7 -Methyl -substituted

Errors of this magnitude make the useful prediction of free energies a difficult task, when differences of only one to three kcal/mol are involved. Nevertheless, within the error limits of the computed free energy differences, the trend is that relative to 8-methyl-N5-deazapterin or 8-methyl-pterin, the compounds methyl substituted in the 5, 6 or 7 positions are thermodynamically more stable when bound to DHFR largely by virtue of a hydrophobic effect, i.e. methyl substitution reduces the affinity of the ligand for the solvent more than it reduces affinity for the DHFR active-site. The stability of ligand binding to DHFR appears to be optimal with a 6-methyl substituent additional 5-methyl and/or 7-methyl substitution has little effect... 

Ring opening of the oxo derivative of the tetrazolo[l,5- ]pyrimidine ring system has also been reported <1996JHC229>. Treatment of the 6-hydroxyethyl-7-methyl substituted compound 59 with triphenylphosphine gave the phosphinimine derivative 60 in nearly quantitative yield (Scheme 10). 

Table I presents the comparison between the calculated and experimental, 5N chemical shifts in purine. The assignment of the NMR resonances is straight-forward using the liquid state, in 7-methyl substituted purine (22), and calculated values. As expected, in the predominat N7-H form, N7 experiences a large up field shift while N9 shows a similar down field shift as a consequence of the migration of the proton from N9 in the liquid to N7 in the solid. The isotropic values for the N9-H form in the solid are quite similar to the values observed in the liquid, the largest difference between corresponding chemical shift values is 12 ppm.

Figure 5.50 shows three related molecules, the 7-methyl substituted (the visual orbital progression explained here is not quite as smooth for the unsubstituted molecules) derivatives of the 7-norbomyl cation (a), the neutral alkene norbomene (b), and the 7-norbomenyl cation (c). For each species an orbital is shown as a 3D region of space, rather than mapping it onto a surface as was done in Fig. 5.49. In (a) we see the LUMO, which is as expected essentially an empty p atomic orbital on C7, and in (b) the HOMO, which is, as expected, largely the n molecular orbital of the double bond. The interesting conclusion from (c) is that in this ion the HOMO of the double bond has donated electron density into the vacant orbital on C7 forming a three-center, two-electron bond. Two n electrons may be cyclically delocalized, making the cation a bishomo (meaning expansion by two carbons) analogue of the aromatic cyclopropenyl cation [326], This delocalized bishomocyclopropenyl structure for 7-norbomenyl cations has been controversial, but is supported by NMR studies [327].

The above approaches can be extended to 1,2-carboranes in which the BH vertices are substituted with alkyl groups <1996101235, 1996JA70>. The 9- and 12-boron vertices are the furthest from the carbon atoms in 1,2-carborane 7. Methyl substitution of 7 at these positions is accomplished by iodine substitution to form 9,12-diiodo-l,2-carborane 13 then treatment with alkyl Grignard reagent in the presence of a palladium catalyst affords 9,12-Me2-l,2-carborane 14, which can be deprotonated at the carbon vertices in the same manner as the parent 7. Using the same strategy to prepare cyclic trimer 5, dimethyl 14 is deprotonated and treated with mercuric acetate to form 5-hexamethyl-[9]-mercuracarborand-3 15 in 60% yield (Equation 1). 

Demercuration of metallacycle 42 with an alkaline solution of sodium borohydride provided a (7-methyl-substituted five-membered heterocycle 43 (Equation 3) <2001JGU1874>. 

Salts 470 72 were obtained from amine 427 and bromoketones or bromoacet-aldehyde. They were later converted into imidazo[4,5-c]imidazo[l,2-a]pyridine derivatives 473, 474 and 477 by treatment with alkali. However, ketones like phenacyl bromide and its />-nitro- and /7-methyl-substituted analogues do not give stable quaternary salts with amine 427 yielding instead tricyclic bases 475 and 476 (86KG227). 

For phenolic and indoleamines, a 100 pg amount of the isothiocyanate derivative was reacted with BSTFA/ TMCS (99 1) at 90 °C for 15 min. For 2- or 7-methyl substituted tryptamines, it was necessary to extend the reaction time to 1 h at 100 °C to ensure complete silyla-tion of the indole nitrogen, presumably because of steric hindrance from the alkyl substituent. 

T. D. Greenwood, R. A. Kahley, and J. E Wolfe, 7/-methyl-substituted aromatic polyamides, Journal of Polymer Science Polymer Chemistry Edition, 18, 1047(1980). 

IX.4), isolated from Guatteria scandens. They are the first members of a new class of aporphinoids as they are 7-methyl substituted and they cannot be r arded as oxoaporphines, since ring B is not aromatic. 

For the N=10 phenyl substituted compounds,standard Sp was used, for the N=7 methyl substituted compounds, standard S,... 

Nesselrodt D R, Potts A R and Baer T 1995 Stereochemical analysis of methyl-substituted cyclohexanes using 2+1 resonance enhanced multiphoton ionization Anal. Chem. 67 4322-9... 

Cheng Y-W and Dunbar R C 1995 Radiative association kinetics of methyl-substituted benzene ions J. Rhys. Chem. 99 10 802-7... 

Sulfenamidothiazoles heated in acetic anhydride rearrange to 2-acetamido-5-thiophenoxythicLZoles (337) (Scheme 193) (32, 456, 457). Only decomposition products are found when these conditions are applied to 336 with X=C or methyl. Substitution in the 4-position of the thicLZole ring (R = methyl, phenyl), however, favors the rearrangement (see p. 82). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

Goto et al. (386) have qualitatively studied the relationship between the structure and the ease of formation of some 2-aryl- and 2-heteroaryl-A-2-thiazolin-4-one derivatives. It is found that 2-pyridyI, 2-benzimidazoyl, and 2- 6 hydroxy-5 -methyl)-benzothiazolyl derivatives are too unstable to be isolated. 6 -Hydroxy-, 6 -methyl-, and unsubstituted 2-benzothiazoiyl derivatives, as well as naphtothiazolyl derivatives are unstable but isolable. On the other hand, 6 -methoxy-. 6 -acetoxy-. and 5, 7 -dimethyl-6 -hvdroxybenzothiazolyl derivatives as well as most of their 5-methyl substituted derivatives are stable and easily prepared. 

The basicity of a 4-phenyl-substituted thiazole is less than the corresponding methyl-substituted thiazole (16) and the pKa values of quaiemarv salts are in the same order (25). 

TABLE MI. SUBSTITUTION EFFECTS QUALITATIVE VARIATIONS OF NET CHARGES INDUCED BY A METHYL SUBSTITUTION... 

As with methylation, substitution by -Cl or -NHj induces a decrease in 77 electronic density on the substituted carbon atom and a slight increase in both adjacent positions. The perturbation of an -NH2 group is slightly larger than that of a -Cl group. 

For the methyl-substituted compounds (322) the increase in AG and AHf values relative to the unsubstituted thiazole is interpreted as being mainly due to polar effects. Electron-donating methyl groups are expected to stabilize the thiazolium ion, that is to decrease its acid strength. From Table 1-51 it may be seen that there is an increase in AG and AH by about 1 kcal mole for each methyl group. Similar effects have been observed for picolines and lutidines (325). 

Hydration of alkynes follows Markovmkov s rule terminal alkynes yield methyl substituted ketones... 

Recall from Section 24 1 that cresols are methyl substituted derivatives of phenol... 

The Tokuyama Soda single-step catalyst consists of a zirconium phosphate catalyst loaded with 0.1—0.5 wt % paHadium (93—97). Pilot-plant data report (93) that at 140°C, 3 MPa, and a H2 acetone mole ratio of 0.2, the MIBK selectivity is 95% at an acetone conversion of 30%. The reactor product does not contain light methyl substituted methyl pentanes, and allows MIBK recovery in a three-column train with a phase separator between the first and second columns. 

OC-Methylstyrene. This compound is not a styrenic monomer in the strict sense. The methyl substitution on the side chain, rather than the aromatic ring, moderates its reactivity in polymerization. It is used as a specialty monomer in ABS resins, coatings, polyester resins, and hot-melt adhesives. As a copolymer in ABS and polystyrene, it increases the heat-distortion resistance of the product. In coatings and resins, it moderates reaction rates and improves clarity. Physical properties of a-methylstyrene [98-83-9] are shown in Table 12. 

Commercially available VP is usually over 99% pure but does contain several methyl-substituted homologues and 2-pyrrohdinone. Even at this high level of purity, further purification is required if rehable kinetic data concerning rates of polymerisation are desired. This can be accompHshed only by recrystallisation, because distillation will not separate methyl-substituted isomers (7). 

The widespread use of biphenyl and methyl-substituted biphenyls as dye carriers (qv) in the textile industry has given rise to significant environmental concern because of the amount released to the environment in wastewater effluent. Although biphenyl and simple alkylbiphenyls are themselves biodegradable (48—50), the prospect of their conversion by chlorination to PCBs in the course of wastewater treatment has been a subject of environmental focus (51—53). Despite the fact that the lower chlorinated biphenyls are also fairly biodegradable (49,54,55) continued environmental concern has resulted in decreased use of biphenyl as a dye carrier (see Dyes, environmental chemistry). 

Properties. MethylceUulose [9004-67-5] (MC) and its alkylene oxide derivatives hydroxypropylmethylceUulose [9004-65-3] (HPMC), hydroxyethylmethylceUulose [9032-42-2] (HEMC), and hydroxybutyknethylcellulose [9041-56-9] (HBMC) are nonionic, surface-active, water-soluble polymers. Each type of derivative is available in a range of methyl and hydroxyalkyl substitutions. The extent and uniformity of the methyl substitution and the specific type of hydroxyalkyl substituent affect the solubifity, surface activity, thermal gelation, and other properties of the polymers in solution. 

The photochemical ring closure of certain stilbenes, eg, the highly methyl substituted compound (2) [108028-39-3], C22H2g, and their heterocycHc analogues is the basis for another class of photochromic compounds (31—33). 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

For fV-methylpyrazoIe (99), the molecular ion of which is less intense than pyrazole (a common feature for methyl-substituted pyrazoles (67ZOR1540)), the fragmentation pattern involves the methyl group (Scheme 2). These results were established using H, C and N labelling studies. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

Iron pentacarbonyl and l-methoxy-l,4-cyclohexadiene react as shown by Birch and oo-workera, but in dibutyl ether this solvent has been found superior. The tricarbonyl(methoxy-l,3-cyclohexadiene)iron isomers undergo hydride abstraction with triphenylmethyl tetrafluoro-borate to form the dienyl salt mixture of which the 1-methoxy isomer is hydrolyzed by water to the cyclohexadienone complex. The 2-methoxy isomer can be recovered by precipitation as the hexafluoro-phosphate salt. By this method the 3-methyl-substituted dienone complex has also been prepared from l-methoxy-3-methylbenzene. The use of the conjugated 1-methoxy-1,3-cyclohexadiene in Part B led to no increase in yield or rate and resulted chiefly in another product of higher molecular weight. An alternative procedure for the dienone is to react tricarbonyl(l,4-dimethoxycyclohexadiene)iron with sulfuric acid. ... 

Entries 11 and 13 in Table 3.4 present data relating the efiect of methyl substitution on methanol and methylamine. The data show an increased response to methyl substitution. While the propane barrier is 3.4 kcal/mol (compared to 2.88 in ethane), the dimethylamine barrier is 3.6kcal/mol (compared to 1.98 in methylamine) and in dimethyl ether it is 2.7 kcal/mol (compared to 1.07 in methanol). Thus, while methyl-hydrogen eclipsing raised the propane barrier by 0.5 kcal/mol, the increase for both dimethylamine and dimethyl ether is 1.6 kcal/mol. This increase in the barrier is attributed to greater van der Waals repulsions resulting from the shorter C—N and C—O bonds, relative to the C—C bond. 

Further substitution can introduce additional factors, especially nonbonded repulsions, which influence conformational equilibria. For example, methyl substitution at C—2, as in 2-methyl-l-butene, introduces a methyl-methyl gauche interaction in the conformation analogous to B, with the result that in 2-methyl-l-butene the two eclipsed conformations are of approximately equal energy. Increasing the si2e of the group at... 

The thermal rearrangements of methyl-substituted cycloheptatrienes have been proposed to proceed by sigmatropic migration of the norcaradiene valence tautomer. The first step is an electrocyclization analogous to those discussed in Section 11.1. 

Activation of benzouifluonde by a 3-methyl substitution gives nonspecific nitration at the ortho and para sites [21] (equation 17)... 

Cycloaddition reactions where bis(trifluoromethyl)-substituted hetero-1,3-dienes act as dienophiles have been descnbed for open-chain and cyclic dienes [115, 126, 127] The balance of the diene -dienophile activity of bis(tnfluoro-methyl)-substituted hetero-l,3-dienes can be influenced strongly by the substituents bonded to the inuno nitrogen atom For instance, A/-(arylsulfonyl) denvatives of tnfluoroacetaldimine and hexafluoroacetone imine do not act as dienes but exhibit only the dienophile reactivity of electron deficient imines [5 229, 234,235, 236 237] (equation 52)... 

---