CHEM 225 Organic Chemistry II Lecture 1 Notes
CHEM 225 Organic Chemistry II Lecture 1 Notes CHEM 225
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This 22 page Class Notes was uploaded by MelLem on Wednesday January 20, 2016. The Class Notes belongs to CHEM 225 at Simmons College taught by Professor gurney in Spring 2016. Since its upload, it has received 133 views. For similar materials see Organic chemistry 2 in Chemistry at Simmons College.
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CHEM 225 Organic Chemistry II Professor Richard Gurney Simmons College UNIT 1 – Carbonyl Chemistry : Chemistry of Aldehydes, Ketones, and Carbohydrates Lecture 1 – Aldehydes & Ketones Reading from Klein Chapter 20 Sections: 20.120.4, 20.9, 20.10, 20.13 Introduction Nomenclature Nucleophilic Addition Oxidation Reduction Wittig Reagents and Reactions IMPORTANT: The following notes are in order according to the Simmons College CHEM 225 syllabus for reading, and lecture videos. Some portions of material is continued in different sections and labeled according to section and chapter in the two books used during this unit of the course. 20.1 Introduction to Aldehydes and Ketones Aldehyde: (RCHO) Ketone: (R C2) Both aldehydes and ketones are similar in structure. Each contain a C = O, which is called a carbonyl group. Aldehydes and ketones are responsible for many flavors and smells that we experience. Ex. Vanillin – Responsible for the vanilla flavor Many important biological compounds also exhibit carbonyl moiety. (Progesterone & Testosterone, the female and male sex hormones. Simple Aldehydes and Ketones are industrially important as well. Formaldehyde Acetone Compounds containing a carbonyl react with a large variety of nucleophiles, affording a wide range of products. Klein CH. 20.4 Introduction to Nucleophilic addition reactions The electrophilicity of a carbonyl group derives from resonance as well as inductive effects. RESONANCE One of the resonance structures shows carbon with a positive charge, this indicates that the carbon atom is deficient in electron density (delta positive) The carbon atom is originally sp2, making it trigonal planar, but after the nucleophilic attack, the carbon becomes sp3 hybridized and then has a tetrahedral geometry. o In recognition of this geometric change, the resulting alkoxide ion is often called a tetrahedral intermediate. o In general, aldehydes are more reactive than ketons toward nucleophilic attack, this can be explained by both steric and electronic effects. Steric Effects: A ketone has 2 alkyl groups (one on either side of the carbonyl group) that contribute to steric hindrance in the transition state of a nucleophilc attack. In contrast, an aldehyde only has one alkyl group, so the transition state is less crowded and lower in energy. Electronic Effects: We must recall that alkyl groups are electron donating – a ketone has 2 electron donating alkyl groups that can stabilize the delta + on the carbon atom of the carbonyl group. In contrast, aldehydes have only one electron donating group. Ketone: Has 2 Electron donating alkyl groups that stabilize the partial positive charge. Aldehydes: Only has 1 electron donating alkyl group to stabilize the partial positive charge. The delta + of an aldehyde is less stabilized than a ketone. As a result, aldehydes are more electrophilic than ketones and therefore are more reactive. 20.3 Preparing Aldehydes and Ketones (summary of preparation methods and reagents) Summary of Aldehyde Preparation Summary of Ketone Preparation 20.2 Nomenclature Recall that there are 4 discrete steps in naming organic compounds. 1. Identify and name the parent 2. Identify and name the substituents 3. Assign a locant to each substituent 4. Assemble the substituents alphabetically Aldehydes and ketones may also be named using the same 4 step procedure When naming the parent, the suffix – al indicates the presence of an aldehyde group. The suffix –one indicates the presence of a ketone. When choosing the parent chain, identify the longest change that includes the carbon of the aldehydic group. When numbering, the aldehydic carbon is assigned #1. When chirality is present, S & R is necessary at the beginning of the name. A cyclic compound containing an aldehyde group immediately adjacent to the ring is named a carbaldehyde. Ketone Nomenclature: All steps are the same for ketones (not a carbaldehyde however) Suffix – one IUPAC recognizes the common names of many simple ketones, including: Although it is barely used, IUPAC rules allow simple ketones to be name as “alkyl, alkyl ketones” Ex: 20.13 Spectroscopic analysis of aldehydes and ketones Aldehydes and Ketones exhibit several characteristic signals in their IR & NNR Spectra. IR Signals: The carbonyl group produces a strong signal in an IR spectra around 1750 – 1720 cm-1. A conjugated carbonyl may have a lower wavelength however. Ring strain however has the opposite effect on a carbonyl group. Ring strain will increase where the IR signal appears. Aldehydes generally exhibit two signals C – H between 2700 – 2850 cm -1 and a C = O stretch. HNMR Signals: The carbonyl itself does not create a signal, HNMR is commonly known as proton NMR. Aldehydic protons generally produce signals around 10 ppm. CNMR Signals: The carbonyl of a ketone or aldehyde will generally produce a weak signal around 200 ppm. 20.4 Intro to nucleophilic addition reactions (continued & review) Resonance and induction play an important role. O is delta negative C is delta positive Carbon of the carbonyl is the electrophile Aldehydes are more reactive because the (C) delta positive end is less stabilized than that of a ketone which has two electron stabilizing alkyl groups. Grignard Reagent: The Grignard reagent itself provides for strongly basic conditions o This is because Grignard reagents are both strong nucleophiles and strong bases. o This reaction can not take place under acidic conditions because Grignard reagents are destroyed when presented with an acid. ** Grignard Reagents are very strong nucleophiles and will attack aldehydes and ketones to PRODUCE Alcohols. The Grignard reagent follows a general mechanism for the reaction between a nucleophile and a carbonyl group under basic conditions. The general mechanism has 2 steps. o Nucleophilic attack o Proton transfer NUCLEOPHILIC ADDITION UNDER BASIC CONDITIONS INSERT FROM BOOK Aldehydes and Ketones also react with a wide variety of other nucleophiles under acidic conditions. Under acidic conditions 1. The carbonyl is first protonated 2. Undergoes a nucleophilic attack (The steps appear in the opposite order when under acidic conditions) NUCLEOPHILIC ADDITION UNDER ACID CONDITIONS 20.2 pg 922 Mechanism In acidic conditions, the protonating of the carbonyl group generate a very powerful electrophile The ability of the nucleophile being able to function as a leaving group is important. The Grignard reagent is a strong nucleophile, but does NOT act as a leaving group o As a result, the equilibrium greatly favors the products, the reaction only occurs one way. Halides: Halides however are good nucleophiles and good leaving groups. When a halide functions as a nucleophile, the equilibrium favors the starting ketone. 20.10 Carbon Nucleophiles Grignard Reagents: When trated with a Grignard reagent, aldehydes and ketones are converted to alcohols, accompanied by a formation of a new C – C bond. Carbohydrin Formation: When trated with hydrogen cyanide (HCN), aldehydes and ketones are converted into Cyanohydrins, which are categorized by the presence of a cyano group and a hydroxyl group that are connected to the same atom Wittig Reaction (Vittig): Georg Wittig, a german chemist awarded the nobel prize in chemistry in 1979. This reaction can be used to convert a ketone into an alkene by forming a new C –C bond at the location of the carbonyl moiety. The Phosphorus (P) containing reagent is called a Phosphorane, it belongs to a larger class called ylides Ylide: A compound with two oppositely charged atoms adjacent to one another. This phosphorane exhibits a negative charge on the carbon, and a positive charge on the phosphorus. The wittig reagent is a carbanion and can attack the carbonyl group in the first step of the mechanism. o This generates an intermediate called a betaine. Betaine – neutral compound with two oppositely charged atoms that are not adjacent to each other. Wittig reagent preparation Easily prepared by treating triphenylphosphaline with an alkyl halide followed by a strong base. Insert image from notes*** The mechanism for the formation of a wittig reagent involves an Sn2 reaction, is a then followed by a deprotonation with a strong base. 20.9 Hydrogen Nucleophiles When reduced, aldehydes and ketones go to alcohols When trated with a hydride reducing agent (LAH or NaBH4) aldehydes and ketones are reduced to alcohols. The reduction of ketones or aldehydes with hydride agents: Klein – Organic Chemistry Second Language, Second Semester Topics (OCSL 2S) Chapter 5 – Ketones and Aldehydes 5.1 Preparation of ketones and aldehydes Ketones and Aldehydes are made in many ways. The most useful type of transformation is forming a C= O bond from an alcohol. There are three types of alcohols. Primary, secondary, and tertiary. Primary Alcohols: Can be oxidized to form aldehydes Secondary Alcohols: Can be oxidized to form Ketones Tertiary Alcohols: CANNOT be oxidized because carbon can not form five bonds. Alcohols & Reagents Primary Alcohols: Oxidize to aldehyde, but NOT further. With a strong reagent, it can go from alcohol to a carboxylic acid, with a milder reagent, it can go from alcohol to aldehyde. This can be accomplished with a reagent called PYRIDINUM CHLOROCHROMATE, or PCC. PCC Structure 1 This reagent provides milder oxidizing conditions – therefore, the reaction stops at the aldehyde and does not continue to the carboxylic acid. Secondary Alcohols: Can be converted into a ketone upon treatment with sodium dichromate and sulfuric acid. Na 2r 2 7 H 2O ,4H O2 * Alternatively * The JONES reagent can be used, this is formed from CrO3 in aqueous acetone. Whether or not you’re planning to use Na Cr 2 2r 7 e jones reagent, you are performing an oxidation that involves a chromium oxidizing agent. The alcohol is being oxidized, and the chromium is being reduced. Chromium oxidations work well for secondary alcohols, but not for primary alcohols. This is because the conditions are too strong, and oxidize it too far to a carboxylic acid. Ozonolysis: Ozonolysis is another way to form C = O (other than oxidation) The ozonolysis reaction essentially takes every C = C bond in the compound and breaks it to form a C = O. 5.2 Stability and Reactivity of C = O Bonds Ketones and aldehydes are very similar to one another in their structure, however there are differences in their stability and reactivity. Since they are structurally similar to one another, they also react similarly. Basics of C = O C = O is a carbonyl group. It is important to not confuse the term carbonyl with the term acyl. The term “acyl” is used to refer to a carbonyl group together with an alkyl group. When we want to know how a carbonyl will react, we must first look at the electronic effects – where the delta positive and negative areas are on the compound. There are always two factors to explore, induction and resonance. First start with induction: O is more electronegative than Carbon and therefore the oxygen will withdraw electron density. Next we must look as resonance, we still see that the carbon is electro positive, and the oxygen is electro negative, this time because of resonance. IMAGE F This means that the carbon atom is very electrophilic and the oxygen atom is very nucleophilic. The geometry of a carbonyl group facilitates the carbon atom functioning as an electrophile. o SP2 hybridized carbon atoms have a trigonal planar geometry. o This makes is easy for a nucleophile to attack the carbonyl group since there is NO steric hindrance Different nucleophiles are also able to attack carbonyl groups. Carbonyl Groups are Thermodynamically very stable o Generally forming C = O is a process of downhill energy o But converting C = O to C – O is generally a process of uphill energy o The formation of carbonyl groups are generally the driving force in a reaction. Summary of 5.1 & 5.2 Klein OCSL 2 nd Semester The carbon atom of the carbonyl group is the electrophile. The electrophilic C is attacked by the nucleophile. Carbonyl groups are very stable, the carbonyl formation can serve as a driving force GUIDING PRINCIPLES 1. A carbonyl can be attacked by a nucleophile (many different ones) 2. After a carbonyl group is attacked, it will try to reform IF possible. (But it is not always possible. 5.3 H- Nucleophiles Exploration of nucleophiles that can attack ketones and aldehydes Focusing on hydrogen nucleophiles. “Hydrogen” nucleophiles are a source of a negatively charged hydrogen atom that can attack a ketone or aldehyde. (Negatively charged hydrogen atom is called a hydride). The simplest way to get a hydride is from sodium hydride (NaH). Sodium hydride is an ionic compound so it is made up of Na+ and H- NaH is a strong base, therefore you will not see it serve as a hydride nucleophile. The strength of the base is determined by the stability of the negative charge. An unstable negative charge corresponds to a strong base while a stabilized negative charge corresponds to a weak base. Nucleophilicity is not based on stability, but rather on polarizability. Polarizability: the ability of an atom or molecule to distribute its electron density unevenly in response to external influences. Larger atoms are more polarizable = better nucleophiles Smaller atoms are less polarizable = not as strong of nucleophiles. H- is a strong base, but not such a strong nucleophile, this is because hydrogen does not stabilize a charge well. We DO NOT use NaH as a nucleophile source. Although H- itself cannot be used as a nucleophile, ther are many reagents that can serve as a “delivering agent” Sodium borohydride NaBH4, is somewhat selective with what it will react with, it will not react with all carbonyl groups, like esters. BUT it will react with both aldehydes and Ketones. Lithium Aluminum Hydride (LiAlH4) Lithium Aluminum Hydride is more reactive than sodium borohydride. Aluminum is larger than boron, this makes it more polarizable and more reactive than the reagent NaBH4. Both LAH and NaBH4 will react with ketones and aldehydes. ( It will become more important that LAH is more reactive). 5.7 Ketones and Aldehydes – C – nucleophiles Alkyl halides will react with magnesium in the following way The c-Mg bond has significant ionic character. Carbon is not good at stabilizing a negative charge so this reagent (called a Grignard reagent) is highly reactive. It is a very strong nucleophile and strong base. Grignard reagent: Acts as a base and removes a proton from water to form a more stable hydroxide ion The negative charge on the electronegative atom is more stable. As a result, the reaction essentially goes to completion. You can never use a Grignard reagent to attack a compound that has acidic protons. In general proton transfers are faster than nucleophilic attack – when GR removes a proton it irreversibly destroys the GR. Grignard Reagent attacking ketones or aldehydes: 1. The GR attakcs the carbon atom of the carbonyl group 2. The intermediate will then attempt to reform the carbonyl group Rules for reforming: Reform carbonyl if you can, but never expel H- or C- In the example, our intermediate is unable to reform the carbonyl group because there are no leaving groups to expel. This is true whether or not it attacks a ketone or aldehyde, in either case, the reaction is complete. When you write down the reagents of a Grignard reaction, (in a synthesis problem) make sure you show proton source in a separate source then the reagent. Proton source must come after the Grignard reagent, due to the fact that they can not survive in acidic condition. Close look of what happens after a hydrogen nucleophile attacks a carbonyl group Behavior of a carbonyl group o It is easily attacked by nucleophiles o After a carbonyl group is attacked, it will try to reform if possible. In trying to reform, we realize that the central carbon atom can not form a fifth both, in order for a carbonyl to reform, a leaving group must be expelled. Hydrogen and Carbon CAN NOT act as a leaving group o Once a hydrogen nucleophile delivers a H- to the carbonyl group, it will be impossible to reform. o Last step is to add a source of protons to protonate – source of acid. o Must come following the reaction o H2O, or H3O+ can be used asnd source of protons. o Must be showed in the 2 step below the arrow. Unless it is reacting with NaBH4, if so, the source of protons can be in the same step since NaBH4 is the milder form. LAH and NaBH4 are important and very useful reagents, they allow us to reduce a ketone or aldehyde to an alcohol. There are two more carbon nucleophiles to be explored: o Both carbon nucleophiles are different than Grignard reagents o Both reactions involve ylides HOW YLIDES ARE PREPARED An ylide is a compound with two oppositely charged compounds that are adjacent to one another When a ketone or aldehyde is treated with a wittig reagent, it undergoes a wittig reaction. Wittig Reaction: o A wittig reagent attakcs the carbonyl group in much the same way as a nucleophile would. o C = O bonds are thermodynamically stable o Can not expel H or C so it can not reform the carbonyl group o There is another bond that is very stable, P – O and P = O bonds are very stable. Chemists will say phosphorus is oxophilic, meaning that phosphorus tends to form bonds with oxygen (when and if they can).
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