Morpholine, basicity

Keywords aromatic/heteroaromatic chloride, piperidine, morpholine, basic alumina, nucleophilic aromatic substitution, microwave irradiation... 

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

Mel, CH3CN morpholine or diethylamine, methanol, 76-95% yield. These conditions also cleave tlie 4 -pyridyl derivative. The Pet ester is stable to the acidic conditions required to remove the BOC and r-butyl ester groups, to the basic conditions required to remove the Fmoc and Fm groups, and to hydrogenolysis. It is not recommended for use in peptides that contain methionine or histidine since these are susceptible to alkylation with methyl iodide. 

The results of more recent investigations by Blicke with Maxwell and with Kaplan covering a wide range of basic components and of acyl residues, do not lend themselves to a simple generalisation. The basic components were mainly dialkylamino-derivatives of aliphatic hydrocarbons from ethane to pentane, e.g.,. CHj. CHj. NMcj to. CHj. CMcj. CHj. NEtj, and similar but shorter series of derivatives of piperidine (CgHjoN), morpholine, e.g.,. CHj. CHj. NC HgO, and methylcj/clohexylamine... 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

The basicity of the enamine has an overriding influence on the yield of product. Good yields are obtained from the pyrrolidine enamines, poor yields from the piperidine enamines, and the morpholine enamines fail to... 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

The data show that in some cases basicity has a strong influence on reactivity. For example, the reaction of 2-chloropyridine derivatives with piperidine is about 3000 times as fast as that with pyridine the basicity change involved is in the order of 6 pA units. However, piperidine is only 4 times as reactive as morpholine with 2- or 4-chloropyrimidine as the substrate, although -dpAo in these cases is still fairly large, 2.5 units. Furthermore, even the qualitative correlation sometimes fails, and aniline is more reactive than pyridine in contrast to the expectations from their basicities. 

The rate of reaction of a series of nucleophiles with a single substrate is related to the basicity when the nucleophilic atom is the same and the nucleophiles are closely related in chemical type. Thus, although the rates parallel the basicities of anilines (Tables VII and VIII) as a class and of pyridine bases (Tables VII and VIII) as a class, the less basic anilines are much more reactive. This difference in reactivity is based on a lower energy of activation as is the reactivity sequence piperidine > ammonia > aniline. Further relationships among the nucleophiles found in this work are morpholine vs. piperidine (Table III) methoxide vs. 4-nitrophenoxide (Table II) and alkoxides vs. piperidine (Tables II, III, and VIII). Hydrogen bonding in the transition state and acid catalysis increase the rates of reaction of anilines. Reaction rates of the pyridine bases are decreased by steric hindrance between their alpha hydrogens and the substituents or... 

The kinetic comparison of amination of the chloropyridines is incomplete due to the intervention of acid catalysis. The reaction of 2-chloropyridine with piperidine shows a constant rate coefficient as the reaction proceeds to completion, but, with the less basic morpholine, a rising coefficient indicative of acid catalysis is observed. 4-Chloropyridine exhibits a rising rate coefficient even with piperidine. ... 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

In much the same vein, the basic ester 7 can be obtained by reaction of the same chloroacid with morpholine derivative 6. Reaction with aniline 4 affords mornif1umate (8). 

C) Preparation of Doxapram Hydrochloride [3,3-Diphenyl-1-Ethyl-4-(2-Morpholino-Ethylj-2-Pyrrolidinone Hydrochloride Monohydrate] A solution of 25 grams (0.076 mol) of 4-(2-chloroethyl)-3,3-diphenyl-1-ethyl-2-pyrrolidinone and 13.3 grams (0.153 mol) of morpholine in 500 ml of absolute ethanol was heated at 95°-120°C for 21 hours in a closed system and concentrated in vacuo. The residue was dissolved in 3(X) ml of two normal hydrochloric acid and extracted with 150 ml of ethyl acetate. A solid crystallized (13 g) during the extraction and was removed by filtration. MP 217°-219°C. The acid extracts were made basic with sodium hydroxide and extracted with ether, and the ether solution was concentrated in vacuo and the residue was suspended in six normal hydrochloric acid. Additional crystalline product formed and was recrystallized from two normal hydrochloric acid. Yield, 10 grams MP 217°-219°C. Total yield, 23 grams (70%). 

Various amines find application for pH control. The most commonly used are ammonia, morpholine, cyclohexylamine, and, more recently AMP (2-amino-2-methyl-l-propanol). The amount of each needed to produce a given pH depends upon the basicity constant, and values of this are given in Table 17.4. The volatility also influences their utility and their selection for any particular application. Like other substances, amines tend towards equilibrium concentrations in each phase of the steam/water mixture, the equilibrium being temperature dependent. Values of the distribution coefficient, Kp, are also given in Table 17.4. These factors need to be taken into account when estimating the pH attainable at any given point in a circuit so as to provide appropriate protection for each location. 

Interpreting HMQC/HSQC spectra is relatively straightforward as you can see from the HSQC spectrum of the morpholine compound (Spectrum 9.3). Basically, it s a case of lining up the proton signal with the contour, and reading off the 13C chemical shift. The technique is extremely powerful - particularly when used in combination with HMBC as we ll see later. In examples like this one, it... 

To synthesize new surfactants, having incorporated both structural elements, the known siloxanyl modified halogenated esters and ethers of dicyclopentadiene [5] were treated with different amines according to the reaction scheme. Triethylamine yielded quaternary ammonium salts directly. Alternatively, after reaction with diethylamine or morpholine, the isolated siloxanyl-modified tertiary amines were also converted to quaternary species. To obtain anionic surfactants, the halogenated precursors were initially reacted with n-propylamine. In subsequent reaction steps the secondary amines formed were converted with maleic anhydride into amides, and the remaining acid functions neutralized. Course and rate of each single reaction strongly depended on the structure of the initial ester or ether compound and the amine applied. The basicity of the latter played a less important role [6]. 

The initiating nucleophile in the vast majority of these studies is the hydroxide anion. However, in principle, any nucleophile can add to the keto or formyl group to give rise to an anionic intermediate, which then could act as an intramolecular nucleophile and effect hydrolysis of the ester. Their relative effectiveness will depend on two factors the relative extent of formation and the nucleophilicity of the adduct. The nucleophiles that have been investigated are hydroxide, cyanide, morpholine and piperazine. The only quantitative comparison available is that of hydroxide, morpholine and piperazine, which are effective in the order of ca. 102 10-3 1 (Bender et al., 1965 Dahlgren and Schell, 1967). For morpholine and piperazine this is as expected on the basis of their relative basicities. However, the expected order of increasing formation of the adducts would be cyanide > nitrogen bases > hydroxide (Hine, 1971). At this time, these results cannot be analysed further, but more work on the systems could enable the structural dependence and reactivity to be elucidated. 

Amines with higher basicity showed higher reactivity. For example, the yields of the 1 1 adducts of morpholine (pK = 9.61), aniline (9.42), n-butylamine (3.39), and piperidine (2.80) were 79, 67, 19, and 29%, respectively. Telomerization of butadiene with diethylamine catalyzed by... 

Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1 200. 

Wright found it more suitable to use the nitrate salts of the more basic amines, like in the case of morpholine, which ignites at ambient temperature in the presence of nitric acid-acetic anhydride mixtures. Morpholine nitrate is not nitrated with acetic anhydride-nitric acid in the absence of chloride ion at room temperature, but the addition of 4 mole % of zinc chloride generates a 65 % yield of A-nitromorpholine, and this yield rises to 93 % if the hydrochloride salt of morpholine is directly nitrated. While morpholine nitrate is unaffected by treatment with acetic anhydride-nitric acid at room temperature, the same reaction in the presence of ammonium nitrate at 65 °C is reported to yield A-nitromorpholine in 48 % yield. ... 

From the pATa values shown, there is relatively little difference in basicities for diethylamine, pyrrolidine, or piperidine. Note, however, that morpholine and piperazine are weaker bases than piperidine. This is the result of an electron-withdrawing inductive effect from the second heteroatom, making the nitrogen atom both less basic and also less nucleophilic. This makes morpholine a useful base with basicity between that of piperidine and pyridine pK 5.2) (see Section 4.6). The second pK value for the diamine piperazine is substantially lower than the first, since the inductive effect from the protonated amine will withdraw electrons away from the unprotonated amine (see Section 4.7). 

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