Sensitive fluorescent detection and Lewis basicity of aliphatic amines

In this contribution is reported the sensitive properties of the Zn(II) Schiff base complex, 1, in dichloromethane with respect a series of primary, secondary, and tertiary aliphatic amines through the study of fluorescence enhancement upon amine coordination to the Lewis acidic Zn(II) metal center with formation of 1:1 adducts. It is found that complex 1 exhibits selectivity and nanomolar sensitivity for primary and alicyclic amines. A distinct selectivity is also observed along the series of secondary or tertiary amines, paralleling the increasing steric hindrance at the nitrogen atom. The binding interaction can be related to the Lewis basicity of the coordinating amine; thus, complex 1 represents a suitable reference Lewis acid, and estimated binding constants within the investigated amine series can be related to their relative Lewis basicity. A relative order of the Lewis basicity can be established for acyclic amines, primary > secondary > tertiary, while an inverted order, tertiary > secondary ≈ primary (acyclic), is found in the case of alicyclic amines. The present approach represents a simple, suitable method to ranking the relative Lewis basicity of aliphatic amines in low-polarity, nonprotogenic solvents.     

Parallel protocol for the selective methylation and alkylation of primary amines

One of the still unresolved problems in parallel synthesis is the availability of a general and rapid method for the transformation of a primary amine into the corresponding secondary amine without the issue of polyalkylation. Following the Fukuyama method, which is based on the alkylation of o-nitrobenzenesulfonamides, followed by removal of the sulfonyl group, we have developed a simple protocol which can be easily applied to parallel synthesis making use of supported reagents and scavengers. To verify the robustness of the method, a small representative array of secondary amines have been prepared. Moreover, taking advantage of the possibility to use different supported reagents in the same pot, we also prepared, starting from primary amines, a series of differently substituted tertiary amines.     

A C-13 study of the reaction of 2,4,6-triarylpyrylium cations with amines

The reaction of primary and secondary amines with 2,4,6-triarylpyryliums is shown by C-13 NMR to proceed by fast ring opening to a vinylogous amide; in the case of primary amines this closes slowly to a pyridinium salt. The reaction in DMSO gives the pyridinium salt quantitatively when 2 moles of amines are used, with less amine significant quantities of a diketone intermediate are produced which results in slower conversion.     

Reactions of chloroalkyl-gem-dichlorocyclopropanes with amines

N-Alkylation of primary and secondary amines with monochloroalkyl-gem-dichlorocyclopropanes under conditions of thermal and microwave heating results in the corresponding amino-gem-dichlorocyclopropanes. With microwave irradiation heating, the reaction time has been decreased to 1 h, the yields of the amines containing gem-dichlorocyclopropane moiety being the same. Formation of the bicyclic amine in reaction of cis-2,3-dichloromethyl-gem-dichlorocyclopropane with primary amines under conditions of phasetransfer catalysis has been studied.     

One-pot synthesis of secondary or tertiary amines from alcohols and amines via alkoxyphosphonium salts

Secondary or tertiary amines may be prepared from primary alcohols and primary or secondary amines by treating triphenylphosphine with N-bromosuccinimide (NBS) in the presence of the alcohol at low temperature, followed by addition of the amine and heating for about 1 h. The yield of amine is good to fair, decreasing sharply with sterically congested alcohols and starting amines.     

Acceleration of amine/epoxy reactions with N‐methyl secondary amines

Kinetic studies established that the monomethylation of a primary amine leads to significantly higher reaction rates with glycidyl ethers. The relative rates for approximately 25 amines were determined in an alcohol solvent under pseudo‐first‐order conditions (excess epoxy). The rates were referenced to aniline. For the aliphatic amines, reactivity consistently increased upon going from a primary amine to the corresponding N‐methyl secondary amine. This acceleration effect was not seen for aniline. The enhanced reactivity was also seen in curing systems, both with pure methylated amine curing agents and with complex mixtures obtained from the partial methylation of polyamines. Economically viable partially methylated amine curing agents were obtained by the reductive alkylation of commercial polyamines with formaldehyde and by the reaction of monomethylamine with 3‐(N‐methylamino)propionitrile in the presence of hydrogen and a hydrogenation catalyst. Although actual cure performance is based on a complex combination of several factors, the acceleration due to monomethylation could be a useful tool for enhancing amine/epoxy curing reactions. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 921–930, 2000     

Selective N-alkylation of amines using nitriles under hydrogenation conditions: facile synthesis of secondary and tertiary amines

Nitriles were found to be highly effective alkylating reagents for the selective N-alkylation of amines under catalytic hydrogenation conditions. For the aromatic primary amines, the corresponding secondary amines were selectively obtained under Pd/C-catalyzed hydrogenation conditions. Although the use of electron poor aromatic amines or bulky nitriles showed a lower reactivity toward the reductive alkylation, the addition of NH(4)OAc enhanced the reactivity to give secondary aromatic amines in good to excellent yields. Under the same reaction conditions, aromatic nitro compounds instead of the aromatic primary amines could be directly transformed into secondary amines via a domino reaction involving the one-pot hydrogenation of the nitro group and the reductive alkylation of the amines. While aliphatic amines were effectively converted to the corresponding tertiary amines under Pd/C-catalyzed conditions, Rh/C was a highly effective catalyst for the N-monoalkylation of aliphatic primary amines without over-alkylation to the tertiary amines. Furthermore, the combination of the Rh/C-catalyzed N-monoalkylation of the aliphatic primary amines and additional Pd/C-catalyzed alkylation of the resulting secondary aliphatic amines could selectively prepare aliphatic tertiary amines possessing three different alkyl groups. According to the mechanistic studies, it seems reasonable to conclude that nitriles were reduced to aldimines before the nucleophilic attack of the amine during the first step of the reaction.     

Simultaneous spectrophotometric analysis of aliphatic amines utilizing thermochromism of charge-transfer complexes with tetrabromophenolphthalein ethyl ester.

Aliphatic amines, such as n-hexylamine (primary), di-n-hexylamine (secondary) and tri-n-hexylamine (tertiary amine), react with tetrabromophenolphthalein ethyl ester molecules (TBPEH) to form reddish or red-violet charge-transfer complexes (CT complexes) in 1,2-dichloroethane (DCE). The absorption maxima of the CT complexes with all primary amines occur at around 560 nm, with secondary amines at 570 nm and, with tertiary amines at 580 nm. The CT complex formation constants with TBPEH in DCE increase in the order of the primary, secondary and tertiary amines, but their constants decrease quantitatively with an increase in temperature. This phenomenon (thermochromism) could be applied to the simultaneous spectrophotometric determination of primary amine and secondary amine, or secondary amine and tertiary amine in a mixed solution utilizing the difference of absorbance with temperature changes.     

Spectrophotometric determination of aliphatic primary and secondary amines by reaction with p-benzoquinone

A simple, sensitive and selective spectrophotometric method has been developed for determination of aliphatic primary and secondary amines. It is based on a reaction with excess of p-benzoquinone in ethanol whereby 1:1 (amine:quinone) coloured products are obtained, which have maximum absorption at 510 nm and E(1cm)(1%) in the range 400-650. The effect of solvent, temperature, concentration of quinone and the presence of water have been kinetically investigated by the initial rate method. The conditions for monitoring amine concentrations as low as 0.1 microg/ml are optimized in the light of the kinetic data. Results with an average recovery of 98.5% and mean standard deviation of 1.9% are obtained with 9 different amines without interference from tertiary amines, ammonia, amides, imides, anilides, hydrazines and alpha-amino-acids.     

Electrochemical chlorination of amines

We have studied the laws governing the electrochemical chlorination of primary and secondary amines in aqueous solution on a ruthenium-titanium anode under conditions of diaphragm electrolysis. It was found that in order to ensure the most complete conversion of the amines into the corresponding chloramines it is necessary to add NaHCO₃ to the electrolyte [amine:NaHCO₃=1(1.5–3)]. Under the conditions of electrolysis primary amines are converted almost quantitatively into dichloramines. High yields of the N-chloro-derivatives of secondary amines can be obtained with high current densities and concentrations of NaCl.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 620–625, March, 1990.     

Hydrogen bonding by alcohols and amines

The pure base calorimetric method has been used to determine the enthalpies of hydrogen bond complex formation between aliphatic amines and alcohols. The enthalpies of complexation for the series methanol-n-butanol bonding with triethylamine increase with decreasing alkyl chain length in accordance with the electron donating properties of alkyl groups. Unexpectedly, the enthalpies for the complexes of n-butanol with tributylamine, tripropylamine, and triethylamine increase with decreasing alkyl chain length.Primary and secondary amines form hydrogen bonded complexes with n-butanol in which the amine protons form an NH···O bond with the alcohol and the alcohol hydroxyl proton donates a proton to the amine nitrogen. The difference in enthalpy of complex formation between tertiary amines and secondary amines is largely accounted for by the involvement of the amine proton of the secondary amine. Primary amines, like secondary amines, donate only one proton to the complex with n-butanol but have a larger complex enthalpy than secondary amines probably because of steric hindrance and differences in basicity.     

Analysis of amines in petroleum

An analytical method for differentiation of primary, secondary, and tertiary amines using exhaustive trifluoroacetylation prior to GC/MS has been developed. Using the conditions described in the report, most primary amines add two and secondary amines add one trifluoroacetyl group. In general, tertiary amines do not react. GC retention indices and relative GC/MS total ion current response factors for 102 trifluoroacetyl derivatives are reported. Examples of the application of the method to petroleum and coal liquid products are provided. Because of the limited thermal stability of the derivatives of primary amines, the method is applicable only to distillates boiling below 370 °C (700 °F).     

Efficient synthesis of tertiary amines from secondary amines

Reliable N-alkylations of secondary amines have been developed. By using DIAD and TPP (or PS-TPP) a variety of secondary amines can be converted to the corresponding tertiary amines in good to excellent yields with diverse alkylhalides; no formation of quaternary amine salts are observed. These protocols are amenable to combinatorial chemistry libraries, and are also useful for the syntheses of secondary amines by an acid lysis of the cleavable tertiary amino resins.     

Synthesis of amides from esters and amines with liberation of H2 under neutral conditions

Efficient synthesis of amides directly from esters and amines is achieved under mild, neutral conditions with the liberation of molecular hydrogen. Both primary and secondary amines can be utilized. This unprecedented, general, environmentally benign reaction is homogeneously catalyzed under neutral conditions by a dearomatized ruthenium-pincer PNN complex and proceeds in toluene under an inert atmosphere with a high turnover number (up to 1000). PNP analogues do not catalyze this transformation, underlining the crucial importance of the amine arm of the pincer ligand. A mechanism is proposed involving metal-ligand cooperation via aromatization-dearomatization of the pyridine moiety and hemilability of the amine arm.     

Effect of amine nature on reaction mechanism: aminolyses of o-4-nitrophenyl thionobenzoate with primary and secondary amines

Pseudo-first-order rate constants (k(obs)) have been measured spectrophotometrically for reactions of O-4-nitrophenyl thionobenzoate (2) with a series of primary and acyclic secondary amines. The plots of k(obs) vs amine concentration are linear for the reaction of 2 with primary amines. The slope of the Br?nsted-type plot for the reaction of 2 with primary amines decreases from 0.77 to 0.17 as the amine basicity increases, indicating that the reaction proceeds through a zwitterionic addition intermediate in which the rate-determining step changes from the breakdown of the intermediate to the reaction products to the formation of the intermediate as the amine basicity increases. On the other hand, for reactions with all the acyclic secondary amines studied, the plot of k(obs) vs amine concentration exhibits an upward curvature, suggesting that the reaction proceeds through two intermediates, e.g., a zwitterionic addition intermediate and an anionic intermediate. The microscopic rate constants (k(1), k(-)(1), k(2), and k(3) where available) have been determined for the reactions of 2 with all the primary and secondary amines studied. The k(1) value is larger for the reaction with the primary amine than for the reaction with the isobasic acyclic secondary amines, while the k(-)(1) value is much larger for the latter reaction than for the former reaction. The k(3) value for the reaction with secondary amine is independent of the amine basicity. The small k(2)/k(-)(1) ratio is proposed to be responsible for the deprotonation process observed in aminolyses of carbonyl or thiocarbonyl derivatives.     

One-pot amide synthesis from allyl or benzyl halides and amines by Pd-catalysed carbonylation

Amides can be prepared from allyl or benzyl halides and primary or secondary amines, using Pd(0) catalyst under CO pressure, in a one-pot synthesis. The reaction proceeds through the acyl palladium halide formation which undergoes an acylic nucleophilic substitution from the amine.     

Large steric effect in the substitution reaction of amines with phosphoimidazolide-activated nucleosides

Aliphatic amines react with phosphoimidazolide-activated derivatives of guanosine and cytidine (ImpN) by replacing the imidazole group. The kinetics of reaction of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) with glycine ethyl ester, glycinamide, 2-methoxyethylamine, n-butylamine, morpholine, dimethylamine (Me2NH), ethylmethylamine (EtNHMe), diethylamine (Et2NH), pyrrolidine, and piperidine were determined in water at 37 degrees C. With primary amines, a plot of the logarithm of the rate constant for attack by the amine on the protonated substrate, log kSH(A), versus the pKa of the amine exhibits a good linear correlation with a Bronsted slope, beta nuc = 0.48. Most of the secondary amines tested react with slightly higher reactivity than primary amines of similar pKa. Interestingly, some secondary amines show substantially lower reactivity than might be expected: EtNHMe reacts about eight times, and Et2NH at least 100 times, more slowly than Me2NH although all three amines are of similar basicity. For comparison, the kinetics of reaction of guanosine 5'-phosphoimidazolide (ImpG) and cytidine 5'-phosphoimidazolide (ImpC) were determined with Me2NH, EtNHMe, and Et2NH, and similar results were obtained. These results establish that the increased steric hindrance observed with the successive addition of ethyl groups are not due to any special steric requirements imposed by the guanosine or the methyl on the 2-methylimidazole leaving group of 2-MeImpG. It is concluded that addition of ethyl and, perhaps, groups larger than ethyl dramatically increases the kinetic barrier for addition of aliphatic secondary amines to the P-N bond of ImpN. This study supports the observation that the primary amino groups on the natural polyamines are at least 2 orders of magnitude more reactive than the secondary amino groups in the reaction with ImpN.     

Preparation and characterization of novel hyperbranched poly(amido amine)s from Michael addition polymerizations of trifunctional amines with diacrylamides

Novel hyperbranched poly(amido amine)s containing tertiary amines in the backbones and acryl as terminal groups were synthesized via the Michael addition polymerizations of trifunctional amines with twofold molar diacrylamide. The hyperbranched structures of these poly(amido amine)s were verified by ¹³C NMR (INVGATE). The polymerization mechanisms were clarified by following the polymerization process with NMR method, and the results show that the reactivity of secondary amine formed in situ is much lower than that of the secondary amine in 1‐(2‐aminoethyl) piperazine (AEPZ) ring and the primary amine. The secondary amine formed in situ was almost kept out of the reaction before the primary and secondary amines in AEPZ were consumed, leading to the formation of the AB2 intermediate, and the further reaction of the AB2 yielded the hyperbranched polymers. The molecular weights and properties of poly(amindo amine)s obtained were characterized by GPC, DSC, and TGA, respectively. Based on the reaction of active acryl groups in the polymers obtained with glucosamine, hyperbranched polymers containing sugar were formed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5127–5137, 2005     

Solvent- and catalyst-free N-formylations of amines at ambient condition: Exploring the usability of aromatic formates as N-formylating agents

A solvent- and catalyst-free N-formylation protocol has been developed for amines (1s–21s) where aromatic formates (1r–6r) were used as the N-formylating agents. The amine substrates include both primary and secondary aromatic amines (1s–19s) as well as aliphatic amine (20s) and a primary amide (21s). Structures of both the aromatic formate and amine components strongly influenced the rate of the reaction and yield of the N-formamide products. The reaction condition is mild and easy to operate. This protocol can be done smoothly under ambient conditions and gives high yield of formamide products. Furthermore, the present method cannot be applied for the formylation of thiol group (22s). This signifies its possible use for the chemoselective N-formylation of amine in the presence of thiol functionality.     

Catalyst-free chemoselective N-tert-butyloxycarbonylation of amines in water

[Structure: see text] Catalyst-free N-tert-butyloxycarbonylation of amines in water is reported. The N-t-Boc derivatives were formed chemoselectively without any isocyanate, urea, N,N-di-t-Boc, and O/S-t-Boc as side products. Chiral amines, esters of alpha-amino acids, and beta-amino alcohol afforded optically pure N-t-Boc derivatives. Amino alcohol and 2-aminophenol afforded the N-t-Boc derivative without oxazolidinone formation. Selectivity was observed during competition of aromatic amine vs aliphatic amine, amine vs amino acid ester, amine vs amino alcohol, and primary amine vs secondary amine.