Phenols hydroxymethylation

Photolysis of pyridazine IV-oxide and alkylated pyridazine IV-oxides results in deoxygenation. When this is carried out in the presence of aromatic or methylated aromatic solvents or cyclohexane, the corresponding phenols, hydroxymethyl derivatives or cyclohexanol are formed in addition to pyridazines. In the presence of cyclohexene, cyclohexene oxide and cyclohexanone are generated. 

Phenol-formaldehyde resin. Phenol-formaldehyde resin is prepared from phenol by reaction with formaldehyde. Phenol is an enol, the 2-, 4-, and 6-positions of which are activated for reaction with an electrophile. Phenol is sequentially hydroxymethylated approximately as illustrated below. Dehydration of the phenolic hydroxymethyl groups affords a benzyl cation, a new electrophile that can react with another substituted or unsubstituted molecule of phenol. Both linear polymerization and cross-linking are possible, depending on the ratio of the reactants and the polymerization conditions. 

Polymers. AH nitro alcohols are sources of formaldehyde for cross-linking in polymers of urea, melamine, phenols, resorcinol, etc (see Amino RESINS AND PLASTICS). Nitrodiols and 2-hydroxymethyl-2-nitro-l,3-propanediol can be used as polyols to form polyester or polyurethane products (see Polyesters Urethane polymers). 2-Methyl-2-nitro-l-propanol is used in tires to promote the adhesion of mbber to tire cord (qv). Nitro alcohols are used as hardening agents in photographic processes, and 2-hydroxymethyl-2-nitro-l,3-propanediol is a cross-linking agent for starch adhesives, polyamides, urea resins, or wool, and in tanning operations (17—25). Wrinkle-resistant fabric with reduced free formaldehyde content is obtained by treatment with... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Ethers, esters, amides and imidazolidines containing an epithio group are said to be effective in enhancing the antiwear and extreme pressure peiformance of lubricants. Other uses of thiiranes are as follows fuel gas odorant (2-methylthiirane), improvement of antistatic and wetting properties of fibers and films [poly(ethyleneglycol) ethers of 2-hydroxymethyl thiirane], inhibition of alkene metathesis (2-methylthiirane), stabilizers for poly(thiirane) (halogen adducts of thiiranes), enhancement of respiration of tobacco leaves (thiirane), tobacco additives to reduce nicotine and to reduce phenol levels in smoke [2-(methoxymethyl)thiirane], stabilizers for trichloroethylene and 1,1,1-trichloroethane (2-methylthiirane, 2-hydroxymethylthiirane) and stabilizers for organic compounds (0,0-dialkyldithiophosphate esters of 2-mercaptomethylthiirane). The product of the reaction of aniline with thiirane is reported to be useful in the flotation of zinc sulfide. 

A somewhat different approach to the production of thermoplastic polyolefin rubbers has been adopted by Allied Chemical with their ET polymers. With these materials butyl rubber is grafted on to polyethylene chains using a phenolic material such as brominated hydroxymethyl phenol. The initial grades of these polymers, which were introduced commercially towards the end of the 1970s, had polyethylene butyl rubber ratios of 50 50 and 75 25. Both low-density and high-density polyethylene-based varieties were produced. 

Various phenols can be selectively hydroxymethylated at the ortho position by heating with paraformaldehyde and phenylboronic acid. 

Prior to 1890, formaldehyde was not commercially available [2]. Thus the first phenol-formaldehyde resins were made using formaldehyde equivalents such as methylene diacetate or methylal [2,20]. The first true phenol-formaldehyde resin was made by Kleeberg at the direction of Emil Fisher in 1891 [2,21]. Saliginen (o-hydroxymethyl phenol) was recognized as a condensation product of phenol and formaldehyde in 1894 and was the subject of United States patents in 1894 and 1896 [22,23]. 

In general, the reaction between a phenol and an aldehyde is classified as an electrophilic aromatic substitution, though some researchers have classed it as a nucleophilic substitution (Sn2) on aldehyde [84]. These mechanisms are probably indistinguishable on the basis of kinetics, though the charge-dispersed sp carbon structure of phenate does not fit our normal concept of a good nucleophile. In phenol-formaldehyde resins, the observed hydroxymethylation kinetics are second-order, first-order in phenol and first-order in formaldehyde. 

The second phase in resole formation is reaction of the activated phenol with the aldehyde to form the phenol alcohol derivative. When the aldehyde is formaldehyde, the derivative is a hydroxymethyl phenol and the process is known as methylolation. Scheme 2 illustrates this reaction. Since resoles are usually made with excess aldehyde, more than one substitution may be made on the ring. When the reactants are phenol and formaldehyde, up to three methylol groups may be substituted. This reaction has been extensively studied and the rates of... 

The final phase of resole manufacture is known as the condensation stage (Scheme 3). This is the actual process by which molecular weight is developed and involves the combination of the hydroxymethyl phenol intermediates to form oligomers. It can be reasonably well separated from the resole methylolation reaction in practice by maintaining reaction temperatures below about 70°C. The activation energy for condensation is higher than that for methylolation. This is not to say that condensation does not occur at temperatures below 70°C. It simply means that the methylolation is much faster than condensation at this temperature. 

Whereas Freeman and Lewis reported the first comprehensive analysis of hydroxymethylation of phenol, they were not the last to study this system. A number of reports issued since their work have confirmed the general trends that they discovered while differing in some of the relative rates observed [80,84-99], Gardziella et al. have summarized a number of these reports ([18], pp. 29-35). In addition to providing new data under a variety of conditions, the other studies have improved on the accuracy of Freeman and Lewis, provided activation parameters, and added new methodologies for measuring product development [97-99],... 

Scheme 4b depicts condensation between a hydroxymethyl group and a phenolic ring where the hydroxybenzyl attacks at a ring position that is already hydroxymethylated. In this case, a methylene linkage is produced between the rings with concurrent loss of one mole each of formaldehyde and water. Both Jones and Grenier-Loustalot et al. demonstrated the occurrence of this reaction pathway beyond doubt under basic conditions. 

Sprung and Gladstone were the first to show the formation of dibenzyl ether linkages during the condensation of hydroxymethyl phenols, as depicted in Scheme 4c [152], These results have been corroborated by a number of researchers since [128,144,147,148], This condensation was reportedly second-order and takes place at pH conditions near neutral and at temperatures less than 130°C [128,147,153], At temperatures of 160°C the dibenzyl ethers are converted to something else, most likely to methylene linkages and formaldehyde [132],... 

Kim et al, observed a number of facts gleaned from C-NMR that led to an overall picture of the reactivity of various hydroxymethyl phenols (HMPs) [144, 148], Grenier-Loustalot and co-workers did a number of important experiments that expanded Kim s findings and clearly delineated the reactivity of the various functional groups position-by-position [128], The two studies show excellent agreement. The materials that follow are drawn from these two reports without further citation. As shown in Scheme 5, the condensation of 2-HMP at pH 8 and 60°C resulted in only one product. This product is the result of p-attack on the ring by the hydroxymethyl group. 

Scheme 10. Mechanislic possibililies for PF condensalion. Mechanism a involves an SN2-like attack of a phenolic ring on a methylol. This attack would be face-on. Such a mechanism is necessarily second-order. Mechanism b involves formation of a quinone methide intermediate and should be Hrst-order. The quinone methide should react with any nucleophile and should show ethers through both the phenolic and hydroxymethyl oxygens. Reaction c would not be likely in an alkaline solution and is probably illustrative of the mechanism for novolac condensation. The slow step should be formation of the benzyl carbocation. Therefore, this should be a first-order reaction also. Though carbocation formation responds to proton concentration, the effects of acidity will not usually be seen in the reaction kinetics in a given experiment because proton concentration will not vary.

The mild nitrating agents thionyl chloride nitrate (equation 2a) and thionyl nitrate (equation 2b) rewith alcohols and phenols to form stable nitrates The trinitrate of 2,6-di(hydroxymethyl)-4-fluorophenol is prepared by either agent [2] (equation 2)... 

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

More recently, the reaction advancement of resole syntheses (pH = 8 and 60°C) was monitored using high-performance liquid chromatography (HPLC), 13C NMR, and chemical assays.55,56 The disappearance of phenol and the appearances of various hydroxymethyl-substituted phenolic monomers and dimers have been measured. By assessing the residual monomer as a function of reaction time, this work also demonstrated the unusually high reactivity of 2,6-dihydroxymethyl-phenol. The rate constants for phenolic monomers toward formaldehyde substitution have been measured (Table 7.6). 

As the reactions proceed, the disappearance of phenol is delayed due to competition for reaction with formaldehyde between phenol and the faster reacting hydroxymethyl-substituted phenols. Competition also exists between formaldehyde substitution reactions and condensation reactions between rings. Condensation reactions between two ortho-hydroxymethyl substituents are the least favorable condensation pathway. Depending on the reaction conditions, substitutions occur... 

The mechanisms for model condensation reactions of para-hydroxymethyl-substituted phenol (and therefore para-quinone methide) with reactive ortho positions are described in Fig. 7.29. The phenolate derivatives react with para-quinone... 

The reaction conditions, formaldehyde-to-phenol ratios, and concentration and type of catalyst govern the mechanisms and kinetics of resole syntheses. Higher formaldehyde-to-phenol ratios accelerate the reaction rates. This is to be expected since phenol-formaldehyde reactions follow second-order kinetics. Increased hydroxymethyl substitution on phenols due to higher formaldehyde compositions also leads to more condensation products.55... 

Crosslinking resoles in the presence of sodium carbonate or potassium carbonate lead to preferential formation of ortho-ortho methylene linkages.63 Resole networks crosslinked under basic conditions showed that crosslink density depends on the degree of hydroxymethyl substitution, which is affected by the formaldehyde-to-phenol ratio, the reaction time, and the type and concentration of catalyst (uncatalyzed, with 2% NaOH, with 5% NaOH).64 As expected, NaOH accelerated the rates of both hydroxymethyl substitution and methylene ether formation. Significant rate increases were observed for ortho substitutions as die amount of NaOH increased. The para substitution, which does not occur in the absence of the catalyst, formed only in small amounts in the presence of NaOH. 

Condensation reactions of hydroxymethyl groups on phenolic resoles and amines on melamine take place between pH 5 and 6 (Fig. 7.33). Only selfcondensations of hydroxymethyl substituents occur under strongly acidic or basic conditions. 

Thermal degradation below 300°C in inert atmospheres produces only small amounts of gaseous products. These are mostly unreacted monomers or water, which are by-products eliminated from condensation reactions between hydroxymethyl groups and reactive ortho or para positions on phenolic rings. A small... 

Hydroxyl number, 94 Hydroxymethylated compounds, 403 Hydroxymethylated phenol, 378. See also Hy droxy me thy lphenol Hydroxymethyl condensation reactions, 399-400... 

Hydroxymethyl-4,6-dimethylphenol, 406 Hydroxymethylphenol. See also Hydroxymethylated phenol reaction with melamine, 411 reaction with urea, 410 Hydroxymethyl substituents, condensation reactions of, 403... 

The diarylation reaction is especicdly common with phenols (the diaryl product here is called a bisphenol). The reaction is normally carried out in alkaline solution on the phenolate ion. The hydroxymethylation of phenols with formaldehyde is called the Lederer-Manasse reaction. This reaction must be carefully controlled, since it is possible for the para and both ortho positions to be substituted and for each of... 

Two methods, both involving boron-containing reagents, have been devised for the regioselective ortho hydroxymethylation of phenols or aromatic amines. 

Although coordination of the heterocyclic nitrogen does not occur, two cobalt(II) complexes of 3-hydroxy-5-hydroxymethyl-2-methyl-4-formylpyridine have been isolated with stereochemistry [Co(34-H)A] 2H2O (A = NO3, OAc) [173], For both complexes coordination is ONS (deprotonated phenolic oxygen), but magnetic or electronic spectral data are not included. 

Various phenols can be selectively hydroxymethylated at the ortho position by heating with paraformaldehyde and phenylboronic acid. An intermediate 18-1 having the formula C14H1302B for the case shown can be isolated prior to the oxidation. Suggest a structure for the intermediate and comment on its role in the reaction. 

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