Factors steric

A clear demonstration of the relative importance of steric and resonance factors in radical additions to carbon-carbon double bonds can be found by considering the effect of (non-polar) sub.stitucnts on the rate of attack of (nonpolar) radicals. Substituents on the double bond strongly retard addition at the substituted carbon while leaving the rate of addition to the other end essentially unaffected (for example, Table 1.3). This is in keeping with expectation if steric factors deteniiine the regiospecificity of addition, but contrary to expectation if resonance factors are dominant. 

It is possible to resolve steric factors into several tenns  

Radical additions are typically highly exothermic and activation energies are 

Various ab initio and scmi-cmpirical molecular orbital calculations have been carried out on the reaction of radicals with simple alkenes with the aim of defining the nature of the transition state (Section These calculations all predict 

The rate of radical addition is most dramatically affected by substituents cither at the site of attack or at the radical center. Remote substituents generally have only a small influence on the stereochemistry and regiospecificity of addition unless these groups are very bulky or the geometry of the molecules is constrained e.g. intramolecular addition - Section 1.2.4). 

Although the stabilities of products and intermediates are very important factors in determining ion abundances, steric factors also affect the fragmentation kinetics. Stereochemistry can sometimes be deduced from mass spectra (Green 1976 Mandelbaum 1977,1982 Turecek 1987), especially if the spectra of complementary stereoisomers are available for comparison. Stereochemical effects can be different for OE versus EE ions and for simple bond dissociations versus rearrangements. 

Route (b), giving the more-stable toluene ion, is disfavored because of a tighter four-membered transition state for the hydrogen transfer. 

Steric effects can also arise from non-bonding strain due to steric crowding in the molecular ion the fragmentation by loss of a substituent results in strain relief, which promotes the dissociation (Pihlaja et at. 1982). For example, the appearance potential of (M - CHg) from o-di-tert-butylbenzene is 0.9 eV lower than that from the m- and p-isomers this was attributed to the difference in the strain energies in the corresponding molecular ions (Arnett 1967). 

Unknown 8.1. What is unusual about this ion series  

Intermediate complexes. Quite different steric effects operate in fragmentations proceeding via ion-molecule complexes (Morton 1982, McAdoo 1988 Bowen 

Donor molecules may be different in shape and size. When a single donor molecule is coordinated steric factors are likely to be of little importance, unless the available space at the coordination site is very small. Indeed steric contributions were not considered when the donor number was introduced. The situation is, however, different, when coordination of several solvent molecules occurs or when little room is available for the solvent molecules within the coordination sphere. Thus steric considerations will become important when small ions are to be coordinated by several large or bulky ligands. The results obtained will then not be in agreement with the donor number of the particular solvent. 

With many other transition metal cations such steric considerations will be of importance to account for the observed behaviour. 

It should be noted that the inductive effect is not the only factor affecting the rate of hydrolysis. The substituent may also have a steric effect. For example, a bulky substituent may shield the ester from attack and lower the rate of hydrolysis. It is therefore necessary to separate out these two effects. This can be done by measuring hydrolysis rates under basic conditions and also under acidic conditions. Under basic conditions, steric and electronic factors are important, whereas under acidic conditions only steric factors are important. By comparing the rates, values for the electronic effect (ar), and for the steric effect (Es) (see below) can be determined. 

In order for a drug to interact with an enzyme or a receptor, it has to approach, then bind to a binding site. The bulk, size, and shape of the drug may have an influence on this process. For example, a bulky substituent may act like a shield and hinder the ideal interaction between drug and receptor. Alternatively, a bulky substituent may help to orientate a drug properly for maximum receptor binding and increase activity. 

Quantifying steric properties is more difficult than quantifying hydrophobic or electronic properties. Several methods have been tried and three are described here. It is highly unlikely that a drug s biological activity will be affected by steric factors alone, but these factors are frequently to be found in Hansch equations (Section 9.4.). 

Attempts have been made to quantify the steric features of substituents by using Taft s steric factor (Es). The value for Es can be obtained as described in Section 9.3.2. However, the number of substituents which can be studied by this method is restricted. 

Another measure of the steric factor is provided by a parameter known as molar refractivity (MR). This is a measure of the volume occupied by an atom or group of atoms. The molar refractivity is obtained from the following equation  

The first term is of importance in all atom abstraction reactions, however, since the reactions are often highly exothermic with consequent early transition slates, the effect may be small. 

FIGURE 2.34 Change of dihedral angles upon changing the ring conformation. 

FIGURE 2.36 The a,p-anomeric ratio of some D-glucopyranose derivatives. 

C-X bond is axially oriented that is, they apply only to the conformation of the a-D-anomers and to the 4 conformation of the (3-D-anomers. 

FIGURE 2.39 Three Cl — O xo rotamers of the a-D-anomer and their Newman projections. 

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The importance of steric factors in the formation of penetration complexes is made evident by the observation that although sodium cetyl sulfate plus cetyl alcohol gives an excellent emulsion, the use of oleyl alcohol instead of cetyl alcohol leads to very poor emulsions. As illustrated in Fig. XIV-3, the explanation may lie in the difficulty in accommodating the kinked oleyl alcohol chain in the film. 

Once the molecules are aligned, a molecular field is computed on a grid of points in space around the molecule. This field must provide a description of how each molecule will tend to bind in the active site. Field descriptors typically consist of a sum of one or more spatial properties, such as steric factors, van der Waals parameters, or the electrostatic potential. The choice of grid points will also affect the quality of the final results. 

The cases of pentamethylbenzene and anthracene reacting with nitronium tetrafluoroborate in sulpholan were mentioned above. Each compound forms a stable intermediate very rapidly, and the intermediate then decomposes slowly. It seems that here we have cases where the first stage of the two-step process is very rapid (reaction may even be occurring upon encounter), but the second stages are slow either because of steric factors or because of the feeble basicity of the solvent. The course of the subsequent slow decomposition of the intermediate from pentamethylbenzene is not yet fully understood, but it gives only a poor yield of pentamethylnitrobenzene. The intermediate from anthracene decomposes at a measurable speed to 9-nitroanthracene and the observations are compatible with a two-step mechanism in which k i k E and i[N02" ] > / i. There is a kinetic isotope effect (table 6.1), its value for the reaction in acetonitrile being near to the... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

The regioselectivity of the reaction appears to be determined by a balance of electronic and steric factors. For acrylate and propiolate esters, the carb-oxylate group is found preferentially at C3 of the carbazole product[6-8]. Interestingly, a 4-methyl substituent seems to reinforce the preference for the EW group to appear at C3 (compare Entries 4 and 5 in Table 16.2). For disubstituted acetylenic dicnophiles, there is a preference for the EW group to be at C2 of the carbazole ring[6]. This is reinforced by additional steric bulk in the other substituent[6,9]. 

The steric effects of alkyl substituents (R= methyl, ethyl, i-propyl, f-butyl) on the nitrogen have been related to the steric factors of these same groups as measured in kinetic studies (152). 

Numerous studies have probed how novolac microstmcture influences resist hthographic properties. In one example, a series of resists were formulated from novolacs prepared with varying feed ratios ofpara-jmeta-cmso. These researchers found that the dissolution rate decreased, and the resist contrast increased, as thepara-jmeta-cmso feed ratio increased (33). Condensation can only occur at the ortho position ofpara-cmso but can occur at both the ortho- and i ra-positions of meta-cmso. It is beheved that increased steric factors and chain rigidity that accompany increasedpara-cmso content modify the polymer solubihty. 

Steric Factors. Initially, most of the coUisions of fluorine molecules with saturated or aromatic hydrocarbons occur at a hydrogen site or at a TT-bond (unsaturated) site. When coUision occurs at the TT-bond, the double bond disappears but the single bond remains because the energy released in initiation (eq. 4) is insufficient to fracture the carbon—carbon single bond. Once carbon—fluorine bonds have begun to form on the carbon skeleton of either an unsaturated or alkane system, the carbon skeleton is somewhat stericaUy protected by the sheath of fluorine atoms. Figure 2, which shows the crowded hehcal arrangement of fluorine around the carbon backbone of polytetrafluoroethylene (PTFE), is an example of an extreme case of steric protection of carbon—carbon bonds (29). 

Free-radical reaction rates of maleic anhydride and its derivatives depend on polar and steric factors. Substituents added to maleic anhydride that decrease planarity of the transition state decrease the reaction rate. The reactivity decreases in the order maleic anhydride > fumarate ester > maleate ester. 

In the presence of a large excess of PH, primary phosphines, RPH2, are formed predominantiy. Secondary phosphines, R2PH, must be either isolated from mixtures with primary and tertiary products or made in special multistep procedures. Certain secondary phosphines can be produced if steric factors preclude conversion to a tertiary product. Both primary and secondary phosphines can be substituted with olefins. After the proper selection of substituents, mixed phosphines of the type RRTH or RR R T can be made. 

Amines can also swell the polymer, lea ding to very rapid reactions. Pyridine, for example, would be a fairly good solvent for a VDC copolymer if it did not attack the polymer chemically. However, when pyridine is part of a solvent mixture that does not dissolve the polymer, pyridine does not penetrate into the polymer phase (108). Studies of single crystals indicate that pyridine removes hydrogen chloride only from the surface. Kinetic studies and product characterizations suggest that the reaction of two units in each chain-fold can easily take place further reaction is greatiy retarded either by the inabiUty of pyridine to diffuse into the crystal or by steric factors. 

Steric factors are important ia transesterification reactions. With a given alcohol, primary alkyl borates react at a rate too fast to measure, secondary alkyl borates react at measurable rates, and tert-huty borate reacts very slowly. 

These reactions are also quite sensitive to steric factors, as shown by the fact that if 1-butene reacts with di(j iAisoamyl)borane the initially formed product is 99% substituted in the 1-position (15) compared to 93% for unsubstituted borane. Similarly, the product obtained from hydroformylation of isobutylene is about 97% isoamyl alcohol and 3% neopentyl alcohol (17). Reaction of isobutylene with aluminum hydride yields only triisobutjlaluininum. 

Steric Selectivity. In addition to the normal regularities that can be rationalized by electronic considerations, steric factors are important in coordination chemistry. To illustrate, 8-hydroxyquinoline, or 8-quinolinol (Hq) [148-24-3J, at 100°C precipitates both Mg " and AE" from aqueous solution as hydrated Mg(q)2 (formulated as Mg(q)2(H20)2 [56531 -18-1]) and as Al(q)3 [2085-33-8] respectively. 2-Meth54-8-hydroxyquinohne [826-81-3] (6),... 

Another important factor affecting the electronic properties is the steric barrier to planarity along the polymer chain. Since polyheterocycles and polyarylenes must adopt a planar geometry in the ionized state to form quinoid-like segments, steric factors that limit the ability of the polymer to adopt geometries which are planar with respect to adjacent rings have a detrimental effect on the electronic properties (181). 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

The triethylsilyl ether is approximately 10-100 times more stable than the TMS ether and thus shows a greater stability to many reagents. Although TMS ethers can be cleaved in the presence of TES ethers, steric factors will play an important role in determining selectivity. The TES ether can be cleaved in the presence of a /-butyldimethylsilyl ether using 2% HE in acetonitrile. In general, methods used to cleave the TBDMS ether are effective for cleavage of the TES ether. 

EtSNa, DMF, reflux, 3 h, 94-98% yield.Potassium thiophenoxide has been used to cleave an aryl methyl ether without causing migration of a double bond. odium benzylselenide (PhCH2SeNa) and sodium thiocre-solate (p-CH3C6H4SNa) cleave a dimethoxyaryl compound regioselec-tively, reportedly as a result of steric factors in the former case and electronic factors in the latter case. ... 

Camphor cannot be protected with this reagent indicating that steric factors will prevent its use in vcr> hindered systems. 

HS(CH2) SH, BF3-Et20, CH2CI2, 25°, 12 h, high yield, n = 2, n = 3. In a,/3-unsaturated ketones the olefin does not isomerize to the /3,7-position as occurs when an ethylene ketal is prepared. Aldehydes are selectively protected in the presence of ketones except when steric factors force the ketone to be protected as in the example below." A TBDMS group is not stable to these conditions. ... 

It should be noted that when a BOC-protected amide is subjected to MeONa treatment the amide bond is cleaved in preference to the BOC group (85-96% yield) because of the difference in steric factors. The BOC group can be removed by the methods used to remove it from simple amines. 

The size of the group attached to the main chain carbon atom can influence the glass transition point. For example, in polytetrafluoroethylene, which differs from polyethylene in having fluorine instead of hydrogen atoms attached to the backbone, the size of the fluorine atoms requires the molecule to take up a twisted zigzag configuration with the fluorine atoms packed tightly around the chain. In this case steric factors affect the inherent flexibility of the chain. 

The conformation adopted by a molecule in the crystalline structure will also affect the density. Whereas polyethylene adopts a planar zigzag conformation, because of steric factors a polypropylene molecule adopts a helical conformation in the crystalline zone. This requires somewhat more space and isotactic polypropylene has a lower density than polyethylene. 

Moderate stereoselectivity is also seen in the addition of phenoxycarbene to cyclohexene (enby 4), in which the product ratio is apparently influenced by steric factors that favor introduction of the larger group (PhO versus H) in the less crowded exo position. 

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