Opsin proteins, differing in a few amino acids, absorb light at different wavelengths as retinal-bound pigments. The cones of the human eye are maximally receptive to short (S), medium (M), and long (L) wavelengths of light. Although L-cones are often referred to as red receptors, spectrophotometry has shown that their peak sensitivity is in the yellow region of the spectrum. Three different iodopsins (rhodopsin analogs) form the protein-pigment complexes photopsin I (L-cones), II (M-cones), and III (S-cones). These photopsins have absorption maxima for yellowish-green (photopsin I, 500–700 nm), green (photopsin II, 450–630 nm), and bluish-violet light (photopsin III, 400–500 nm). It is these differences that produce the remarkable color distinction that we enjoy.
Human erythrocytes (red blood cells) have a lifetime of about 3 months. When erythrocytes get old or are damaged, they are destroyed in the spleen and bone marrow. This releases hemoglobin, which is broken down to heme and component amino acids. The porphyrin ring of the heme molecule is oxidatively cleaved at a α-methine bridge, forming a water-soluble green pigment, biliverdin. As shown in the following diagram, biliverdin is reduced by the enzyme biliverdin reductase to bilirubin, a toxic yellow pigment. Bilirubin is then bound to albumin for transport to the liver. The changing color of a bruise from purple to yellow over time reflects this reaction. Excretion of bilirubin leads to the brown color of feces.
Neonatal jaundice occurs when bilirubin builds up faster than a newborn's still-developing liver can break it down, resulting in deposition of water- insoluble bilirubin in the skin and other internal organs. High levels of bilirubin can cause deafness, cerebral palsy, or brain damage in some infants.
The name Vitamin D is applied, often casually, to several different steroidal substances. Chemists commonly use it as shown in the following diagram. The stable Provitamin may be ingested or metabolically produced. When irradiated in the epidermis by ultraviolet light (UVB, 270–290 nm), it undergoes an electrocyclic opening of ring-B to form an unstable Previtamin, which then rearranges to Vitamin D (Calciferol) by a thermal (> 20 ºC) sigmatropic hydrogen shift. Two families of this vitamin differ only in the structure of the long side-chain on ring D. Vitamin D2 comes from fungal and plant sources as the provitamin ergosterol, which is not synthesized in the human body. Vitamin D3 is derived from animal sources and comes from the provitamin 7-dehydrocholesterol. Commercial vitamin D supplements are usually D3 (cholecalciferol). An early crystalline substance called vitamin D1 proved to be a 1:1 mixture of D2 and lumisterol.
All of the conjugated dienes and trienes drawn here absorb strongly in the 260–300 nm region of the ultraviolet. Indeed, several other photochemical and thermal reactions take place and are shown in the diagram. These include photochemical electrocyclization of the previtamin to lumisterol (Lum) and the provitamin (Pro), photochemical stereoisomerization to tachysterol (Tac), and thermal (> 100 ºC) electrocyclization to stereoisomeric pyrocalciferols.
The remarkable stereoselectivity displayed by many of the transformations in the vitamin D field helped stimulate interest in a varied group of concerted reactions, sometimes referred to as "no-mechanism" reactions. This eventually led to enunciation of the Woodward-Hoffmann rules for pericyclic reactions. The reversible photochemical conrotatory ring opening of the 8,9-anti isomers Pro and Lum to Pre, and the thermal disrotatory electrocyclic closure of Pre to the 8,9-syn isomers Pyc and Ipc provided early examples of the importance of orbital symmetry control in such reactions. Additional evidence came from the disrotatory photocyclization of Pyc and Ipc to the cyclobutene compounds photopyrocalciferol and isophotopyrocalciferol, as shown on the right.
Santonin and Related Compounds
The exceptionally rich photochemistry of santonin is displayed in the following diagram. In dioxane or benzene solution irradiation with 254 nm light gave a high yield of a tetracyclic isomer named lumisantonin. If the solvent is changed to 45% aqueous acetic acid a different hydrated product, isophotosantonic lactone, is formed. Other minor photoproducts include [2+2]-dimers of lumisantonin and mazdasantonin. Lumisantonin itself undergoes additional solvent dependent photochemical transformations, shown in the bottom part of the diagram.
Rationalizing the formation of isophotosantonic lactone from santonin by irradiation in aqueous acetic acid was complicated by the fact that this hydrated enone was also obtained by heating lumisantonin in the same solvent. Nevertheless, the photochemical reaction is unlikely to proceed by way of lumisantonin, since heat is not required and photolysis of lumisantonin in aqueous acetic acid yields photosantonic acid rather than isophotosantonic lactone. Suggested mechanisms for the photochemical transformation of santonin and the thermal reaction of lumisantonin will be shown above by clicking on the diagram a second time. Note that the bond shift (c) that leads to lumisantonin from the initial dipolar state changes to bond a in acetic acid, possibly due to protonation of the enolate anion moiety. Both shifts produce a three-membered ring, which in the latter case is activated for nucleophilic opening by the carbonyl function. The thermal isomerization of lumisantonin in acetic acid is drawn at the bottom of the diagram.
A noteworthy aspect of santonin photochemistry is the absence of phenolic products, even though strong acid readily isomerizes santonin to the phenol, desmotroposantonin, as shown on the right. Other 2,5-cyclohexadienones often yield phenols on irradiation, examples being 4,4-diphenyl-2,5-cyclohexadienone and the four reactions drawn in the following diagram. The presence of a C-4 methyl substituent (steroid numbering, as shown in #4) is one factor, but the trans-fused γ-lactone at the C-6:C-7 bond appears to be the chief impediment to formation of phenolic products from santonin. As shown in example #3, a spiro carbocation intermediate lies on the reaction path leading to phenols. In santonin, such an intermediate would be destabilized by the strain introduced by the trans-lactone, and the inductive effect of the lactone oxygen would diminish the positive charge concentration at C-4 that induces the ring contraction.