Impact of Reaction Dynamics on Synthesis of Novel Nitrogen containing Aldehydes

Impact of solvent dynamics, base employed and temperature conditions on the synthesis of novel Nitrogen containing aldehydes was studied.Piperazine, pyrrolidine and piperidine aldehydes were obtained in maximum yield and puritywith the K2CO3 base in presence of DMF solventand at 800 C temperatures.The synthesized compounds were characterized by IR, 1HNMR and MS Spectroscopy. key words: Nitrogen-containing-aldehyde, Reaction dynamics, N-arylation. compounds like anti depressant drug13-14 and vasolidators15. Piperidine is also commonly used in sequencing of DNA16 and in solid phase peptide synthesis17. As per the review about recent trends in chemistry of pyrrolidine, piperazine and piperidine derivatives, their demand in pharmaceuticals is increasing and still lies scope for the exploration of pharmaco-kinetics of these compounds. All these facts were driving force to study the synthesis of 4(-4methyl piperazine-l-yl) benzaldehyde, (4pyrrolidin-l-yl) benzaldehyde and (4-piperidine-l-yl) benzaldehyde.The present work is concerned solely with the chemistry i.e. the yield of the above mentioned products, for which the dynamics of the environment (solvent, base and temperature) can be responsible. 1532 MARKANDEwAR et al., Orient. J. Chem., Vol. 29(4), 1531-1534 (2013) Study of different parameters on the synthesis of aldehyde In continuation to explore the pharmaceutical significance of N-arylated moiety, thepiperazine, piperidine and pyrrolidinemoieties, it was planned to conduct a thorough study of the different parameters on the yield of 4-(4-methyl-piperazinel-yl) benzaldehyde, (4-pyrrolidine-l-yl) benzaldelyde and (4-piperidine-l-yl) benzaldehyde. The systematic study was carried out keeping in view their significance on the yield by virtue of effect of bases, solvents and temperature conditions as depicted in Table 1-3. ExpERIMENTAL All the melting points were carried out in open capillary tubes and are uncorrected. The Thin Layer Chromatography was performed on precoated silica plates and Iodine vapor is used for visualization. IR spectra were recorded in KBr disc on Shimadzu FT-IR 8300 spectrophotometer. 1HNMR spectra were recorded in DMSO-d6 on a Brucker Advance II400 MHz Spectrometer using TMS as an internal standard. Mass spectra were recorded on VG7070H mass spectrometer. Synthesis of 4-(4-methyl piperazine-l-yl) benzaldehyde[1a] In 4.0 ml of DMF, 1-methyl piperazine (0.1 gm. 0.001mol) was dissolved. To this solution K2CO3 (0.20gm, 0.00015 mol) was added and heated at 800C with stirring. After 30 min 4-flurobenzaldehyde (0.124 gm, 0.001mol) was added and heating was continued for 6 hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice-water. The separated product was filtered and dried. The product obtained was pure and used further without any purification.(M.P. 60-620C) Table 1: Effect of different bases S. Name of % Yield obtained No Base Used 1a 1b 1c 1. K2CO3 92% 94% 89% 2. CsCO3 88% 90% 80% 3. Na2CO3 87% 84% 73% 4. KHCO3 85% 80% 60% 5. NaHCO3 80% 76% 50% Table 2: Effect of different solvents S. Name of % Yield obtained No Base Used 1a 1b 1c 1. DMF 95% 96% 90% 2. DMSO 90% 89% 84% 3. Toluene 70% 65% 62% 4. Xylene 75% 75% 50% 5. Methanol No No No reaction reaction reaction 6. Acetone No No No reaction reaction reaction Table 3: Effect of different Temperature S. Name of % Yield obtained No Base Used 1a 1b 1c 1) 80-900C 92% 86% 90% 2) 110-1200C 55% 60% 50% 3) 150-1600C Decom Decom Decom posed* posed* posed* *no of spots formed on TLC Spectral Analysis IR:(cm-1): 1686 (C=O); 1561 (C=C). 1HNMR :.(DMSO) δppm : 2.0 (s,3H,CH3); 2.3 (t,4h,CH2); 3.3 (t,4H CH2); 7.2 (dd, 2H, aromatic) 8.1 (dd, 2H, aromatic) ; 9.9 (s, 1H, CHO) Mass: Mass (m/z): 204 1533 MARKANDEwAR et al., Orient. J. Chem., Vol. 29(4), 1531-1534 (2013) Synthesis of (4-pyrrolidine-l-yl) benzaldehyde [1b] In 4.0 ml of DMF of pyrrolidine (0.1 gm, 0.001mol) was dissolved. To this solution K2CO3 (0.27 gm, 0.002mol) was added and heated at 800C with stirring. After 30 min 4fluorobenzaldehyde (0.174 gm, 0.001 mol) was added and heating was continued for six hours. On completion of reaction, the reaction mixture was cooled and added dropwise to ice water. The separated product was filtered and dried. The product obtained was pure and used further without any purification (M.P880 C) Spectral Analysis IR:(Cm-1) : 1653 (C=O); 1524 (C=C). 1HNMR :( DMSO) δppm: 2.2 (t,4H, CH2), 3.2 (t, 4H, CH2), 6.4 (d, 2H,aromatic) 7.7.(d, 2H,aromatic), 9.8 (s, 1H CHO). Mass: Mass (m/z) -175(M+ion) Synthesis of (4-piperidine-l-yl-) benzaldehyde [1c] In 4.0ml of DMF of piperidine (0.0gm, 0.001mol) was dissolved. To this solution K2CO3 (0.27gm, 0.002mol) was added and heated at 800C with stirring. After 30 min 4-fluorobenzaldehyde (0.175 gm, 0.001mol) was added and heating was continued for six hours. On completion of reaction, the reaction mixture was cooled and added drop wise to ice water. The separated product was filtered and dried. The product obtained was pure and used further without any purification. (M.P.-2890C) Spectral Analysis IR:(cm-1): 1651 (C=O), 1597 (C=C) 1HNMR (DMSO) δppm: 3.3 (t, 6H,CH2), 3.5 (t,4H,CH2),6.9 (d, 2H,aromatic), 7.6 (t,2H, aromatic) ,9.7 (s,1H,CHO). Mass: Mass (m/z): 189.


INTRODUCTION
Nitrogen containing compounds are used as structural components of pharmaceuticals and agrochemicals due to their high biological activities 1 .There are many nitrogen containing chemicals, ranging from simple structural compounds as pyridine to complicated compounds as pharmaceutical ingredients and their number is growing rapidly year by year 2 .Pyrrolidine based compounds have wide application in pharmaceutics ranging from use in the treatment of cancer 3 ,obesity 4 , fungal and viral infections 5 , HIV infection 6 and diabetes [7][8] .Piperazine nucleus is one of the most important heterocycle, exhibiting remarkable pharmacological activities as anthelminitis 9 , anti-HIV agent, antanginals 10 , urological 11 and anticonvulsant compounds 12 .Piperidine and its derivatives are ubiquitous building blocks in the synthesis of pharmaceuticals key words: Nitrogen-containing-aldehyde, Reaction dynamics, N-arylation.compounds like anti depressant drug [13][14] and vasolidators 15 .Piperidine is also commonly used in sequencing of DNA 16 and in solid phase peptide synthesis 17 .
As per the review about recent trends in chemistry of pyrrolidine, piperazine and piperidine derivatives, their demand in pharmaceuticals is increasing and still lies scope for the exploration of pharmaco-kinetics of these compounds.All these facts were driving force to study the synthesis of 4(-4methyl piperazine-l-yl) benzaldehyde, (4-pyrrolidin-l-yl) benzaldehyde and (4-piperidine-l-yl) benzaldehyde.The present work is concerned solely with the chemistry i.e. the yield of the above mentioned products, for which the dynamics of the environment (solvent, base and temperature) can be responsible.

Study of different parameters on the synthesis of aldehyde
In continuation to explore the pharmaceutical significance of N-arylated moiety, thepiperazine, piperidine and pyrrolidinemoieties, it was planned to conduct a thorough study of the different parameters on the yield of 4-(4-methyl-piperazinel-yl) benzaldehyde, (4-pyrrolidine-l-yl) benzaldelyde and (4-piperidine-l-yl) benzaldehyde.The systematic study was carried out keeping in view their significance on the yield by virtue of effect of bases, solvents and temperature conditions as depicted in Table 1-3.

ExpERIMENTAL
All the melting points were carried out in open capillary tubes and are uncorrected.The Thin Layer Chromatography was performed on precoated silica plates and Iodine vapor is used for visualization.IR spectra were recorded in KBr disc on Shimadzu FT-IR 8300 spectrophotometer. 1 HNMR spectra were recorded in DMSO-d6 on a Brucker Advance II-400 MHz Spectrometer using TMS as an internal standard.Mass spectra were recorded on VG7070H mass spectrometer.

Synthesis of 4-(4-methyl piperazine-l-yl) benzaldehyde[1a]
In 4.0 ml of DMF, 1-methyl piperazine (0.1 gm.0.001mol) was dissolved.To this solution K 2 CO 3 (0.20gm, 0.00015 mol) was added and heated at 80 0 C with stirring.After 30 min 4-flurobenzaldehyde (0.124 gm, 0.001mol) was added and heating was continued for 6 hours.On completion of reaction, the reaction mixture was cooled and added drop wise to ice-water.The separated product was filtered and dried.The product obtained was pure and used further without any purification.(M.P. 60-62 0 C)

Synthesis of (4-pyrrolidine-l-yl) benzaldehyde [1b]
In 4.0 ml of DMF of pyrrolidine (0.1 gm, 0.001mol) was dissolved.To this solution K 2 CO 3 (0.27 gm, 0.002mol) was added and heated at 80 0 C with stirring.After 30 min 4-fluorobenzaldehyde (0.174 gm, 0.001 mol) was added and heating was continued for six hours.On completion of reaction, the reaction mixture was cooled and added dropwise to ice water.The separated product was filtered and dried.The product obtained was pure and used further without any purification (M.P-88 0 C) Spectral Analysis IR:(Cm -1 ) : 1653 (C=O); 1524 (C=C).

CONCLUSION
Our studies showed that K 2 CO 3 was the most effective base, while the use of other bases such as CsCO 3 and Na 2 CO 3 was less successful.DMF was found to be the optimal solvent, although the use of DMSO was also effective.In conclusion, the synthesis of wide variety of Nitrogen containing aldehydes is described with proper choice of base, solvent and temperature conditions.This work is underway to ameliorate difficulties which remain, especially in finding suitable reaction dynamics that efficiently increases the yield.