Description:Field of Invention: This invention describes the synthesis of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p) prepared by refluxing the ethanolic solution of 1-[1-aryl-5-hydroxy-3-methylpyrazol-4-yl]-butane-1,3-diones (4a-p), hydroxylamine hydrochloride and NaHCO3 and few drops of hydrochloric acid.

Background: Organic compounds that are cyclic and contain one or more heteroatoms are known as heterocyclic compounds. Because of their ability to treat a variety of diseases, heterocyclic compounds have been described as one of the essential classes of organic compounds. Hemoglobin, Chlorophyll, DNA, and RNA, as well as vitamins and many biological components include heterocyclic rings as the main skeletons [IJPSR, 2012, 3, 2947-2954; Chem. Rev., 2013, 113, 2958-3043; Der Pharma Chemica., 2017, 9, 141-147]. Among heterocycles, pyrazoles and isoxazoles are five-membered heterocyclic compounds that have a variety of biological properties which are highly significant [
J. Fluor. Chem., 2015, 180, 55-97, Eur. J. Med. Chem. 2013, 70, 740, Med. Chem. Res. 2015, 24, 3863]. Isoxazole contains an oxygen atom adjacent to the nitrogen present in five-membered ring. Some drugs having isoxazole moiety like Sulfisoxazole has been approved for the treatment of chronic urinary tract infections and it works by inhibiting the enzyme dihydropteroate synthetase. Risperidone is another drug for the treatment of schizophrenia in adults. NVP-AUY922 is an experimental cancer treatment drug, having isoxazole moiety and developed by Vernalis [J. Med. Chem., 2014, 57, 2136; Curr. Org. Chem., 2011, 15, 1423].
Moreover, pyrazole is a five-membered ring having two nitrogen atoms at adjacent positions. The compounds having pyrazole moiety possess applications as antimicrobial, diuretic, antipyretic, analgesic, tranquilizer, antihypertensive, anti-inflammatory, anticonvulsant, and antitumor agents [Mini-Rev Med. Chem., 2022, 22, 770-804; Chem. Data Coll., 2020, 28, 1004087-11; Asian J. Chem., 2019, 31, 522-526; Eur. J. Med. Chem., 2014, 81, 267-276.; Chem. Rev., 2011, 111, 6984–7034]. There are some commercially available drugs that contain pyrazole ring like Fipronil used as insecticide, Rimonabant used as antiobesity drug, Tepoxalin and Celecoxib are used as COX-2 selectivies nonsteroidal anti-inflammatory drugs (NSAID’s).
Furthermore, there are some compounds in which both isoxazole as well as pyrazole rings are present, show good biological activity [Anti-Cancer Agents Med. Chem., 2019, 19, 948-959; Molecules, 2022, 27, 3752; J Heterocyclic Chem., 2022, 59, 341–350]. In considering the various applications and as part of our ongoing research in order to develop pharmacologically potent compounds, we intended to synthesize new heterocyclic hybrids by combining the pyrazole and isoxazole nuclei. Here, 16 new 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives were synthesized and characterized.
Detailed description of the invention:
Synthesis of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p) is outlined in Scheme 1. Initially, phenyl hydrazine derivatives (2a-p) were synthesized from aniline derivatives according to the literature procedure [Aust. J. Chem., 1974, 27, 1361-5], which on condensation with dehydroacetic acid in ethanol resulted the formation of the hydrazone derivatives of DHA (3a-p) the key intermediates. The compounds (3a-p) on refluxing in glacial acetic acid yielded another type of key intermediates 1-[1-Aryl-5-hydroxy-3-methylpyrazol-4-yl]-butane-1,3- diones (4a-p) which on reaction with hydroxylamine hydrochloride in the presence of NaHCO3 and few drops of HCl in ethanol gave the final compounds (5a-p) with good yields under refluxing conditions. All the newly synthesized compounds structures have been confirmed by analyzing their mass, NMR (1H and 13C), and infrared spectral data.
In IR spectrum of compound 5a, absorption bands at 2446-3421 cm -1 (OH str.), 1640 cm -1 (C=N str.), 1504 cm -1 (C=C str.) more appeared. In 1H NMR spectrum, 5a shows two singlets at about d 2.25 and 2.46 ppm due to methyl protons attached to Carbon C-3' and Carbon C-3, respectively. Further it was also observed that the signals due to keto-enol forms of diketone (the starting material) disappeared and new signal at 6.47 ppm due to (C4'-H) isoxazolic proton has been appeared, therefore it indicated the formation of new ring in the product and multiplet of five aromatic protons resonate in the range of d 7.27-7.96 ppm. In 13C NMR spectrum, characteristic signal at around 94.90 ppm corresponds to C4' carbon of isoxazole further confirmed the formation of 5a. In HRMS analysis, the peak appearance at 256.1091 (m/z) due to molecular ion further supported the structure of compound 5a.
The methyl protons signals were also explained by 2D NMR spectroscopy in which NOSEY spectra of compound 5a have shown a proton-proton correlation of methyl protons attached to C3' carbon (d 2.2 ppm) with C4'-H isoxazolic proton (d 6.4 ppm), and methyl protons attached to C3 carbon (d 2.4 ppm) with C4'-H isoxazolic proton (d 6.4 ppm). In COSY spectra only methyl protons attached to C3' carbon (d 2.2 ppm) with C4'-H isoxazolic proton (d 6.4 ppm) have shown correlation as no other methyl group protons (d 2.4 ppm) correlation was seen.
Further the structure of final compound 5a was also demonstrated that it exists in B form rather than A form by NOSY spectra, the correlation between methyl protons attached to Carbon C-3 and (C4'-H) isoxazolic proton prove that the compound structure exists in B form.

Compounds a b c d e f g h
R H 4-F 3-F 2-F 4-Br 3-Br 2-Br 4-Cl
Compounds i j k l m n o p
R 3-Cl 2-Cl 4-CH3 3-CH3 2-CH3 4-OCH3 3-OCH3 2-OCH3

Scheme 1. Synthesis of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives
General procedure for Synthesis of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p)
The final product 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p) were synthesize by refluxing the ethanolic mixture of 1-[1-aryl-5-hydroxy-3-methylpyrazol-4-yl]-butane-1,3-diones (4a-p) (0.81mmole), hydroxylamine hydrochloride (0.81mmole), NaHCO3 (0.81mmole) and few drop HCl for one hr. After that the solvent was distilled out and filtered the product obtained and recrystallized from ethanol.

Characterization data of the compounds (5a-p)
3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol 5a
Yield: 88%; m.pt. 70-73°C; IR (?max, cm-1): 2446-3421 (OH str.), 1640 (C=N str.), 1504 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.46 (s, 3H, C3-CH3), 6.47 (s, 1H, isoxazole C4'-H), 7.28-7.32 (t, 1H, Ar- 4''H), 7.48- 7.52 (t, 2H, Ar- 3'', 5''H), 7.71-7.73 (d, 2H, Ar- 2'', 3''H, 3JH-H - 8Hz); 13C NMR (400 MHz, DMSO-d6, d): 11.38, 13.69, 94.90, 99.36, 120.86, 126.29, 129.54, 137,13, 146.43, 159.62, 164.22 MS: m/z 256.10 (M+)
1-(4''-Fluorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5b
Yield: 82%; m.pt. 129- 131°C; IR (?max, cm-1): 2446-3421 (OH str.), 1640 (C=N str.), 1504 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.44 (s, 3H, C3-CH3), 6.45 (s, 1H, isoxazole C4'-H), 7.32- 7.38 (m, 2H, Ar- 3'',5''H) 7.71- 7.75 (m, 2H, Ar- 2''- 6''H); 13C NMR (400 MHz, DMSO-d6, d): 11.38, 13.76, 94.71, 99.39, 116.20, 116.43, 123.24, 133.62, 146.42, 159.06, 159.62, 161.47, 164.15; MS: m/z 274.10 (M+)
1-(3''-Fluorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5c
Yield: 84%; m.pt. 108-110°C; IR (?max, cm-1): 2450-3228 (OH str.), 1613 (C=N str.), 1491 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.47 (s, 3H, C3-CH3), 6.48 (s, 1H, isoxazole C4'-H), 7.10-7.15 (m, 1H, Ar- 2''H), 7.51- 7.67 (m, 3H, Ar- 3'', 4'', 5''H), 12.41 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.37, 13.66, 95.12, 99.54, 107.05, 107.32, 112.45, 112.66, 115.77, 131.31, 131.40, 138.48, 138.59, 147.33, 159.64, 161.35, 163.77, 163.94; MS: m/z 274.10 (M+)
1-(2''-Fluorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5d
Yield: 88%; m.pt. 110- 114°C; IR (?max, cm-1): 2290-3159 (OH str.), 1617 (C=N str.), 1495 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.42 (s, 3H, C3-CH3), 6.41 (s, 1H, isoxazole C4'-H), 7.34-7.38 (m, 1H, Ar- 3''H), 7.43- 7.48 (m, 1H, Ar- 5''H), 7.50-7.59 (m, 2H, Ar- 4'', 6''H), 12.61 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.89, 93.23, 99.15, 117.03, 117.22, 125.42, 125.45, 129.23, 130.95, 131.03, 146.65, 155.59, 158.09, 159.61, 164.31; MS: m/z 274.09 (M+)
1-(4''-Bromophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5e
Yield: 80%; m.pt. 198- 200°C; IR (?max, cm-1): 2551-3212 (OH str.), 1615 (C=N str.), 1489 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.45 (s, 3H, C3-CH3), 6.47 (s, 1H, isoxazole C4'-H), 7.68-7.73 (m, 4H, Ar- 2'', 3'', 5'', 6''H), 12.46 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.75, 95.01, 99.51, 118.32, 122.34, 132.41, 136.49, 147.01, 159.64, 163.99; MS: m/z 334.02 (M+) 336.01 (M++2) in the ratio showing typical bromine isotopic profile (1:1)
1-(3''-Bromophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5f
Yield: 86%; m.pt. 188- 191°C; IR (?max, cm-1): 2191-3110 (OH str.), 1602 (C=N str.), 1473 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.46 (s, 3H, C3-CH3), 6.48 (s, 1H, isoxazole C4'-H), 7.44-7.47 (2H, Ar- 4'', 5''H), 7.75-7.78 (m, 1H, Ar- 6''H), 7.99 (s, 1H, Ar- 2''H), 12.53 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.67, 95.03, 99.51, 118.88, 122.22, 122.47, 128.61, 131.55, 138.41, 147.40, 159.63, 163.94; MS: m/z 334.01 (M+) 336.01 (M++2) in the ratio showing typical bromine isotopic profile (1:1)
1-(2''-Bromophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5g
Yield: 78%; m.pt. 190- 193°C; IR (?max, cm-1): 2156-3147 (OH str.), 1604 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.41 (s, 3H, C3-CH3), 6.40 (s, 1H, isoxazole C4'-H), 7.44-7.50 (m, 1H, Ar-4''H), 7.54- 7.57 (2H, Ar-5'', 6''H), 7.83- 7.85 (d, 1H, Ar-3''H, 3JH-H- 8Hz), 12.70 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.87, 93.01, 98.92, 122.73, 129.11, 131.23, 131.70, 133.75, 145.88, 159.57, 164.50; MS: m/z 334.01 (M+) 336.01 (M++2) in the ratio showing typical bromine isotopic profile (1:1)
1-(4''-Chlorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5h
Yield: 75%; m.pt. 206- 208°C; IR (?max, cm-1): 2251-3185 (OH str.), 1617 (C=N str.), 1494 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.45 (s, 3H, C3-CH3), 6.47 (s, 1H, isoxazole C4'-H), 7.55-7.58 (d, 2H, Ar- 4''H, 3JH-H- 12Hz), 7.76- 7.78 (d, 2H, Ar- 5'', 6''H, 3JH-H- 8Hz), 12.46 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.38, 13.74, 94.97, 99.50, 122.07, 129.50, 130.14, 136.06, 147.03, 159.63, 164.01; MS: m/z 290.07 (M+), 292.06 (M++2) in the ratio showing typical chlorine isotopic profile (3:1)
1-(3''-Chlorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5i
Yield: 83%; m.pt. 180- 184°C; IR (?max, cm-1): 2105-3045 (OH str.), 1600 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.46 (s, 3H, C3-CH3), 6.48 (s, 1H, isoxazole C4'-H), 7.33-7.36 (d, 1H, Ar-5''H, 3JH-H- 12Hz), 7.51- 7.55 (t, 1H, Ar-4''H), 7.72- 7.74 (d, 1H, Ar-6''H, 3JH-H- 8Hz), 7.87 (s, 1H, Ar-2''H), 12.37 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.38, 13.66, 95.06, 99.53, 118.48, 119.67, 125.70, 131,29, 133.88, 138.31, 147.40, 159.63, 163.93; MS: m/z 290.07 (M+), 292.06 (M++2) in the ratio showing typical chlorine isotopic profile (3:1)
1-(2''-Chlorophenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5j
Yield: 87%; m.pt. 234-235°C; IR (?max, cm-1): 2164-3115 (OH str.), 1606 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.42 (s, 3H, C3-CH3), 6.41 (s, 1H, isoxazole C4'-H), 7.49-7.58 (m, 3H, Ar-3'', 4'', 5''), 7.68- 7.70 (1H, Ar-6''H), 12.68 (Bs, 1H, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.77, 93.01, 98.98, 128.55, 130.66, 130.90, 131.38, 132.19, 146.15, 159.58, 164.45; MS: m/z 290.07 (M+), 292.06 (M++2) in the ratio showing typical chlorine isotopic profile (3:1)
3-methyl-4-(3'-methylisoxazol-5'-yl)-1-(p-tolyl)-1H-pyrazol-5-ol 5k
Yield: 73%; m.pt. 160-162°C; IR (?max, cm-1): 2078-3115 (OH str.), 1633 (C=N str.), 1512 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.33 (s, 3H, C3''-CH3) 2.45 (s, 3H, C3-CH3), 6.46 (s, 1H, isoxazole C4'-H), 7.28-7.30 (d, 2H, Ar-3'', 5''H, 3JH-H- 8Hz), 7.59-7.61 (d, 2H, Ar-2'', 6''H, 3JH-H- 8Hz); 13C NMR (400 MHz, DMSO-d6, d): 10.87, 13.10, 20.47, 94.28, 98.76, 120.46, 129.38, 134.21, 135.15, 145.47, 156.08, 159.09, 163.82; MS: m/z 270.12 (M+)
3-methyl-4-(3'-methylisoxazol-5'-yl)-1-(m-tolyl)-1H-pyrazol-5-ol 5l
Yield: 84%; m.pt. 180-183°C; IR (?max, cm-1): 2164-3115 (OH str.), 1606 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.37 (s, 3H C3''-CH3), 2.47 (s, 3H, C3-CH3), 6.47 (s, 1H, isoxazole C4'-H), 7.10-7.12 (d, 1H, Ar-4''H, 3JH-H- 8Hz), 7.35- 7.38 (t, 1H, Ar-5''H), 7.54-7.55 (d, 1H, Ar-6''H, 3JH-H- 4Hz), 7.57 (s, 1H, Ar-2''H); 13C NMR (400 MHz, DMSO-d6, d): 10.89, 13.05, 21.04, 94.39, 98.78, 117.44, 120.75, 126.39, 128.83, 136.51, 138.47, 145.77, 156.48, 159.10, 163.80; MS: m/z 270.12 (M+)
3-methyl-4-(3'-methylisoxazol-5'-yl)-1-(o-tolyl)-1H-pyrazol-5-ol 5m
Yield: 88%; m.pt. 229-233°C; IR (?max, cm-1): 2148-3094 (OH str.), 1600 (C=N str.), 1487 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.19 (s, 3H, C3'-CH3) 2.25 (s, 3H, C3''-CH3), 2.43 (s, 3H, C3-CH3), 6.42 (s, 1H, isoxazole C4'-H), 7.33-7.40 (m, 4H, Ar-3'', 4'', 5'', 6''H), 12.63 (Bs, OH, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.87, 18.03, 93.15, 98.82, 127.08, 128.13, 129.42, 131.29, 136.21, 145.32, 159.54, 164.71; MS: m/z 270.12 (M+)
1-(4''-methoxyphenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5n
Yield: 71%; m.pt. 177-180°C; IR (?max, cm-1): 2164-3115 (OH str.), 1606 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.25 (s, 3H, C3'-CH3), 2.42 (s, 3H, C3-CH3), 3.79 (s, 3H, C4''-OCH3) 6.43 (s, 1H, isoxazole C4'-H), 7.05-7.07 (d, 2H, Ar-3'', 5''H, 3JH-H- 8Hz), 7.57- 7.59 (d, 2H, Ar-2'', 6''H, 3JH-H- 8Hz), 12.16 (Bs, OH, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.78, 55.85, 94.44, 99.11, 114.36, 114.65, 115.11, 123.38, 123.53, 130.31, 145.25, 145.43, 157.88, 159.57, 164.44; MS: m/z 286.12 (M+)
1-(3''-methoxyphenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5o
Yield: 87%; m.pt. 198-201°C; IR (?max, cm-1): 2164-3115 (OH str.), 1606 (C=N str.), 1475 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.44 (s, 3H, C3'-CH3), 2.51 (s, 3H, C3-CH3), 3.88 (s, 3H, C3''-OCH3), 6.17 (s, 1H, isoxazole C4'-H), 7.03-7.05 (d, 1H, Ar-4''H, 3JH-H- 8Hz), 7.41 (s, 1H, Ar-2''H), 7.43- 7.45 (d, 1H, Ar-6''H, 3JH-H- 8Hz), 7.51- 7.55 (t, 1H, Ar-5''H); 13C NMR (400 MHz, DMSO-d6, d): 14.01, 19.35, 55.90, 106.51, 107.02, 111.98, 113.29, 113.44, 130.95, 138.09, 145.79, 153.73, 160.37, 163.30, 175.15; MS: m/z 290.07 (M+)
1-(2''-methoxyphenyl)-3-methyl-4-(3'-methylisoxazol-5'-yl)-1H-pyrazol-5-ol 5p
Yield: 89%; m.pt. 180- 182°C; IR (?max, cm-1): 2126-3085 (OH str.), 1635 (C=N str.), 1506 (C=C str.); 1H NMR (400 MHz, DMSO-d6, d): 2.26 (s, 3H, C3'-CH3), 2.42 (s, 3H, C3-CH3), 3.80 (s, 3H, C2''-OCH3), 6.41 (s, 1H, isoxazole C4'-H), 7.49-7.58 (m, 3H, Ar-3'', 4'', 5''), 7.68- 7.70 (1H, Ar-6''H), 12.68 (Bs, OH, C5-OH); 13C NMR (400 MHz, DMSO-d6, d): 11.39, 13.77, 55.89, 93.01, 98.98, 128.55, 130.66, 130.90, 131.38, 132.19, 146.15, 159.58, 164.45; MS: m/z 290.07 (M+)
, Claims:I/We claim:

1. The synthesis of a new series of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p) with Formula-1 where R may be H, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3.

Formula-I

2. The process for synthesis of 3-Methyl-4-(3'-methylisoxazol-5'-yl)-1-aryl-1H-pyrazol-5-ol derivatives (5a-p) (Formula-1) by refluxing the ethanolic mixture of 1-[1-aryl-5-hydroxy-3-methylpyrazol-4-yl]-butane-1,3-diones (4a-p) (0.81mmole), hydroxylamine hydrochloride (0.81mmole), NaHCO3 (0.81mmole) and few drops HCl. After that the solvent was distilled out and filtered the product obtained and recrystallized from ethanol.
3. The process, as mentioned in claim 2, wherein the desired products (5a-p) synthesized regioselectively and without formation of any by-products.