Preparation of Amines

12 Key excerpts on "Preparation of Amines"

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  eBook - PDF

  Introduction to General, Organic, and Biochemistry

  • Morris Hein, Scott Pattison, Susan Arena, Leo R. Best(Authors)
  • 2014(Publication Date)
  • Wiley

    (Publisher)

  25.6 Preparation of Amines Be able to write reactions that make amines from ammonia, nitriles, amides, or aromatic nitro compounds. Alkylation of Ammonia and Amines The substitution of alkyl groups for hydrogen atoms of ammonia can be done by reacting ammonia with alkyl halides. Thus, in successive reactions, a primary, a secondary, and a tertiary amine can be formed: CH 3 NH 2 (CH 3 ) 2 NH (CH 3 ) 3 N methylamine dimethylamine trimethylamine CH 3 Br CH 3 Br CH 3 Br NH 3 (1°) (2°) (3°) Tertiary amines can be further alkylated so that four organic groups bond to the nitrogen atom. In compounds that have four organic groups bonded to a nitrogen atom, the nitrogen atom is positively charged and the compounds are called quaternary ammonium salts. The positive charge is on the nitrogen atom, as in ammonium salts. Here’s an example: N CH 3 CH 3 CH 3 � CH 3 Br N � CH 3 CH 3 CH 3 CH 3 Br � tetramethylammonium bromide Quaternary ammonium salts are well known in biologically active compounds and in many popular medicinals. For example, acetylcholine, an active neurotransmitter in the brain, is a quaternary ammonium salt. Choline is an important component of many biological membranes. CH 3 CH 3 CH 2 CH 2 OH choline CH 3 CH 3 CH 3 CH 2 CH 2 O CCH 3 acetylcholine the acetyl group CH 3 O ¯˘˙ The quaternary ammonium salt thiamine hydrochloride is marketed as vitamin B 1 . Many well-known fabric softening agents used in laundering clothes are quaternary ammonium salts. Reduction of Amides and Nitriles Amides can be reduced with lithium aluminum hydride to give amines. For example, acetamide can be reduced to ethylamine; and when N,N-diethylacetamide is reduced, triethylamine is formed: NH 2 CH 3 C O CH 3 CH 2 NH 2 ethylamine LiAlH 4 N CH 3 C O (CH 3 CH 2 ) 3 N triethylamine LiAlH 4 CH 2 CH 3 CH 2 CH 3 KEY TERMS primary (1˚), secondary (2˚), and tertiary (3˚) amines quaternary ammonium salt LEARNING OBJECTIVE

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  Organic Chemistry

  • David R. Klein(Author)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  1066 CHAPTER 22 Amines 22.5 Preparation of Amines via Substitution Reactions Alkylation of Ammonia Ammonia is a very good nucleophile and will readily undergo alkylation when treated with an alkyl halide. Ammonia A primary amine H 3 C H N H H CH 3 H N H H H N CH 3 H H N H H + - This reaction proceeds via an S N 2 process followed by deprotonation to give a primary amine. As the primary amine is formed, it can undergo further alkylation to produce a secondary amine, which undergoes further alkylation to produce a tertiary amine. Finally, the tertiary amine undergoes alkylation one more time to produce a quaternary ammonium salt. A primary amine H N H A secondary amine N H A tertiary amine N A quaternary ammonium salt N H 3 C N H H N H CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 H 3 C H 3 C CH 3 CH 3 CH 3 CH 3 H 3 C H 3 C H N H H H N H H + - + - + - If the quaternary ammonium salt is the desired product, then an excess of the alkyl halide is used, and ammonia is said to undergo exhaustive alkylation. However, monoalkylation is difficult to For example, a nitro group can be reduced selectively in the presence of a carbonyl group: H O O 2 N H 2 N O H 1) SnCl 2 , H 3 O + 2) NaOH When reducing a nitro group in acidic conditions, the reaction must be followed up with a base, such as sodium hydroxide, because the resulting amino group will be protonated under acidic con- ditions (as we saw in Section 22.3). CONCEPTUAL CHECKPOINT 22.10 Each of the following amines can be prepared from either an alkyl halide or a carboxylic acid. For each amine, draw the struc- tures of both possible starting materials. (a) NH 2 (b) NH 2 (c) NH 2 22.11 The following compound cannot be prepared from an alkyl halide or a carboxylic acid using the methods described in this sec- tion. Explain why each synthesis cannot be performed. NH 2 22.5 Preparation of Amines via Substitution Reactions 1067 achieve because each successive alkylation renders the nitrogen atom more nucleophilic.

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  Principles of Organic Chemistry

  • Robert J. Ouellette, J. David Rawn(Authors)
  • 2015(Publication Date)
  • Elsevier

    (Publisher)

  Acetaminophen, the analgesic in many drugs, is an amide. Draw the structures of the compounds that could be used to produce it. What possible complications might occur with this combination of reactants?

  12.9 Synthesis of Amines

  We have seen many of the general methods to synthesize amines discussed in preceding sections and chapters. Except for the displacement reaction of an alkyl halide by ammonia or an amine, the remaining methods involve compounds that already have a nitrogen atom contained in a functional group, which is then transformed into an amine functional group.

  Alkylation of Amines by Alkyl Halides

  In Section 12.7 we saw that a nucleophilic substitution reaction of ammonia with an alkyl halide yields a mixture of products resulting from multiple alkylation. The chances for multiple alkylation can be diminished somewhat by selecting the proper reaction conditions. For example, if the reaction of an alkyl halide with ammonia is carried out with excess ammonia, an alkyl halide can be converted to a primary amine. When the concentration of ammonia is greater than the concentration of the primary amine product, the probability that the primary amine will continue to react with the alkyl halide decreases.

  Reduction of Imines

  We recall that the carbonyl group of aldehydes or ketones is reduced to an alcohol by either catalytic hydrogenation or metal hydrides. Imines are the nitrogen analogs of carbonyl compounds, and they are also reduced by the same reagents.

  Imines do not have to be prepared and isolated for subsequent reduction. A mixture of a carbonyl compound and ammonia or the appropriate amine reacts in the presence of hydrogen gas and a metal catalyst. The imine that forms initially is reduced to an amine. The overall process is called reductive amination.

  Reduction of Amides

  Reduction of amides is one of the most frequently used methods of preparing amines. The method is very versatile because primary, secondary, and tertiary amines are easily prepared from the corresponding class of amide. Amides are prepared by acylation of amines using activated acyl derivatives such as acid chlorides or acid anhydrides (Section 12.6 ). Subsequent reduction of the amide with LiAlH4

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  Organic Chemistry

  • David R. Klein(Author)
  • 2016(Publication Date)
  • Wiley

    (Publisher)

  When preparing a primary amine, the available starting materials will dictate which of the three methods will be chosen. Secondary amines are readily prepared from primary amines via reductive amination. Similarly, tertiary amines are readily prepared from secondary amines via reductive amination. Primary amine N H H R Secondary amine N H R R Tertiary amine N R R R Reductive amination Reductive amination RCHO, [H + ], NaBH 3 CN RCHO, [H + ], NaBH 3 CN Direct alkylation of the primary amine is not efficient because polyalkylation is generally unavoid- able, as seen in Section 22.5. Therefore, it is more efficient to use reductive amination as an indirect method for alkylating the nitrogen atom of an amine. Tertiary amines can be converted into quaternary ammonium salts via alkylation. This process is efficient because polyalkylation is not possible with tertiary amines. Tertiary amine N R R R Alkylation R X X Quaternary ammonium salt N R R R R ⊝ ⊕ Using just a few reactions, it is possible to prepare a wide variety of amines from simple starting materials. Gabriel synthesis Azide synthesis Reductive amination Primary amine Secondary amine Tertiary amine N O O N N N H N H H N H H R N H R R N R R R Reductive amination Reductive amination Quaternary ammonium ion N R R R R Alkylation ⊝ ⊝ ⊝ ⊕ ⊕ Using potassium phthalimide, sodium azide, or ammonia together with suitable alkyl halides, ketones, or aldehydes, it is possible to generate a large variety of primary, secondary, and tertiary amines as well as quaternary ammonium salts. Let’s get some practice using these methods to prepare amines. SKILLBUILDER 22.4 PROPOSING A SYNTHESIS FOR AN AMINE Using ammonia as your source of nitrogen, show what reagents you would use to prepare the following amine: N H LEARN the skill 22.7 Synthesis Strategies 1027 SOLUTION Begin by identifying the alkyl groups connected to the nitrogen atom and determine whether the amine is primary, secondary, or tertiary.

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  Concerning Amines

  Their Properties, Preparation and Reactions

  • David Ginsburg, Robert Robinson(Authors)
  • 2016(Publication Date)
  • Pergamon

    (Publisher)

  We shall therefore be selective and discuss only the more practicable methods for the Preparation of Amines and not the behaviour of all of the abovementioned classes of compounds upon attempted reduction. Another consideration in the Preparation of Amines (or, for that matter, of any other class of compounds) is the economics of the process involved. This aspect will be exemplified as our discussion proceeds but one must always realize that the industrial preparation of organic compounds will place overwhelming emphasis on the economics of the process because the manage-ment presumably wishes to keep their jobs by paying dividends to the shareholders. In preparing the same compound on a bench scale for some further laboratory-scale synthetic sequence, convenience and time spent by the investigator involved are usually the overriding factors in the choice of the synthetic method. Let us take a case in point. We shall see that reduction of nitro compounds is definitely a reasonable and a practicable method for preparing primary amines. Anihne is prepared industrially by reduction of nitrobenzene which is, in turn, obtained by nitration of benzene. PROPERTIES, PREPARATION AND REACTIONS 19 pushed with cheap iron fihngs in the presence of hydrochloric acid, another heavy inorganic chemical available in commerce in large quantities and therefore relatively cheap. Now, imdoubtedly the reduction step may be accomplished by means of other reagents. There is no doubt that nitrobenzene may be catalytically reduced in the presence of hydrogen to give anihne. This would, however, require an investment in the catalyst; even if this were recoverable, its recovery would cost us a certain sum. It might also require the use of pressure equipment, since hydrogen is a gas, and this equipment would require a capital expenditure which a manager of an anihne production plant would probably find it unwise to make.

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  Klein's Organic Chemistry

  • David R. Klein(Author)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  When preparing a primary amine, the available starting materials will dictate which of the three methods will be chosen. Secondary amines are readily prepared from primary amines via reductive amination. Similarly, tertiary amines are readily prepared from secondary amines via reductive amination. Primary amine N H H R Secondary amine N H R R Tertiary amine N R R R Reductive amination Reductive amination RCHO, [H + ], NaBH 3 CN RCHO, [H + ], NaBH 3 CN Direct alkylation of the primary amine is not efficient because polyalkylation is generally unavoid- able, as seen in Section 23.5. Therefore, it is more efficient to use reductive amination as an indirect method for alkylating the nitrogen atom of an amine. Tertiary amines can be converted into quaternary ammonium salts via alkylation. This process is efficient because polyalkylation is not possible with tertiary amines. Tertiary amine N R R R Alkylation R X X Quaternary ammonium salt N R R R R ⊝ ⊕ Using just a few reactions, it is possible to prepare a wide variety of amines from simple starting materials. Gabriel synthesis Azide synthesis Reductive amination Primary amine Secondary amine Tertiary amine N O O N N N H N H H N H H R N H R R N R R R Reductive amination Reductive amination Quaternary ammonium ion N R R R R Alkylation ⊝ ⊝ ⊝ ⊕ ⊕ Using potassium phthalimide, sodium azide, or ammonia together with suitable alkyl halides, ketones, or aldehydes, it is possible to generate a large variety of primary, secondary, and tertiary amines as well as quaternary ammonium salts. Let’s get some practice using these methods to prepare amines. SKILLBUILDER LEARN the skill 23.4 PROPOSING A SYNTHESIS FOR AN AMINE Using ammonia as your source of nitrogen, show what reagents you would use to prepare the following amine: N H 23.7 Synthesis Strategies 1071 SOLUTION Begin by identifying the alkyl groups connected to the nitrogen atom and determine whether the amine is primary, secondary, or tertiary.

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  BIOS Instant Notes in Organic Chemistry

  • Graham Patrick(Author)
  • 2004(Publication Date)
  • Taylor & Francis

    (Publisher)

  SECTION O — AMINES AND NITRILES

  O1 Preparation of Amines

  Key Notes

  Reduction	Nitriles can be reduced to primary amines with lithium aluminum hydride (LiAlH4 ). Primary secondary and tertiary amides can be reduced with LiAlH4 to primary secondary and tertiary amines respectively.
  Substitution with NH2	Nucleophilic substitution of an alkyl halide with an azide ion gives an alkyl azide which can then be reduced with LiAlH4 to give a primary amine. Alternatively nucleophilic substitution of an alkyl halide with a phthalimide ion is carried out and the N -alkylated phthalimide is then hydrolyzed to the primary amine. Reductive animation of an aldehyde with ammonia is a third method of introducing an NH2 group. A fourth possible method is to react an alkyl halide with ammonia, but this is less satisfactory since over-alkylation is possible.
  Alkylation of alkylamines	Primary and secondary alkylamines can be alkylated to secondary and tertiary alkylamines, respectively, by reaction with an alkyl halide. Primary alkylamines can also be synthesized if ammonia is used instead of an alkylamine. However, these reactions are difficult to control and over-alkylation is common. Reductive animation is a more controlled method of adding an extra alkyl group to an amine, where the amine (or ammonia) is treated with an aldehyde or a ketone in the presence of a reducing agent (sodium cyanoborohydride). Alternatively, primary and secondary amines can be acylated with an acid chloride or acid anhydride and then reduced with LiAlH4 to give a secondary and tertiary amine, respectively.
  Rearrangements	The Hofmann and Curtius rearrangements are used to convert a carboxylic acid derivative to a primary amine with the loss of a carbon unit — the original carbonyl group. In both cases the rearrangement reaction involves the alkyl group being transferred from the carbonyl group to the nitrogen atom to form an isocyanate intermediate. Hydrolysis then results in loss of the original carbonyl group. The Hofmann rearrangement involves the treatment of a primary amide with bromine under basic conditions. The Curtius rearrangement involves heating an acyl azide.

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  Science of Synthesis: Knowledge Updates 2020/2

  • M. Christmann, Z. Huang, J. A. Joule, M. Christmann, Z. Huang, J. A. Joule(Authors)
  • 2020(Publication Date)
  • Thieme

    (Publisher)

  315 40.1. 1.4.3 Synthesis of Amines by Rearrangement (Update 2020) C. I. Ochoa and U. K. Tambar General Introduction The synthesis of amines is one of the most important areas of research in organic chemis-try due to the prevalence of nitrogen atoms in many functional molecules, including nat-ural products, pharmaceutical drugs, and agrochemicals. The synthesis of amines through rearrangement reactions has been heavily researched and discussed over the past few decades. One of the most comprehensive reviews of this topic was included in Science of Synthesis (Section 40.1.1.4). The chapter was arranged in two sections: rearrange-ments from carbon to nitrogen, and rearrangements from nitrogen to carbon. In this ex-tension of the original chapter, the same organization is preserved for consistency and ease of cross-referencing between the two chapters. The purpose of this chapter is to pro-vide an up-to-date account of new methods and synthetic developments in amine re-arrangement reactions within the last decade. Over this period of time, new chemistry has been developed which was not discussed in any particular section in the original ac-count on this topic. Thus, this chapter will not only serve as a supplementary document to the previous volume. It will also be a source of new synthetic strategies not discussed previously. It should be noted that although this section of Science of Synthesis is focused on the formation of alkyl-and cycloalkylamines, some examples shown in this chapter give products that are not part of these two categories; examples that give products such as anilines, amides, and ureas, have also been included to highlight both the broad scope and the power of the rearrangement reactions discussed. Every effort has been made to make this an in-depth review; however, there may be publications that have been inten-tionally or unintentionally omitted. 40.1. 1.4.3.1 Rearrangements from Nitrogen to Carbon 40.1.

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  Practical Functional Group Synthesis

  • Robert A. Stockland, Jr.(Authors)
  • 2016(Publication Date)
  • Wiley

    (Publisher)

  3 SYNTHESIS OF AMINES, AMIDES, AND RELATED COMPOUNDS

  ALKYLAMINES

  3.1 SYNTHESIS OF ALKYLAMINES AND RELATED COMPOUNDS THROUGH NITROGEN–CARBON(SP

  3

  ) BOND-FORMING REACTIONS

  The preparative routes leading to the formation of alkylamines and related compounds are quite diverse. The following section will highlight a number of these approaches with special attention paid to methods that are operationally simple, high yielding, or exhibit broad functional group tolerance.

  Substitution chemistry remains one of the most popular and simplest approaches to the formation of nitrogen–carbon(sp3 ) bonds. An example of this method involved the addition of pyrimidines to brominated esters (Scheme 3.1 ) [1]. The first step in this sequence was the protection of the primary amine in order to direct the reaction to the N(1)-H of the pyrimidine. Once the protection was complete, addition of a strong base deprotonated the N(1)-H and generated the amide that attacked the brominated ester to generate the new nitrogen–carbon(sp3 ) bond.

  SCHEME 3.1

  Classic synthesis of nitrogen–carbon(sp3 ) bonds through substitution chemistry [1].

  Another example of this chemistry generated seven-membered heterocycles through a double substitution reaction (Scheme 3.2

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  Pyrolysis of Organic Molecules

  Applications to Health and Environmental Issues

  • Serban C. Moldoveanu(Author)
  • 2009(Publication Date)
  • Elsevier Science

    (Publisher)

  hapter 13 Pyrolysis of Amines and Imines

  S.C. Moldoveanu

  13.1. Primary amines

  General aspects

  Primary amines can be considered as compounds derived from ammonia by the substitution of a hydrogen atom with an organic radical alkyl or aryl, or as compounds resulting from the substitution of a hydrogen atom from an organic molecule with the group NH2 . The general formula of primary amines is R–NH2 (for aromatic primary amines the formula Ar–NH2 is sometimes used). Continuing the substitution of hydrogens from ammonia with alkyl or aryl organic radicals, secondary amines (R2 NH) and tertiary amines (R3 N) are generated. The formation of quaternary ammonium cations ( ) is also possible, these compounds being the equivalent of ion having the hydrogen substituted with organic radicals. The amines are named either using the name of the organic radical with the suffix amine (e.g., methylamine for CH3 –NH2 ) or using the prefix amino followed by the name of the hydrocarbon (e.g., aminomethane for CH3 –NH2 ). The substitution of a hydrogen from ammonia with an acyl radical (R–C(O)–) leads to the formation of amides. Amides can be considered derivatives of acids, and their pyrolysis is discussed in Chapter 20. Amine oxides can also be considered compounds different from amines and are discussed in Section 14.4.

  Aliphatic primary amines

  Aliphatic primary amines have a carbon with sp3 hybridization and two hydrogen atoms connected to the nitrogen atom. Pyrolysis of these compounds can take place with the involvement of the NH2 group. In this case, there are two common paths, one with ammonia elimination and formation of an unsaturated hydrocarbon (similar to water elimination in alcohols) and the other with hydrogen elimination and formation of a nitrile. These two types of reactions are shown below:

  (13.1.1)

  (13.1.2)

  Other reactions involving the amino group were also noticed during pyrolysis of some amines, such as generation of HCN, N2

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  Organic Chemistry Study Guide

  Key Concepts, Problems, and Solutions

  • Robert J. Ouellette, J. David Rawn(Authors)
  • 2014(Publication Date)
  • Elsevier

    (Publisher)

  23

  Amines and Amides

  Keys to the Chapter

  23.1 Organic Nitrogen Compounds

  Because nitrogen has five valence shell electrons, it can form three covalent bonds in neutral compounds, leaving one nonbonding electron pair. These bonds can be three single bonds as in amines and amides, one double bond and a single bond in imines, or a triple bond in nitriles.

  Nitrogen is found in many biologically important compounds that have a wide range of physiological properties. However, once a nitrogen-containing functional group is identified, its chemical reactions can often be predicted since the functional groups in these compounds, whose structures are often complex, have the characteristic reactivities of much simpler compounds.

  23.2 Bonding and Structure of Amines

  Amines are pyramidal at the nitrogen atom, with approximately tetrahedral bond angles to all bonded atoms. The nitrogen atom in amines is sp3 hybridized. However, the configuration of an amine is not static. Amines undergo nitrogen inversion to give mixtures of mirror images. The process occurs via a planar transition state. The energy barrier to inversion is low, and nitrogen inversion is rapid so that amines with chiral nitrogen atoms cannot be isolated.

  23.3 Classification and Nomenclature of Amines

  Amines are classified according to the number of alkyl or aryl groups bonded to the nitrogen atom. Primary, secondary, and tertiary amines have 1, 2, and 3 groups bonded, respectively. Amides are classified the same way, with the acyl group counting as one of the carbon groups bonded to the nitrogen atom. Abbreviations for the classes of amines and amides are 1°, 2°, and 3°.

  The common names of simple amines are based on the identity of the alkyl or aryl groups bonded to the nitrogen atom. The names of the alkyl groups are written in alphabetical sequence as one word, followed by the word amine.

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  Organic Chemistry, Volume One

  Part I: Aliphatic Compounds Part II: Alicyclic Compounds

  • Frank C. Whitmore(Author)
  • 2012(Publication Date)
  • Dover Publications

    (Publisher)

  VIII. AMINES, ALKYL DERIVATIVES OF AMMONIA

  Depending on the number of H atoms replaced in NH3 , the amines are primary, secondary and tertiary, RNH2 (amino group, −NH2 ), RR´NH (imino group, =NH), and RR′R′′N respectively. They have the basic properties of ammonia but form more strongly basic solutions probably because of the greater stability of their “hydrates” as compared with that of ammonia. The primary and secondary amines are “alcohols of the ammonia system”730 , while the tertiary amines are “ethers” on the same basis. The lower amines have characteristic odors somewhat resembling that of NH3 . The three methylamines and primary ethylamine boil below 20°. The others are liquids with boiling points increasing with their molecular weights to heptadecylamine at 340° and tri-n -octylamine at 366°. Branching lowers the boiling points as in the alcohols. This is shown by the following isomeric (metameric) amines: Et3 N, 90°; Pr2 NH, 110°; HexNH2 , 129°. The densities of the amines range from 0.66 to 0.77.

  The preparations and reactions of the amines can be more safely generalized than can those of the alcohols. There are few reactions of amines in which the C−N linkage is broken whereas most reactions of alcohols involve the breaking of the C−O linkage. The outstanding example of the breaking of a C−N linkage, the action of nitrous acid with a primary amine, presents even more irregularities than any alcohol reaction (p. 172).

  The amines unite with HX in the same way that NH3 does, forming salts such as NH4 Cl, RNH3 Cl, R2 NH2 Cl, R3 NHCl, etc. The substituted ammonium salts (amine hydrochlorides etc.) have much the same properties as the parent substance. They are very soluble crystalline compounds. They are more soluble in organic liquids than the simple ammonium salts. Ammonia and the amines add certain alkyl halides to give ammonium salts having one more alkyl group than the starting material. The last possible stage is a quaternary ammonium compound R4 NX. The corresponding hydroxides RNH3 OH, R2 NH2 OH, R3 NHOH, R4 NOH, act as stronger bases than the parent ammonium hydroxide probably because of their greater stability. Me4 NOH can be obtained as a solid resembling KOH in physical and chemical properties. On heating, however, it decomposes giving Me3 N and MeOH. Secondary amines give stronger bases than either the corresponding primary or tertiary amines.731

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