ARTICLE

Received 22 Oct 2016 | Accepted 20 Feb 2017 | Published 5 May 2017 DOI: 10.1038/ncomms14993 OPEN

Nickel-catalysed retro-hydroamidocarbonylation
of aliphatic amides to olefins
Jiefeng Hu1, Minyan Wang1, Xinghui Pu1 & Zhuangzhi Shi1

Amide and olefins are important synthetic intermediates with complementary reactivity
which play a key role in the construction of natural products, pharmaceuticals and manmade
materials. Converting the normally highly stable aliphatic amides into olefins directly
is a challenging task. Here we show that a Ni/NHC-catalytic system has been established
for decarbonylative elimination of aliphatic amides to generate various olefins via C–N and
C–C bond cleavage. This study not only overcomes the acyl C–N bond activation in aliphatic
amides, but also encompasses distinct chemical advances on a new type of elimination
reaction called retro-hydroamidocarbonylation. This transformation shows good functional
group compatibility and can serve as a powerful synthetic tool for late-stage olefination of
amide groups in complex compounds.

1 State
Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
Correspondence and requests for materials should be addressed to Z.S. (email: shiz@nju.edu.cn).

NATURE COMMUNICATIONS | 8:14993 | DOI: 10.1038/ncomms14993 | www.nature.com/naturecommunications 1

ARTICLE
A
liphatic amide skeletons are key building blocks in a broad
range of natural and artificial compounds such as proteins
and nylons. Resonance stabilization of the amide bond
confers stable characteristic in such compounds. Although amide
C–N bonds can readily be cleaved by enzymes (Fig. 1a)1,
transformations that allow direct functionalization of amide
C–N bonds remains quite difficult. (Commonly used methods to
cleave amide C–N bonds include the reductive conversion of
amides to aldehydes using Schwartz’s reagent and the
displacement of Weinreb’s N-OMe-N-Me amides with
organometallic reagents en route to ketones2.) Elegant work by
the groups of Garg and Houk has shown that nickel catalysis is
effective to promote the conversion of amide derivatives to esters
by acyl C–N bond activation (Fig. 1b)3–6. However, all these
reported methods are limited to aryl and heteroaryl amide
substrates7–9. Nevertheless, the development of catalytic system
for the efficient transformation of amides derived from aliphatic
carboxylic acids is still in high demand.
The alkene moiety is vital in many broad synthetic applications
including Heck reaction, electrophilic addition and olefin
metathesis reaction. The ability to interconvert other functional
groups with alkene is significant in synthetic chemistry10. For
instance, as the reverse reaction of hydrohalogenation11,
regioselective dehydrohalogenations of alkyl bromides have
been achieved in the presence of cobalt12 and palladium13
catalyst. Hydroformylation is an important homogeneously
catalysed industrial process for the production of aldehydes
from olefins14,15. In 2015, Dong and coworkers have disclosed
rhodium-catalysed dehydroformylation of aldehyde substrates to
olefins via transfer hydroformylation (Fig. 1c)16,17. Most recently,
Morandi et al. have also achieved a remarkable interconversion
between alkyl nitriles and alkenes by nickel-catalysed transfer
hydrocyanation reactions (Fig. 1d)18. Inspired by these precedent
results, a pathway involving decarbonylative elimination of
aliphatic amides to olefin19 developed as the reverse conversion
of hydroamidocarbonylation process20,21 seems meaningful to
expand the synthetic utility (Fig. 1e).
To achieve this transformation, several difficulties need to be
considered: (1) this transformation is to cleave a stable C–N bond
while forming an easily transformable carbon–carbon double
bond; (2) the C–N bond scission has a high activation energy
and its selective cleavage in the presence of C–CN, C–O and
C–F bonds is challenging; (3) the olefination products have a
tendency to undergo decarbonylative Heck reaction with
unconsumed amides22. Herein we disclose the first case of a
retro-hydroamidocarbonylation process by chemoselective
a Enzyme-catalysed aliphatic amide C–N bond cleavage
O H
H
N H
N N
H H
O n
enzymes
O R2
H
N C-terminus
N-terminus N
H - H & CN
R1 O
b Aryl amide C–N bond functionalization
O O
cat.[Ni]
R1
N Nuc Garg & Houk, 2015
Ar Nucleophile Ar
R2
Figure 1 | Development of a retro-hydroamidocarbonylation protocol. (a) Biodegradation of nylon 66 and hydrolysis of protein. (b) Ni-catalysed
activation of aryl amide C–N bonds. (c) Rh and Ir-catalysed decarbonylative elimination of aldehydes to olefins. (d) Ni-catalysed transformation of nitriles
to olefins. (e) Ni-catalysed decarbonylative elimination of aliphatic amides to olefins.
2 NATURE COMMUNICATIONS | 8:14993 | DOI: 10.1038/ncomms14993 | www.nature.com/naturecommunications
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms14993
activation of aliphatic amide C–N bonds using nickel-
catalysis23–29.
Results
Reaction design. We have recently reported nickel-catalysed
decarbonylative cross-coupling of aryl amides to build
C–B bonds30,31. As the key intermediate, the structure of the acyl
nickel complex B (Ar ¼ 4-methyl-1-naphthyl) was first confirmed
by X-ray analysis, which displayed the square planar geometry
with two carbene (ICy: 1,3-dicyclohexylimidazol-2-ylidene)
ligands mutually in trans position to each other. Furthermore,
the decarbonylative product C was also confirmed by X-ray
analysis. These findings uncovered key mechanistic features
of the acyl C–N bond activation process (Fig. 2, left cycle).
We proposed a similar acyl nickel species B0 as the key
intermediate for further transformation in aliphatic amides. The
intermediate B0 , if formed, would undergo decarbonylation and a
subsequent b-H elimination process would generate olefination
products (Fig. 2,right cycle). Thus, an efficient retro-
hydroamidocarbonylation process of aliphatic amides is
theoretically possible.
Investigation of reaction conditions. Initial studies involved the
evaluation of decarbonylative elimination of substrate 1 by acyl
C–N bond activation (Table 1). This compound was chosen as
the model substrate because of its structure, containing
both ester32–39 and amide group, and selective activation of
amide C–N bond was very meaningful. In the presence
of 10 mol% Ni(COD)2, 20 mol% ICy  HCl, 20 mol% NaOtBu
and 3.0 equiv K3PO4, at 130 °C under an argon atmosphere
in toluene, we indeed observed the desired product 2 in 33% yield
after 36 h in GC-MS (Table 1, entry 1). We further studied
the performance of other NHC ligands such as IMes  HCl
(Table 1, entry 2) and IPr  HCl (Table 1, entry 3) under these
conditions and found that ICy  HCl promoted a dramatic
reactivity for this transformation. It is noted that K2CO3 was
slightly better than K3PO4 (Table 1, entry 4), and 44% yield of the
desired product was observed by employing KOAc as the base
(Table 1, entry 5). Under these conditions, changing the solvent
to cyclohexane provided 51% yield of 2 (Table 1, entry 6). Using a
binary solvent system, toluene and cyclohexane (v/v ¼ 1:2)
resulted in 58% yield (Table 1, entry 7). Interestingly, more
improvement could be achieved employing ICy as the ligand
(Table 1, entry 8). To our delight, the utilization of 0.5 equiv
Mg(OAc)2 as an additive exhibited higher reactivity and afforded
c Retro-hydroformylation
O cat. [Rh]/[Ir]
Dong, 2015
- H2 & CO Nozaki, 2015
O
N d Retro-hydrocyanation
H
H N cat. [Ni]
Morandi, 2016
e Retro-hydroamidocarbonylation
O
H cat. [Ni]
R1 This work
N
- CO & HNR1R2
Nuc = OR, NR2, Ar et al. R2
 RSC Advances
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Eco-friendly synthesis of fused pyrano[2,3-b]pyrans

via ammonium acetate-mediated formal oxa-[3 + 3]
Open Access Article. Published on 16 September 2020. Downloaded on 9/17/2020 8:37:41 PM.

Cite this: RSC Adv., 2020, 10, 34344

cycloaddition of 4H-chromene-3-carbaldehydes
and cyclic 1,3-dicarbonyl compounds†
Vitaly A. Osyanin,*a Dmitry V. Osipov, a Irina A. Semenova,a Kirill S. Korzhenko,a
A. V. Lukashenko,a Oleg P. Demidovb and Yuri N. Klimochkina

Received 24th July 2020
Accepted 26th August 2020
DOI: 10.1039/d0ra06450e
rsc.li/rsc-advances
Various substituted polycyclic pyrano[2,3-b]pyrans were synthesized via the condensation of 4H-
chromene-3-carbaldehydes and their areno-condensed analogues with hetero- and carbocyclic 1,3-
dicarbonyl compounds in acetic acid. Ammonium acetate was used as a green catalyst for the reaction.
The process also involves the subsequent Knoevenagel condensation and 6p-electrocyclization of the 1-
oxatriene intermediates formed. Fused pyridines were isolated as the products of the conjugated
addition of ammonia to 1-oxatriene intermediates while using carbocyclic 1,3-dicarbonyl compounds
and increasing the reaction time, indicating the reversibility of the electrocyclization stage. The
calculated values of the Gibbs free energies and reaction rate constants for the 1-oxatriene – 2H-pyran
equilibrium also testified to the irreversibility of pyrano[2,3-b]pyran formation in the case of using of
heterocyclic 1,3-dicarbonyl compounds.

Despite the obvious advantages of formal oxa-[3 + 3]-

Introduction
Among the effective approaches to the synthesis of six-
membered oxygen- and nitrogen-containing heterocycles are
the reactions of formal [3 + 3]-cycloaddition, including the
Knoevenagel condensation followed by 6p-electrocyclization.1
The net result is the formation of a new stereocenter adjacent to
the pyran oxygen atom, two s-bonds and ring (Scheme 1).
Oxa-[3 + 3]-annulation is a powerful synthetic strategy in the
preparation of natural compounds and represents a comple-
mentary approach to oxa-[4 + 2]-cycloaddition. This method has
already been widely used in the synthesis of various terpenes
and alkaloids.1a–c At the same time, the set of possible substrates
is limited almost exclusively to acyclic a,b-unsaturated alde-
hydes. The involvement of other types of conjugated aldehydes,
in particular 4H-chromen-3-carbaldehydes, in this type of
transformation stimulates signicant interest because it will
provide access to the synthesis of a large number of new poly-
condensed heterocycles.
cycloaddition, the use of this methodology has long been
limited due to the presence of a large number of competitive
processes that reduce the yield of the target product. These
include competition between the 1,2- and 1,4-addition to the
a,b-unsaturated aldehyde, while the ambident nature of the
nucleophile can lead to the initial O- or C-attack of the conju-
gated system (Fig. 1). At the same time, acyclic a,b-unsaturated
enones and enals usually give 1,4-addition products (Michael
adducts) as the predominant or sole products.2
2H,5H-Pyrano[4,3-b]pyran-5-one and 2,6-dihydro-5H-pyrano
[3,2-c]pyridin-5-one are important scaffolds that are present in
many natural products with potent biological activities and
structural diversity. The pyrano[3,2-c]quinolone moiety is
a structural motif present in several pyranoquinolone alkaloids
including haplophytin A,3a oricine3b and simulenoline,3c which

a
Department of Organic Chemistry, Chemical Technological Faculty, Samara State
Technical University, 244 Molodogvardeyskaya St., Samara 443100, Russia. E-mail:
VOsyanin@mail.ru
b
Department of Chemistry, North Caucasus Federal University, 1 Pushkin St.,
Stavropol 355009, Russia
† Electronic supplementary information (ESI) available: Characterization data of
products and copies of 1H and 13C NMR spectra. CCDC 1939651 and 1943197. Scheme 1 The formal [3 + 3]-cycloaddition approach leading to the
For ESI and crystallographic data in CIF or other electronic format see DOI: fused 2H-pyran motifs.
10.1039/d0ra06450e

34344 | RSC Adv., 2020, 10, 34344–34354 This journal is © The Royal Society of Chemistry 2020
 View Article Online

RSC Advances Paper

Table 1 Optimization of the reaction conditionsa Table 2 Substrate scopea

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

Entry Catalyst (x equiv.) Time Yieldb (%)

1 Piperidine (0.2) 2 min 34

2 Piperidine (1.0) 2 min 39
Open Access Article. Published on 16 September 2020. Downloaded on 9/17/2020 8:37:41 PM.

3 Piperidine (0.2) 30 min 71

4 Piperidine (0.2) 2h 73
5c Piperidine (0.2) 5h 40
6d Piperidine (0.2) 14 h 49
7e Piperidine (0.2) 14 h 46
8f Piperidine (0.2) 30 min 31
9 Et3N (0.2) 2h 78
10 DBU (0.2) 2h 79
11 N-Methylimidazole (0.2) 2 min 13
12 N-Methylimidazole (0.2) 2h 74
13 TMGg (0.2) 2 min 13
14 TMG (1.0) 1h 80
15 Py (0.2) 2 min 37
16 Py (1.0) 1h 76
17 AcONH4 (1.0) 20 min 89
18 AcONH4 (1.0) 1h 95
19 AcONH4 (0.2) 2h 93
a
20h AcONH4 (0.2) 2h 52 All reactions were carried out with 1 (1 mmol), 2 (1 mmol) and
21 p-TSA (1.0) 2h — ammonium acetate (0.2 mmol) in AcOH under reux for 1 h. b X-ray
22 None 8h 43 with 50% probability displacement.
23h None 1h 46
24h None 2h 44
a
All reactions were carried out with 1a (1 mmol), 2a (1 mmol) and
catalyst in 3 mL of AcOH under reux (unless otherwise indicated) chromenecarbaldehyde 1 and 1,3-dicarbonyl compound 2.
and an air atmosphere. b Isolated yields. c CH3CN. d 1,2- Ammonium acetate is a very cheap and nontoxic catalyst,
Dichloroethane. e 1,4-Dioxane. f DMF at 100  C. g 1,1,3,3- therefore, this procedure presents a green method for the
Tetramethylguanidine. h EtOH.
diversity-oriented synthesis of biologically active compounds.
The structures of all products were determined on the basis
of their analytical data. The cyclic nature of products 3 was
(entry 19). Ethanol was also used in the ammonium acetate conrmed by the absence of phenolic OH-stretching frequen-
catalyzed reaction as a solvent, but the yield of 3aa was lower cies in the IR spectra and phenolic proton signals in the 1H
(entry 20). When we carried out the same transformation in the NMR spectra. A characteristic feature of the 1H NMR spectra is
presence of 1.0 equiv. of p-TSA in AcOH, a complex mixture of the presence of two one-proton singlet signals in the region of
unidentied products was obtained along with the starting 6.62–7.03 ppm, corresponding to the acetal and olenic
aldehyde 1a (entry 21). To determine the role of the catalyst, the protons. Methylene protons of 3 were observed, as a rule, as two
reaction was carried out in the absence of ammonium acetate in separate doublets at 3.54–5.30 ppm (JAB ¼ 15.8–19.2 Hz) due to
AcOH or ethanol and 3aa was isolated from the reaction mixture the chiral acetal center in these molecules. NH protons in the
1
in 43–46% yield (entries 22–24). This indicates that a secondary H NMR spectra of the N-unsubstituted derivatives of pyr-
amine, or ammonium acetate, is not necessary for this trans- idinone and quinolinone were seen as singlets at 10.93–
formation, but they accelerate the reaction and increase the 12.20 ppm. In the 13C NMR spectra of 3, a signal in the region of
yields. The synthesis of compound 3aa was repeated under 95.8–98.2 ppm was assigned to the acetal carbon atom. Meth-
optimized conditions on several different scales (up to 20 ylene carbon atoms appeared at 29.8–37.2 ppm. The DEPT
mmol), all with comparable yields. spectra showed that the number of protons directly attached to
With the optimized reaction parameters, we extended this the carbon atoms corresponds to the assigned structures. The
methodology to various formylchromones 1a–f and cyclic 1,3- structure of 3cc was also conrmed by single-crystal X-ray
dicarbonyl compounds 2a–g such as 4-hydroxy-6-methyl-2H- diffraction analysis.
pyran-2-one, 4-hydroxy-6-methylpyridin-2(1H)-ones and their We also studied the reaction of 1H-benzo[f]chromene-2-
benzocondensed analogues. As shown in Table 2, polycyclic carbaldehyde 1a with 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-
acetals 3 were prepared in 64–85% isolated yields. All reactions dione 2h in the presence of ammonium acetate. In this reaction,
were carried out using a 1 : 1 molar ratio of the formation of two electrocyclic products was potentially

34346 | RSC Adv., 2020, 10, 34344–34354 This journal is © The Royal Society of Chemistry 2020
 Journal of Chromatographic Science, 2019, 1–9
doi: 10.1093/chromsci/bmz077
Article

Downloaded from https://academic.oup.com/chromsci/advance-article-abstract/doi/10.1093/chromsci/bmz077/5560313 by Uppsala Universitetsbibliotek user on 19 September 2019

Article

An Orthogonal Approach for Determination of

Acetamide Content in Pharmaceutical Drug
Substance and Base-Contaminated Acetonitrile
by GC and GC-MS External Method
Nagaraju Rajana 1,2,*, Kaviaraj M. Yarbagi1 , K. Balakumaran1 ,
M. V. Madhubabu1 , J. Mosesbabu1 , K. Basavaiah2 and
Dharamasoth Rama Devi3
1 Technology Development centre, Custom Pharmaceutical Services, Dr. Reddys Laboratories Ltd., Miyapur,
Hyderabad 500 049, India, 2 Department of Inorganic and Analytical Chemistry, Andhra University, Vishakhapatnam,
India and 3 A.U. College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, India
∗ Author to whom correspondence should be addressed. Email: nagarajurajana@drreddys.com

Received 28 January 2019; Revised 11 June 2019; Accepted 8 August 2019

Abstract
Acetamide is a potential genotoxic impurity; it should control in drug substance based on
daily dosage level. It forms from base-contaminated acetonitrile and by-product of some drug
substances. The available methods for acetamide in drug substance and water samples were
determined by GC-MS using internal standard with critical procedures. These developed and
validated methods can assist in evaluating the reaction between acetonitrile and different bases and
also determine trace level acetamide in drug substances. The method development was initiated
with DB-624, 30 m, 0.32 width and 1.0-μm column. The column was used to validate at the 600 ppm
TTC value. Similarly, the CP-SIL 5CB, 60 m, 0.32 width, the 5-μm column was used for the remaining
TTC values. The validation study was performed for all TTC limits. The % RSD for precision at 600,
60, 20, 10 and 2.5 ppm was <15%. The % recovery at all TTC level was in between the 70 and 130%.
Solution stability study was performed up to the 24 h. At 2.5 ppm, the results were <15% variation
from the initial value. The linearities from the 50 to 150% concerning TTC values were more than
limit of 0.98 correlation coefficient. The limit of detection and limit of quantitation values were 0.4
to the 1.3 ppm, respectively, for 2.5 ppm TTC limit method.

Introduction and chromosomal rearrangements and, therefore, act as carcinogenic

Acetamide is class-1 impurity; it should be controlled based on the
linear extrapolation from TD-50 value as per the International coun-
cil for harmonisation of technical requirements for pharmaceuticals
for human use (ICH) M7 addendum guideline. TD-50 value for
acetamide is 180 mg/kg/day in rat (1). The acetamide is the main
source of the basic reactions in the synthetic process and it is a
genotoxic impurity (2). The compounds induce genetic mutations
compounds. These compounds cause damage to Deoxyribonucleic
acid (DNA) by different mechanisms such as alkylation or other
interactions that can lead to a mutation of the genetic codes. The
hazard summary is an overview of the key hazards information of the
compound (3); acetamide is the amide of acetic acid, white crystalline
solid. It is produced by dehydrating ammonium acetate also (3).
Acetamide is a colorless solid crystal with a mousy odor; it causes
mild skin irritation from acute exposure (3).

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
1
 DOI: 10.1002/ajoc.201900317 Minireview

1
2
3 Recent Advances in the Functionalization of Hydrocarbons:
4 Synthesis of Amides and its Derivatives
5
6 Thatikonda Narendar Reddy* and Dênis Pires de Lima*[a]
7
8 Dedicated to Prof. Dr. Vaidya Jayathirtha Rao on the occasion of his 62nd birthday.
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Asian J. Org. Chem. 2019, 8, 1 – 37 1 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

These are not the final page numbers! ��

 Minireview

1
2 Abstract: The functionalization of hydrocarbons represents tion of hydrocarbons to synthesize amides. This review
3 an attractive approach for the synthesis of amides. The amide provides comprehensive coverage on recent reports of
4 bond is one of the most fascinating functional groups in various efficient metal-catalyzed and metal-free methods for
5 nature, owing to its high bond polarity, stability, and the synthesis of amides from hydrocarbons (such as meth-
6 conformational diversity. Amides play an essential role in the ylarenes, alkenes, and alkynes). We also show the reaction
7 composition of many natural products, agrochemicals, pep- mechanisms of representative reactions in a detailed way
8 tides, polymers, proteins, biologically active systems, and with numerous examples and applications of these methods
9 functional materials. The present review focuses on recent in the synthesis of bioactive compounds.
10 breakthroughs and current challenges for the functionaliza-
11
12
13
1. Introduction these attractive features, amide bond formation is one of the
14
most often used reactions in organic and medicinal chemistry.
15
The development of efficient synthetic methods using renew- The traditional methods for the synthesis of amides involve
16
able natural resources has become a powerful tool in the the coupling of carboxylic acids with amines. However, these
17
scientific community. Site-selective functionalization of hydro- methods often require stoichiometric activating reagents and
18
carbons is made considerable achievements and emerged as a harsh reaction conditions and generate a large amount of waste
19
challenging goal because of their inert nature. However, most by-product.[11] Alternatively, a number of elegant metal-cata-
20
of the recent successful studies have focused on the chemical lyzed and metal-free amidation methods have been developed
21
manipulation of hydrocarbons for the synthesis of natural by using aldehydes,[12] ketones,[13] oximes,[14] alcohols,[15]
22
products and bioactive compounds, which can minimize the nitriles,[16] acids or its derivatives,[17] amines or its surrogates,[18]
23
challenging synthetic steps and prefunctionalization of starting aryl halides,[19] alkenes,[20] alkynes,[21] and arenes.[22] Of these
24
materials.[1] In this regard, the functionalization of hydrocarbons aforementioned methods, the synthesis of amides from hydro-
25
using transition-metal catalysts and organocatalysts has be- carbons (such as methylarenes, alkenes, and alkynes) has
26
come one of the most powerful tools for the selective formation attracted much attention due to economic and environmental
27
of carbon-carbon (C C) and carbon-heteroatom (such as C O, prospects.
28
C S, and C N) bonds to access valuable organic molecules. [2] Over the years, several reviews have been published to
29
Among them, direct formation of C O and C N linkages for the explore the scope and development of amides.[23] Although the
30
synthesis of amides has received a great deal of interest from carbonylation of hydrocarbons has been widely described in
31
both academic and industrial fields.[3] some of the previous reviews, there exists no comprehensive
32
Amides play an essential role in the composition of many documentation on this special topic so far.[24] At this stage,
33
natural products, agrochemicals, peptides, polymers, proteins, considering the importance of amide bond formation in the
34
biologically active systems, and functional materials.[4] In fact, scientific domain and based on our continued interest in amide
35
the amide bond is one of the most fascinating functional bond formation,[3,25] we became interested to fill this gap. In our
36
groups in nature, owing to its high bond polarity, stability, and opinion, a review of the functionalization of hydrocarbons to
37
conformational diversity.[5] Amides are frequently found in amides will be attractive and meaningful. The present review
38
various functional group transformations and organic reactions focuses on recent breakthroughs and current challenges for the
39
to access interesting organic molecules, including nitriles, functionalization of hydrocarbons to access amides. We provide
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carbonyls, esters, amino acids, peptides, amines, hydrocarbons, comprehensive coverage on recent reports of various efficient
41
and pharmaceutically active systems.[6] Interestingly, amides are metal-catalyzed and metal-free methods for the synthesis of
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commonly employed as directing groups in C H functionaliza- amides from hydrocarbons (such as methylarenes, alkenes, and
43
tion reactions[7] and also used as electrophiles in cross-coupling alkynes). We also show the reaction mechanisms of representa-
44
reactions.[8] In the recent scenario, aromatic amides are tive reactions in a detailed way with numerous examples and
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indispensable precursors for the synthesis of important nitro- applications of these methods in the synthesis of bioactive
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gen-containing heterocyclic or carbocyclic systems and also compounds. This review is organized according to the type of
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used as raw materials for various industrial fields.[9] Moreover, starting material employed and subsections based on the type
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amides are common structural motifs in 25% of approved of amidation, followed by catalyzed reaction conditions.
49
marketed drugs or drug candidates.[10] Therefore, owing to
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2. Synthesis of Amides from Methylarenes
52
53 [a] Dr. T. N. Reddy, Prof. D. P. de Lima
Instituto de Química (INQUI) Methylarenes are one of the most important raw chemicals in
54 Universidade Federal de Mato Grosso do Sul organic synthesis and are easily accessible by-products in the
55 179074-460, Campo Grande, MS, Brazil
E-mail: tnarendarreddyphd@gmail.com gasoline industry. In this context, direct C H functionalization
56
denis.lima@ufms.br of methylarenes has attracted much attention since they are
57
Asian J. Org. Chem. 2019, 8, 1 – 37 www.AsianJOC.org 2 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

These are not the final page numbers! ��

 Jurnal Biologi Indonesia 6 (3): 353-365 (2010)

Penapisan Mikroba Laut Perombak Senyawa Nitril dan Protein yang

Diisolasi Dari Spons di Perairan Ternate

Rini Riffiani & Nunik Sulistinah

Bidang Mikrobiologi, Pusat Penelitian Biologi-LIPI, Cibinong Science Center
Jl. Raya Jakarta-Bogor Km 46, Cibinong. E-mail : Rar4id@yahoo.com

ABSTRACT

Screening of Nitrile and Protein-Degrading Marine Bacteria Isolated from Sponge in Ternate
Sea Water. Thirty three marine bacteria have been isolated from marine sponge in Ternate by
enrichment culture. Screening bacteria-degrading nitrile was done by microtitter plate method
based on growth ability tested by Iodonitrotetazolium chloride. Product of nitrile degradation
was determined by Gas Chromatography (GC) and the potential bacteria-degrading protein
was also screened by using selected media which contained casein. The results showed that
twenty one isolates were able to show the clearing zone in selected media. Five isolates
capable of utilizing acetamide as the sole source of carbon and nitrogen. Acetate and ammonia
produced for hydrolysis acetonitrile by using resting cell of Lysobacter sp.

Key words: Nitrile, bacterium, sponge, Ternate

PENDAHULUAN cukup besar karena kandungan senyawa

Lautan Indonesia merupakan bagian
wilayah Indopasifik yang mempunyai
keanekaragaman biota laut terbesar di
dunia. Dilaporkan bahwa jenis biota laut
di daerah tropis Indonesia 2-3 kali lebih
besar dibandingkan biota laut di daerah
sub tropis dan daerah beriklim dingin
(Sujatmiko 2000). Terumbu karang
merupakan salah satu sumber daya alam
tersebut dan ekosistem terumbu karang
merupakan bagian dari ekosistem laut
yang menjadi sumber kehidupan bagi
beraneka ragam biota laut. Di dalam
ekosistem terumbu karang hidup lebih
dari 300 jenis karang, 200 jenis ikan dan
beberapa jenis moluska, krustasea,
spounge, algae dan biota lainnya (Var
Soest 1994). Spons merupakan salah satu
organisme laut yang mempunyai potensi
bioaktifnya. Binatang laut ini mampu
hidup sampai kedalaman 50 meter di
bawah permukaan laut. Hasil penelitian
juga menunjukkan bahwa pada porus
sponge (Microcionia prolifera)
ditemukan beberapa jenis bakteri, seperti
genus Pseudomonas, Aerosomonas,
Vibrio, Achromobacter, Flavobac-
terium, Corynebacterium, dan Micro-
coccus (Madri et al. in Reinheimer 1991)
Saat ini eksplorasi mikroba banyak
dilakukan karena mikroba mempunyai
kemampuan mensintesis enzim-enzim
tertentu yang dapat digunakan untuk
kepentingan industri seperti industri
pangan, obat, kimia maupun sebagai agen
bioremediasi lingkungan tercemar.
Beberapa mikroba perombak senyawa
nitril baik alifatik maupun aromatik telah
banyak ditemukan dan dimanfaatkan

353
Riffiani & Sulistinah

(Arthrobacter sp. WPCB190) ID.24. tumbuh dengan baik pada benzamida yaitu
TR (Sphingomonas sp.) dan ID.31.TR ID.02.TR (Micrococcus luteus strain
(Spons bacterium IS8) mampu tumbuh G3-6-08), dan ID.22.TR (Arthrobacter
dalam 100 mM asetamida dan sp. WPCB190) dengan aktivitas enzim
mempunyai aktivitas enzim yang relatif yang relatif rendah. Ketidakmampuan
lebih baik dibandingkan isolat-isolat yang tumbuh isolat pada benzamida disebabkan
lainnya. Dari Tabel 1 tampak bahwa isolat karena benzamida merupakan senyawa
yang mempunyai kemampuan tumbuh turunan benzonitril dan tergolong dalam
yang baik memiliki aktivitas enzim yang amida aromatik yang sangat toksik.
baik mampu tumbuh pada asetamida Disamping itu benzamida dan benzonitril
kemungkinan juga mampu mensintesis mempunyai kelarutan yang sangat rendah
enzim pendegradasi senyawa nitril. Tabel dibandingkan asetamida atau asetonitril,
1 tersebut juga menunjukkan, bahwa sehingga sulit didegradasi dan dimetabo-
Lysobacter sp. menunjukkan kemampu- lisme sebagai sumber energi, karbon dan
an tumbuh dan aktivitas yang paling baik nitrogen untuk pertumbuhan mikroba.
dibandingkan tiga isolat lain. Dengan Dilaporkan sedikit mikroba yang mampu
demikian bakteri Lysobacter sp. merupa- tumbuh pada benzonitril dan benzamida
kan isolat potensial untuk pengujian lebih (Sunarko et al. 2000). Dengan demikian
lanjut. ditunjukkan bahwa kemampuan tumbuh
Penapisan mikroba dengan isolat bakteri pada asetamida lebih tinggi
menggunakan benzamida menunjukkan dibandingkan pada benzamida karena
bahwa hanya 2 isolat bakteri yang mampu asetamida merupakan senyawa alifatik

250

200
A k tiv ita s e n z im p ro te a s e (U /m l)

150

100

50

0
ID.06.TR ID.09.TR ID.19.TR ID.31.TR
Isolat bakteri

Gambar 5. Aktivitas enzim protease isolat ID.06.TR, ID.09.TR, ID.19.TR, ID.31.TR

360
 Penapisan Mikroba Laut Perombak Senyawa

Tabel 3. Identifikasi 9 isolat bakteri laut potensial hasil penapisan

No ID Isolat Hasil identifikasi (16S rDNA) Homologi Kemampuan
(100 %)
1 ID.02.TR Micrococcus luteus strain G3-6-08 98 amidase +
protease +
2 ID.04TR Lysobacter sp. 99 amidase +
protease +
3 ID.12TR Vibrio harveyi 96 protease +
4 ID.13.TR Enterobacteriaceae bacterium B12 89 amidase +

5 ID.19.TR Sphingomonas phyllosphaerae 90 protease +

strain FA2

6 ID.22TR Arthrobacter sp. WPCB190 98 amidase +

7 ID.23.TR Bacillus pumilus strain ST277 96 protease +

8 ID.24. TR Sphingomonas sp. 98 amidase +
9 ID.31.TR Sponge bacterium IS8 99 amidase +
protease +

amida yang cenderung lebih mudah
dihidrolisis oleh mikroba.
Biodegradasi asetonitril
Degradasi asetonitril dengan
menggunakan resting cell Lysobacter
sp. yang ditumbuhkan dalam 100 mM
tampaknya melalui 2 jalur reaksi yang
melibatkan enzim nitril hidratase dan
amidase. Hal ini terbukti dengan
menurunnya konsentrasi asetonitril
selama proses degradasi tersebut dengan
terbentuknya asam asetat dan amonia
memperkuat terjadinya proses degradasi
asetonitril oleh aktivitas enzim
pendegradasi nitril. Secara umum,
biodegradasi senyawa nitril dilaporkan
melalui dua alur reaksi yang
menghasilkan asam karboksilat dan
ammonia (NH 4 + ) sebagai produk
akhirnya (Nagasawa et al. 1987;
Kobayashi1991). Pada alur reaksi
pertama melibatkan enzim nitril hidratase
(E.C. 4.3.2.84) dan amidase (E.C.
3.5.1.4), sedangkan reaksi kedua
melibatkan enzim nitrilase (E.C.3.5.5.1).
Diketahui bahwa degradasi senyawa nitril
alifatik melibatkan nitril-hidratase dan
amidase, sedangkan degradasi nitril
aromatik hanya melibatkan enzim nitrilase
saja (Nagasawa et al. 1987; Banerjee et
al. 2002).
Dari hasil persamaan regresi
menunjukkan bahwa Lysobacter sp
mampu menurunkan konsentrasi
asetonitril (190 mM) sampai konsentrasi
0 mM dalam waktu 5 jam 35 menit
(Gambar 6).
Berdasarkan Uji Korelasi menggu-
nakan program SPSS versi 12 (P=0,05),
menunjukkan bahwa penurunan konsen-
trasi asetonitril ternyata tidak berkorelasi
dengan terbentuknya asetat dan amonia.
Selanjutnya selama penelitian ini
ditunjukkan bahwa penurunan asetonitril

361
 JKPK (JURNAL KIMIA DAN PENDIDIKAN KIMIA), Vol 2, No 1, April 2017 Hal. 13-21
Program Studi Pendidikan Kimia Universitas Sebelas Maret ISSN 2503-4146
https://jurnal.uns.ac.id/jkpk ISSN 2503-4154 (online)

SINTESIS DAN KARAKTERISASI BIOPLASTIK DARI

KITOSAN-PATI GANYONG (Canna edulis)

Synthesis and Characterization of Bioplastic from

Chitosan-Ganyong Starch (Canna edulis)

Agung Nugroho Catur Saputro* dan Arruum Linggar Ovita

Program Studi Pendidikan Kimia, FKIP, Universitas Sebelas Maret

Jl. Ir. Sutami No. 36A, Surakarta, Indonesia 57126

* Untuk Korespondensi, Telp: 081329023054 e-mail: anc_saputro@yahoo.co.id

Received: March 29, 2016 Accepted: April 28, 2016 Online Published: April 30, 2017
DOI : 10.20961/jkpk.v2i1.8526

ABSTRAK
Tujuan penelitian ini adalah untuk mengetahui kualitas plastik kitosan-pati ganyong yang
dihasilkan dibandingkan plastik biodegradable komersil. Penelitian ini dilakukan dengan metode
eksperimen di laboratorium. Pembuatan film bioplastik dilakukan melalui proses pelarutan,
blending, pencetakan, pengeringan, dan penetralan. Karakterisasi film bioplastik dilakukan
dengan uji kuat tarik, % elongation, ketebalan, swelling, kelarutan, biodegradabilitas dan analisis
gugus fungsi dengan FTIR. Hasil karakterisasi bioplastik yang dihasilkan dibandingkan dengan
plastik biodegradable komersil. Hasil penelitian menyimpulkan bahwa bioplastik kitosan-pati
ganyong dibandingkan plastik biodegradable komersil menunjukkan kualitas lebih baik pada
parameter kuat tarik (53,9644 MPa : 18,4109 MPa), % elongation (1,8066 % : 3,7025 %), dan
kemampuan degradasi (5 hari : 30 hari); tetapi lebih rendah pada parameter ketebalan (0,0350
mm : 0,0140 mm), % swelling (0,275 % : 0,010 %), dan kelarutan (0,10 %: 0,05 %).

Kata kunci: Bioplastik, kitosan, pati ganyong, biodegradable, sifat mekanik.

ABSTRACT
The purpose of this study was to produced bioplastic from chitosan-ganyong starch and
compare its quality to commercial biodegradable plastic. This research was carried out by
experimental method in laboratory. Making bioplastic film was done by dissolving, blending,
printing, drying, and neutralizing process. Characterization of bioplastic film was performed by
tensile strength test,% elongation, thickness, swelling, solubility, biodegradability and functional
group analysis with FTIR. The produced bioplastic characterizations were compared to
commercial biodegradable plastics. The results concluded that the qualities of bioplastic chitosan-
ganyong starch are higher than commercial biodegradable plastics on tensile strength parameter
(53,9644 Mpa : 18,4109 MPa),% elongation (1,8066 % : 3,7025%), and degradation ability (5
days : 30 days); but lower in thickness parameters (0.0350 mm: 0.0140 mm), % swelling (0.275%:
0.010%), and solubility (0.10%: 0.05%).

Keywords: Bioplastic, chitosan, ganyong starch, biodegradable, mechanical properties.

13
20 Saputro dan Ovita, Sintesis dan Karakterisasi Bioplastik ...........

Dari Tabel 4, dapat dilihat bahwa KESIMPULAN

adanya pita serapan kuat dan lebar pada
-1 Hasil penelitian yang telah dilakukan
daerah panjang gelombang sekitar 3400 cm
menyimpulkan bahwa (1). Bioplastik kitosan :
menunjukan adanya gugus ─OH tumpang
pati ganyong yang terbaik adalah yang
tindih dengan ─NH2. Dari spektrum a, dan b,
komposisinya 10:0., (2). Berdasarkan analisis
berturut-turut terjadi pelebaran luas area
-1 spektra FTIR, interaksi antara kitosan dengan
pada panjang gelombang sekitar 3400 cm ,
pati ganyong adalah interaksi fisika., (3). Hasil
hal ini disebabkan oleh bertambahnya
karakterisasi bioplastik yang dihasilkan
gugus ─OH karena penambahan pati pada
dibandingkan dengan plastik biodegradable
spektra b.
komersil. Hasil penelitian menyimpulkan
Puncak pada daerah panjang
-1 bahwa bioplastik kitosan-pati ganyong
gelombang sekitar 1600 cm menunjukkan
dibandingkan plastik biodegradable komersil
adanya gugus ─C=O tumpang tindih dengan
menunjukkan kualitas lebih baik pada
C─N yang menunujukkan adanya gugus
parameter kuat tarik (53,9644 MPa : 18,4109
fungsi amida. Amida merupakan gugus fungsi
MPa), % elongation (1,8066 % : 3,7025 %),
yang memiliki gugus karbonil yang berikatan
dan kemampuan degradasi (5 hari : 30 hari);
dengan satu atom N (R-CONH-R’). Pada
tetapi lebih rendah pada parameter ketebalan
penelitian ini, kitosan yang digunakan memiliki
(0,0350 mm : 0,0140 mm), % swelling (0,275
derajat deasetilasi sebesar 88,35%. Ini berarti
% : 0,010 %), dan kelarutan (0,10 %: 0,05 %).
kitosan yang digunakan masih mengandung
sedikit gugus asetil. Adanya gugus amida
yang terbentuk berasal dari gugus asetil pada
DAFTAR RUJUKAN
kitosan yang masih mengandung gugus asetil. [1] Rahmawati, Norma. (2012). Mengurangi
-1 sampah bagian dari investasi. Artikel.
Sedangkan puncak pada daerah 1597,06 cm
-1 http://green.kompasiana.com/polusi/201
- 1593,20 cm menunjukkan adanya gugus - 2/03/21/mengurangi-sampah-bagian-
NH (amina) dari kitosan. Puncak pada daerah dari-investasi-448768.html. Diakses
-1 tanggal 18 Agustus 2013.
panjang gelombang 1033,85 cm - 1024,20
-1 [2] Vedder, Taylor. (2008). Edible Film.
cm menunjukkan adanya gugus CH amina.
-1 - http://japemethe.port5.com diakses 18
Panjang gelombang 894,97 cm - 898,83 cm agustus 2013.
1 -1 -1
; 1024,20 cm - 1033,85 cm ; dan 2877,79
-1 -1 [3] Sanjaya, I Gede, dan Puspita, Tyas.
cm - 2883,58 cm menunjukkan adanya
(2011). Pengaruh Penambahan Khitosan
gugus C-C,C-O dan, -CH yang terdapat pada dan Plasticizer Gliserol Pada Karakteristik
Plastik Biodegradable dari Pati Limbah
molekul pati dan kitosan [14]
Kulit Singkong. Laporan penelitian. FTI
Berdasarkan Gambar 2, pada spektra ITS, Surabaya.
FTIR bioplastik kitosan : pati ganyong tidak
[4] Ban, W., 2006, Journal of Applied Polymer
terlihat adanya puncak gugus fungsi baru yang Science. 15, 30-38.
muncul. Hal ini menunjukkan bahwa bioplastik
[5] Butler, B. L., Vergano,P.J., Testin, R.F.,
yang terbentuk merupakan hasil pencampuran Bunn, J.M., and Wiles, J.L.,1996, J. Food
Sci. Vol 61(5) : 953-955
secara fisik [15].
JOURNAL OF COORDINATION CHEMISTRY
https://doi.org/10.1080/00958972.2018.1555328

Synthesis, characterization, and crystal structures of

iodides and polyiodides of scandium complexes with
urea and acetamide
Elena V. Savinkinaa, Denis V. Golubeva and Mikhail S. Grigorievb
a
Lomonosov Institute of Fine Chemical Technologies, RTU MIREA, Moscow, Russian Federation;
b
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
Moscow, Russian Federation

ABSTRACT ARTICLE HISTORY

Iodides and polyiodides of scandium complexes containing urea Received 22 July 2018
(Ur) and acetamide (AA) have been synthesized and characterized Accepted 29 October 2018
by elemental analysis, IR spectroscopy, and X-ray diffraction. The
trigonal crystals of [Sc(L)6]I3 (L ¼ Ur, AA) and monoclinic crystals of KEYWORDS
[Sc(Ur)6][I3]3 are isomorphous to the earlier reported [M(Ur)6]I3 Polyiodides; iodides;
scandium; urea; acetamide
(M ¼ Ti, V, Cr, Fe) and [Ln(Ur)6][I3]3 (Ln ¼ Yb, Lu), respectively.
Therefore, scandium in its complexes with urea and iodine links
rows of 3d transition elements and rare-earth elements; it contin-
ues the tendency of formation of polyiodides with different struc-
tures from isomorphous iodides, which was found for other
metal(III) urea complexes. In the orthorhombic crystals of
[Sc(AA)6][I5][I3]I, the first example of the M(III) acetamide polyio-
dide, metal ions in complex cations are located at the centers of
distorted octahedral arrangements of oxygen atoms of acetamide;
iodide ions are not coordinated. The crystals of [Sc(AA)6][I5][I3]I
contain V-shaped pentaiodide, linear triiodide, and isolated iodide
anions.

CONTACT Elena V. Savinkina e.savinkina@mail.ru Lomonosov Institute of Fine Chemical Technologies, RTU
MIREA, Moscow, Russian Federation
Supplemental data for this article can be accessed https://doi.org/10.1080/00958972.2018.1555328
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
8 E. V. SAVINKINA ET AL.

Figure 4. Molecular structure of 4.

Table 5. Parameters of the polyiodide ions in 3 and 4.

Distances (Å) Angles ( )
Structure 3
I3– I1–I2 2.9757(4), I2–I3 2.8472 (4) I1–I2–I3 178.340(13)
I3– I4–I5 2.9017(4), I5–I6 2.9431(4) I4–I5–I6 178.097(14)
I3– I7–I8 2.9345(5), I8–I9 2.9191(5) I7–I8–I9 178.901(15)
Structure 4
I3– I5–I6 2.9587(12), I6–I7 2.8799(12) I5–I6–I7 178.52(5)
I5– I2–I3 2.8058(15), I3–I4 3.0716(14), I4–I8 3.222(15), I2–I3–I4 175.27(5), I3–I4–I8 88.80(5),
I8–I9 2.7699(15) I4–I8–I9 179.42(5)

[Ln(AA)4(H2O)4]I3 [11] (Ln ¼ Y, La–Nd, Sm–Lu). The latter contain four organic ligands
and four water molecules in the inner sphere; the coordination number of the central
atoms is 8; crystals are monoclinic, space group P2/n, Z ¼ 2.
Polyiodide [Sc(Ur)6][I3]3 (Figure 3) is isostructural to the similar lutetium polyiodide
[10] (monoclinic, P21/n, Z ¼ 4), but differs significantly from transition-metal complexes
of the same [M(Ur)6][I3]3 composition (M ¼ V [7], Cr [8], Fe [9]) (trigonal, R-3c, Z ¼ 6;
monoclinic, C2/c, Z ¼ 4; hexagonal, P61, Z ¼ 6, respectively; see Table 4).
The structure of the acetamide compound [Sc(AA)6][I5][I3]I is unique (Figure 4). The
crystals of the complex are orthorhombic, space group P212121, Z ¼ 4. The unit cell of
4 contains a [Sc(AA)6]3þ cation and I5–, I3–, and I– anions. In contrast to 3, where the
octahedral [Sc(Ur)6]3þ unit is composed of two sets of three urea molecules with
hydrogen bonding within each set, acetamide molecules in the [Sc(AA)6]3þ cation do
not form hydrogen bonds. The Sc octahedron in 4 is less distorted than in 3 (O–Sc–O
angles are 87.25(4)–91.64(4), 176.91(4) in 3 and 89.51(4), 90.49(4), 180.00(5) in 4).
Acetamide molecules in 4 are planar; the C–O, C–N, and C–C bond lengths
(1.238–1.276, 1.291–1.316, and 1.417–1.501 Å, respectively) are close to that in aceta-
mide [20,21]. All nitrogen atoms of acetamide ligands are involved in short contacts
with iodine atoms; three of them form contacts with iodide ions, two nitrogen atoms
form contacts with one iodide and one triiodide ions, and one nitrogen atom forms
 THE JOURNAL OF CHEMICAL PHYSICS 145, 124313 (2016)

Photoinduced intermolecular dynamics and subsequent fragmentation

in VUV-ionized acetamide clusters
Marta Tarkanovskaja,1,2,a) Kuno Kooser,1,2 Helena Levola,2 Ergo Nõmmiste,1
and Edwin Kukk2
1
Department of Physics, University of Tartu, EST-50411 Tartu, Estonia
2
Department of Physics and Astronomy, University of Turku, FIN-20014 Turku, Finland
(Received 22 June 2016; accepted 10 September 2016; published online 28 September 2016)

Photofragmentation of small gas-phase acetamide clusters (CH3CONH2)n (n ≤ 10) produced by a

supersonic expansion source has been studied using time-of-flight ion mass spectroscopy combined
with tunable vacuum-ultraviolet (VUV) synchrotron radiation. Fragmentation channels of acetamide
clusters under VUV photoionization resulting in protonated and ammoniated clusters formation were
identified with the discussion about the preceding intramolecular rearrangements. Acetamide-2,2,2-
d3 clusters were also studied in an experiment with a gas discharge lamp as a VUV light source;
comparison with the main experiment gave insights into the mechanism of formation of protonated
acetamide clusters, indicating that proton transfer from amino group plays a dominant role in that
process. Geometry of the acetamide dimer was discussed and the most stable arrangement was
concluded to be achieved when subunits of the dimer are connected via two N—H· · · O—C hydrogen
bonds. Also, the influence of the photon energy on the stability of the clusters and their fragmentation
channels has been examined. Published by AIP Publishing. [http://dx.doi.org/10.1063/1.4963224]

I. INTRODUCTION it continues to be the largest interstellar molecule containing

Acetamide (acetic acid amide) is an organic compound
with the chemical formula H3C—CO—NH2, which has been a
focus of many experimental and theoretical studies. The main
reason of the high interest in acetamide lies in its structure:
small amides such as acetamide and formamide are the only
naturally occurring molecules that contain a single peptide
group O==C—N—H in their structure (Figure 1), which makes
them the simplest molecular models for peptide bonds that
are present as a repeat unit links in proteins.1,2 Peptide bonds
in proteins form through a condensation reaction between the
carboxyl group of one amino acid and the amino group of
another.
In addition, acetamide is recognized as a useful
model to study peptide-peptide hydrogen bonding, since
it is capable of contributing to the N—H · · · O==C and
C—H · · · O==C types of intermolecular hydrogen bonds.3,4
Thus, by condensating acetamide molecules into clusters or
investigating its crystalline and liquid forms, it is possible
to study the hydrogen bonding in a simpler model. The
aggregates of acetamide mimic the much larger structures
of macromolecular proteins and DNA molecules; since
hydrogen bonding interactions and cooperativity effects are
very important in proteins and polypeptides in determining
their structural properties and stability,5 acetamide has been
extensively studied from both theoretical and experimental
points of view.2,3,6–9
Exploring acetamide in astrophysical context is another
reason for an elevated interest in this compound.10 In 2006,
acetamide was detected in the interstellar medium11 and so far
a)Electronic mail: marta.tarkanovskaja@gmail.com
a peptide group. Small interstellar molecules with peptide
group like formamide and acetamide are interesting for their
potential role in prebiotic chemistry and origin of life.12,13 It
was predicted that acetamide could be a possible source of
larger peptides because it is one of the most abundant complex
organic species in the north core of the giant molecular
cloud Sagittarius B2.14 In 2015, acetamide detection was
reported for the first time in comets.15 After detection of
acetamide in space, several studies appeared with theoretical
models predicting possible pathways for the formation of
acetamide in interstellar medium.16,17 In space, the primary
species (e.g., H2O, CO, CO2, CH4, and NH3) are subjected
to ultraviolet (UV) light induced photochemical processes
leading to the formation of new species such as acetamide.
This makes it intriguing to study acetamide’s response to
UV radiation in relation to the role of small amides in the
prebiotic formation of amino acids, necessary for synthesis of
proteins, and to explore their survival conditions under UV
irradiation.18
Numerous experimental and computational studies exist
that investigate interactions of vacuum-ultraviolet (VUV)
photons with acetamide.1,10,18–21 Primary photodissociation
channels of the acetamide in the gas phase were determined
to be the C—N (the loss of amino group) and the C—C
(the loss of methyl group) bond fissions. In addition to the
primary neutral products of photodissociation (CH3 and NH2),
formation of neutral species like CO, H2NCO, H2NCHO,
H2O, HCCO, CH2CO, and NH3 has been reported in the gas
phase.18,19,21 Duvernay and co-workers reported on the forma-
tion of molecular complexes HNCOCH4 and COCH3NH2
and acetimidic acid (CH3C(OH)NH) in argon matrix at
110 K.10 They showed experimentally that acetimidic acid

0021-9606/2016/145(12)/124313/9/$30.00 145, 124313-1 Published by AIP Publishing.

Reuse of AIP Publishing content is subject to the terms: https://publishing.aip.org/authors/rights-and-permissions. Downloaded to IP: 193.40.13.166 On: Wed, 26 Oct
2016 15:53:33
 124313-2 Tarkanovskaja et al.
FIG. 1. Structure of acetamide showing a single peptide group (red).
is an intermediate in the dehydration process of acetamide.
The formation of acetimidic acid with further dehydration was
theoretically proposed earlier by Chen et al.20 In aqueous solu-
tion, photodissociation of acetamide leads to CH3CO and NH2
formation.22
Despite the fact that the photodissociation of the aceta-
mide molecule has been extensively studied, experimental
works with gas-phase acetamide clusters are very rare;
some examples are a FTIR spectroscopy study on the
dimerization of four simple amides including acetamide
where dimers were generated in pulsed supersonic jet
expansions23 and a photoelectron spectroscopy study of
electron binding motifs in acetamide cluster anions created
with a supersonic expansion source with slow electron
attachment.24
Until now acetamide clusters have mostly been studied by
exploiting different theoretical approaches: quantum chemical
semi-empirical Parameterized Model number 3 (PM3) method
was employed to study the clusterization process thermo-
dynamics of aliphatic amides at the air/water interface.25
Møller-Plesset perturbation (MP2), density functional theory
(DFT), natural bond orbital (NBO), and atoms in molecules
(AIMs) methods were used to investigate properties such
as binding energies, equilibrium geometries, and N—H
harmonic frequencies of N—H · · · O hydrogen bonding in
linear acetamide clusters (n = 2 − 7).7 DFT and Hartree-
Fock (HF) theory based approaches were used to study
double proton transfer mechanism in the acetamide dimer
in terms of energy profile, reaction force, chemical hardness,
average polarizability, ionization potential, chemical potential,
and interaction energies.6 The structure and energetics of
linear, standard, and circular arrangements of acetamide
clusters containing up to 15 molecules have been explored
using three-parameter hybrid density functional method
(B3LYP/D95**).26
In this study, we present experimental results of valence
photoionization and the consequent fragmentation of gas-
phase acetamide and deuterated acetamide clusters using
ion mass spectroscopy combined with synchrotron and gas
discharge radiation. Comparative measurements of normal and
deuterated samples’ mass spectra and probing of gas-phase
clusters with different photon energies are used to decipher
the fragmentation mechanisms. We discuss the possible
fragmentation channels for VUV-ionized acetamide clusters,
shedding light on the mechanism of formation of protonated
Reuse of AIP Publishing content is subject to the terms: https://publishing.aip.org/authors/rights-and-permissions. Downloaded to IP: 193.40.13.166 On: Wed, 26 Oct
2016 15:53:33
J. Chem. Phys. 145, 124313 (2016)
and ammoniated acetamide clusters, and also investigate the
influence of the photon energy on the stability of the clusters
and their fragmentation channels. We discuss possible aceta-
mide dimer arrangements with conclusions on the most stable
geometry.
II. EXPERIMENT
Mass spectroscopic measurements of gas-phase aceta-
mide clusters were carried out at the Finnish-Estonian
branchline at the normal incidence monochromator beamline
I3 of MAX-III synchrotron storage ring (Lund, Sweden).27 An
Au coated grating was used in the monochromator and a LiF
crystal was used to block the higher harmonics of the undulator
radiation. During the experiment, the pressure in the main
chamber was held below 1.5 × 10−6 mbar, and the pressure in
the expansion chamber was held below 1.2 × 10−4 mbar. The
clusters were produced using a supersonic expansion source in
continuous mode. The powder sample was heated in an oven
and the effusing vapor of acetamide was mixed with argon gas
and expanded through a 7 µm nozzle into vacuum. As a result
of adiabatic expansion and cooling, clusters were formed by
the condensation of acetamide molecules. Prior to entering
the ionization chamber, the molecular beam passed through
a 2 mm skimmer. Photoionized clusters and their fragments
were separated by their mass-to-charge ratio (m/z) using a
home-made Wiley-McLaren type time-of-flight (TOF) mass
spectrometer and detected with a 77 mm Hamamatsu mi-
crochannel plate detector. Ion flight times (T) were converted
into mass-to-charge ratio (m/z) scale using the following
equation:
T = To + C m/z,

(1)
where To and C are the calibration constants obtained
using two known mass peaks of water and argon ions.
The ion TOF spectrometer has been described in detail as
a part of our coincidence setup in Ref. 28. The above-
described experiment was recreated at the Material Research
Laboratory in the University of Turku using the same mass
analyzer and a gas discharge lamp as an ionizing light
source.
The experiments were performed with acetamide (purity
≥99%) purchased from Sigma-Aldrich and deuterated
acetamide CD3CONH2 (99.5 atom % D) purchased from Qmx
Laboratories. Both samples were used as received without
further purifications.
III. RESULTS AND DISCUSSION
In this section, we will first address thermal degradation
concerns of the acetamide, then move on to the identification
of fragments of VUV-ionized acetamide clusters, followed
by discussion about the clusters’ fragmentation pathways and
their dependence on the photon energy. The fragmentation
pathways are considered separately for three main processes
observed: proton transfer, monomer ejection, and ammonia-
tion of the clusters.
 J. Chem. Thermodynamics 105 (2017) 173–178

Contents lists available at ScienceDirect

J. Chem. Thermodynamics
journal homepage: www.elsevier.com/locate/jct

Influence of aliphatic amides on the temperature of maximum density of

water
Andrés Felipe Torres, Carmen M. Romero ⇑
Departamento de Química, Facultad de Ciencias, Universidad Nacional de, Colombia

a r t i c l e i n f o a b s t r a c t

Article history: The influence of dissolved substances on the temperature of the maximum density of water has been
Received 10 June 2016 studied in relation to their effect on water structure as they can change the equilibrium between struc-
Received in revised form 27 September tured and unstructured species of water. However, most work has been performed using salts and the
2016
studies with small organic solutes such as amides are scarce.
Accepted 13 October 2016
Available online 14 October 2016
In this work, the effect of acetamide, propionamide and butyramide on the temperature of maximum
density of water was determined from density measurements using a magnetic float densimeter.
Densities of aqueous solutions were measured within the temperature range from T = (275.65–278.65)
Keywords:
Amides
K at intervals of 0.50 K in the concentration range between (0.10000 and 0.80000) mol
kg1.
Temperature of maximum density The temperature of maximum density was determined from the experimental results. The effect of the
Despretz constant three amides is to decrease the temperature of maximum density of water and the change does not fol-
Water structure low the Despretz equation. The results are discussed in terms of solute-water interactions and the dis-
Solute-solvent interactions rupting effect of amides on water structure.
Ó 2016 Published by Elsevier Ltd.

1. Introduction
One of the characteristic and special properties of water is the
density maximum at 277.13 K [1]. The effect of dissolved sub-
stances on the temperature of maximum density of water ho
induces shifts in the temperature of maximum density and these
changes have been related to the effect of these compounds on
the hydrogen bonded structure of liquid water which changes
the equilibrium between structured and unstructured species of
water [2–5].
The temperature shift Dh can be represented by Eq. (1):
Dh ¼ h s  h o ð1Þ
where hs is the temperature of maximum density of the solution
and ho is the temperature of maximum density of water.
It has been observed that strong electrolytes lower the temper-
ature of maximum density of water and the change is proportional
to the concentration of solute. The behaviour of electrolytes for
dilute and even moderate concentration is usually well repre-
sented by the Despretz equation [2,6–11,5]:
⇑ Corresponding author at: Universidad Nacional de Colombia-Sede Bogotá,
Facultad de Ciencias, Departamento de Química, Grupo de Termodinámica Clásica,
Laboratorio de Investigaciones Básicas, Calle 44 # 45-67 Bloque B9, Bogotá Código
Postal 111311, Colombia.
E-mail address: cmromeroi@unal.edu.co.Tel (C.M. Romero).
Dh ¼ K D m ð2Þ
The concentration is usually expressed as molality m in mol
kg1
and KD is called the Despretz constant and its magnitude depends
on the nature of the solute added as well as on solute–solvent and
solute–solute interactions. Negative Despretz constants corre-
spond to negative shifts like those observed for strong electrolytes
and are supposed to be related to disrupting effects on the solvent
structure; positive changes have been attributed to the stabiliza-
tion of water structure [2,12–15].
However, it has been found that this simple equation is not suf-
ficient to describe the behaviour of all types of solutes in aqueous
solutions, neither the behaviour observed over a wide concentra-
tion range. Therefore other mathematical relationships have been
proposed trying to explain the changes in the Dh as a function of
molality as a result of the different interactions in solution and
the parameters obtained from these equations are used as criteria
for classifying solutes as forming or disrupting solutes of water
structure [2–5,8–15].
Amides have been used as model compounds because these
solutes are non-ionic uncharged molecules that contain amidic
and apolar groups within the molecule and constitute the struc-
tural units of polypeptide chains and proteins [16–21]. For this rea-
son, the study of the thermodynamic properties of these solutes in
aqueous solutions is important because it can contribute to under-

http://dx.doi.org/10.1016/j.jct.2016.10.024
0021-9614/Ó 2016 Published by Elsevier Ltd.
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Article
Assessment of Exposures to Acetamide in Milk, Beef,
and Coffee Using Xanthydrol Derivatization and GC/MS
Ramin Vismeh, Diane Haddad, Janette Moore, Chandra Nielson, Bryan D. Bals, Tim
Campbell, Allen Julian, Farzaneh Teymouri, A. Daniel Jones, and Venkataraman Bringi
J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b02229 • Publication Date (Web): 30 Nov 2017
Downloaded from http://pubs.acs.org on November 30, 2017

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Page 3 of 37 Journal of Agricultural and Food Chemistry

31 INTRODUCTION:

32 Acetamide is a simple amide with the chemical formula CH3CONH2 and is formed by the

33 dehydration of ammonium acetate, hydrolysis of acetonitrile, 1, 2 or ammonolysis of acetate esters

34 from plant cell walls. 3, 4 Acetamide has been classified by the International Agency for Research

35 on Cancer (IARC) as a Group 2B possible human carcinogen,5 as feeding trials on rats have

36 shown an increase in liver carcinoma.6,7 The simplicity of the molecule suggests that it may be

37 formed naturally or as a byproduct of other processes. Acetamide has been found in tobacco

38 smoke,8 industrial water9 and in beef and poultry liver.10,11 Two previous studies measured

39 acetamide in milk to determine exposure due to insecticides (thiodicarb and methomyl), and

40 surprisingly found acetamide in the milk of control animals as well.10-12 Furthermore, measured

41 acetamide levels in controls varied greatly between the two tests; in the methomyl it ranged from

42 2 - 8 ppm in milk, while only 0.3 – 0.5 ppm in the thiodicarb study. Both tests used GC to

43 measure the acetamide in milk, but neither report described the method validation in detail.

44 Artifacts may be anticipated during GC analysis of acetamide in foods, and particularly in milk

45 because of the abundance of N-acetylated (or acetamido) moieties on sugars, amino acid

46 metabolites and proteins. Commonly occurring N-acetylated compounds include the

47 monosaccharides N-acetylglucosamine and N-acetylneuraminic acid (commonly known as sialic

48 acid), and acetylated amino acids such as N-acetylcysteine. Furthermore, abundant glycoproteins

49 in milk including κ-casein and lactoferrin also contain N-acetyl sugars.13 A 2001 report14

50 measured N-acetylglucosamine and N-acetylgalactosamine in milk following brief ultra-high

51 temperature (~5 s at ~150 ˚C) pasteurization, and found combined levels of approximately 100

52 ppm. These N-acetylated compounds are potential sources of artifacts in acetamide analysis by

53 releasing acetamide. Further support for this idea comes from a recent NMR investigation of

ACS Paragon Plus Environment

 Journal of Inorganic Biochemistry 194 (2019) 160–169

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Journal of Inorganic Biochemistry

journal homepage: www.elsevier.com/locate/jinorgbio

Interactions of acetamide and acrylamide with heme models: Synthesis, T

infrared spectra, and solid state molecular structures of five- and six-
coordinate ferric porphyrin derivatives
Nan Xua, , Ye Guanb, Nhi Nguyena, Colin Lingafelta, Douglas R. Powellb,
⁎

George B. Richter-Addob,
⁎

a
Department of Chemistry, Pennsylvania State University Altoona, 3000 Ivyside Park, Altoona 16601, PA, USA
b
Price Family Foundation Institute of Structural Biology, Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman 73019,
OK, USA

ARTICLE INFO ABSTRACT

Keywords: The amide functional group is a fundamental building block of proteins, but is also present in several industrial
Iron porphyrin chemicals such as acetamide and acrylamide. Some acetamide derivatives are known to deplete cytoplasmic
Coordination heme, and some acrylamide derivatives are known to cause porphyria and may activate soluble guanylyl cyclase
X-ray through a heme-dependent mechanism. We have prepared a representative set of six-coordinate acetamide and
Acetamide
acrylamide (L) complexes of iron porphyrins of the form [(por)Fe(L)2]ClO4 (por = TPP (tetra-
Acrylamide
phenylporphyrinato dianion), T(p-OMe)PP (tetrakis(p-methoxyphenyl)porphyrinato dianion)) in 76–83% yields.
Nitric oxide
We have also prepared the five-coordinate derivatives [(OEP)Fe(L)]ClO4 (OEP = octaethylporphyrinato dia-
nion) in 68–75% yields. These compounds were characterized by IR spectroscopy and by single-crystal X-ray
crystallography. The molecular structures reveal the monodentate O-binding of the acetamide and acrylamide
ligands to the ferric centers, with variable H-bonding exhibited between the acetamide/acrylamide –NH2 moi-
eties and the perchlorate anions. The five-coordinate OEP derivatives exhibit a π-π stacking of their porphyrin
macrocycles, with the acetamide complex in the Class I and the acrylamide complex in the Class S groups. These
compounds represent the first structurally characterized acetamide and acrylamide adducts of iron porphyrins.
Reactions of the six-coordinate derivatives with NO result in the nitrosyl [(por)Fe(NO)(L)]ClO4 derivatives that
have been characterized by IR spectroscopy.

1. Introduction disinfection (by chloramines) of wastewater containing pharmaceu-

The amide functional group –C(=O)N– is a very important one in
biology. Not only does it serve as a building block in the assembly of the
primary amino acid sequence of proteins, but it is also present in several
organic derivatives of industrial and biological significance. Acetamide
(CH3C(=O)NH2) and acrylamide (CH2=CHC(=O)NH2) are among the
simplest 1° amides.
Acetamide is used as a solvent and in the plastics industry as a
plasticizer, and is also present in red beetroot [1]. Acetamide deriva-
tives such as haloacetamides have been identified as drinking water
disinfection products (from wastewater disinfection processes) and
there is an intense interest in their mechanism of formation and de-
toxification, as they are generally cytotoxic and genotoxic to mamma-
lian cells [2]. Such haloacetamides are generated during the
ticals such as acetaminophen [3], or by the Fe-enabled decomposition
of the antibiotic chloramphenicol [4]. Acrylamide is also widely used in
the paper, plastics, and polymer industries. Acrylamide is neurotoxic to
humans, and is categorized as a likely human carcinogen. Attention to
the harmful effects of acrylamide increased when it was discovered to
be present in some foods, particularly those that are cooked at high
temperatures [5–7].
The interactions of acetamide and acrylamide derivatives with
heme proteins have received some attention, but the available in-
formation is rather limited. In contrast, their coordination chemistry is
quite well developed. They can bind to a variety of metals such as Fe,
Co, Ni, Zn, Cr, Mn, Cu, Pd, and Pt through either the O-atom of the
carbonyl group, the N-atom of the amide group, or the C]C double
bond (of acrylamide) [8–17]. The monodentate O-binding mode

⁎
Corresponding authors.
E-mail addresses: nxx103@psu.edu (N. Xu), grichteraddo@ou.edu (G.B. Richter-Addo).

https://doi.org/10.1016/j.jinorgbio.2019.03.003
Received 27 December 2018; Received in revised form 26 February 2019; Accepted 1 March 2019
Available online 04 March 2019
0162-0134/ © 2019 Elsevier Inc. All rights reserved.