Morpholine, basicity nucleophilicity

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

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 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. 

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. 

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). 

In this section, emphasis is placed on reactions which are characteristic of the ring systems present and do not depend on the presence of particular substituents. In addition, the well-known and widely applied behavior of morpholine as a basic and nucleophilic secondary amine is not covered and neither is the aniline-like nucleophilic and basic behavior of dihydrobenzoxazines save for a few special examples. 

Much more important in determining pJCjH is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (p H 11-2) and morpholine (p-K"aH 9.8) or piperazine (pfCan 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this... 

However, reaction of acyclic dienamines with hydrazoic acid gives a mixture of products derived by 1,2-, 1,4- and 3,4 + 1,2-addition of HN3 to the diene system. In this case C-protonation is followed immediately by addition of the strongly nucleophilic azide anion, so that equilibrium of the C-protonated enamines cannot occur3c. Treatment of the morpholine dienamine of isophorone with trichloroacetic acid in boiling benzene resulted in decarboxylation and the 1,4-addition of a proton and the trichloromethyl anion. Basic hydrolysis of the adduct gave dienoic acid 54 (Scheme 4). 

In the reaction with methyloxirane in H2O at 20 C, the reactivity of the amines decreases in the order piperazine > dimethylamine > pyrrolidine > piperidine > morpholine > diethylamine > di-n-butylamine > di-n-propylamine. ° Under neutral or basic conditions, nucleophiles generally attack at the sterically less-hindered carbon atom of the oxirane ring. 

Kinetic studies of Michael addition of alicyclic secondary amines to ethyl propiolate in H2O and MeCN have demonstrated a substantial solvent effect on reactivity and transition-state structure. The amines were found to be less reactive in MeCN, although they are by 7-9 units more basic in the aprotic solvent. The reaction rates for morpholine and deuterated morpholine proved to be identical, which rules out both a stepwise mechanism in which proton transfer would occur in the RLS and a concerted mechanism in which nucleophilic attack and proton transfer would occur through a four-membered cyclic transition state. Consequently, a stepwise mechanism with proton transfer occurring after the RLS is probable. Br0nsted-type plots were found to be linear with = 0.29 and 0.51 in H2O and MeCN, respectively, indicating that bond formation is not advanced significantly in the RLS. The small value is also consistent with the absence of isotope effect. ... 

The a-protons of a carbonyl group are acidified by /nduct/Vewithdrawl, and the resulting enolate is resonance stabilised and a good nucleophile. However, although morpholine is a good nucleophile, it is not basic enough to deprotonate a ketone. 

The nucleophilicity within a series, such as amines, is generally correlated with the basicity of the nucleophile. (8) The pKa of protonated morpholine is 8.3 vs. 11.1 for piperidine. (10)... 

Jones et al. (67) also prepared a wide range of water soluble ammonium dithiocarbamate salts, [NH4][S2CNR2] (Fig. 5). They result from the iifitial reaction of the amine with concentrated aqueous ammonia in ethanol, followed by later addition of carbon disulfide at low temperatures. For example, diethanolamine, HN(CH2CH20H)2, forms a yellow precipitate in 65% yield. Castro et al. (68) studied the kinetics and mechanism of the reactions of piperidine, pyrrolidine, morpholine, and benzylamine (69) with carbon disulfide in ethanol (Fig. 6). They proceed via a dithiocarbamic acid intermediate (4), which in turn yields the dithiocarbamate anion (5) upon proton loss to the amine. While for pyrrolidine, formation of the dithiocarbamic acid is rate determining and proceeds to the dithiocarbamate irreversibly, for both morpholine and benzylamine, the transformation is reversible. Further, in these cases the ethoxide anion is found to catalyze the transformations. They have also determined that pyrrolidine is 200 times more nucleophilic toward carbon disulfide than piperidine, despite the later being only slightly more basic, a feature that may relate to the irreversible nature of the formation of pyrrolidine dithiocarbamate. 

---