2444-092611 - EXAM 1 Average Stnd. Dev. 79.5 / 100 16.9 2...

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Unformatted text preview: EXAM 1 Average Stnd. Dev. 79.5 / 100 16.9 2 Grignard Reagents are BASES • A Grignard reagent is a powerful base that reacts with very weak acids. • Water, alcohols, terminal alkynes and even amines react with a Grignard reagent to form the corresponding alkane (the conjugate acid) and the conjugate base of each of the weak acids mentioned. • Methylmagnesium bromide (22) is formed by reaction of iodomethane and magnesium, and will react with water to form methane (the conjugate acid) and hydroxide ion (BrMgOH, the conjugate base). • This reaction effectively destroys the Grignard reagent (breaks the C-Mg bond to form C-H). • Similarly, 22 reacts with ethanol or acetic acid to give methane and ethoxide or the acetate anion, respectively. BrMg !+ Br Mg CH3 22 !" + H O H H CH3 + O H Grignard Reagents are Poor Nucleophiles with RX • In general, a simple Grignard reagent derived from an alkyl halide does not react with an alkyl halide to give a coupling product. • a Grignard reagent from simple aliphatic alkyl halides is a poor nucleophile in an SN2 reaction with a simple aliphatic halide. • An exception to this statement occurs when the Grignard reagent is An unusually reactive and/or the alkyl halide is particularly reactive. • Benzyl bromide or allyl bromide are examples of such reactive alkyl halides. Benzyl Br Mg° Br 23 ether Br 25 MgBr No Coupling 24 Mg MgBr ether 26 ether 27 Br 3 Kharasch Reaction • A Grignard reagent reacts with an alkyl halide if a transition metal salt is added to the reaction. • This variation is called the Kharasch reaction, and the important thing to remember is that a transition metal is needed in order for common Grignard reagents to react with common alkyl halides. • With no transition metal additive, assume that simple aliphatic Grignard no assume reagents do not react with alkyl halides, but that aliphatic Grignard reagents with CuBr or FeBr3 and alkyl halides do give the coupling product. Br MgBr 24 25 CuBr or FeBr3 4 5 Oganolithium Reagents • Reaction of an alkyl halide with the Group 1 metal lithium (Li) gives an organometallic called an organolithium reagent (RLi). • The reaction of 1-bromobutane (23) and lithium metal (which exits primarily as dilithium, Li2) forms 28, where lithium has replaced bromine. • This organolithium reagent is known as n-butyllithium or 1lithiobutane, and it is characterized by a C-Li bond. • The C-Li bond is polarized with a !– carbon and a !+ lithium (see 28) because carbon is more electronegative than lithium. Br 23 !+ Li-Li Li 28 !" + L iB r 6 Oganolithium Reagents • Formation of an organolithium reagent (RLi) is thought to proceed via a radical intermediate (see CH3 in 32), those radicals may react to form other products. • If two radicals come together, they react to form a new molecule. Each radical donates one electron to form a new "-bond (composed of two electrons) in what is known as radical coupling. • Once the CH3 radical is formed it may couple to another methyl radical to generate ethane (CH3CH3), shown in violet using single-headed arrows. • Radical coupling of two alkyl radicals to form an alkane, in the presence of the metal, is called Wurtz coupling. H3C CH3 H3C • I Li I Li • CH3 • Li H3C Li 32 33 7 Oganolithium Reagents • A tertiary organolithium is much more reactive than the secondary organolithium, which is more reactive than primary organolithium reagents. • If tert-butyllithium (36) is mixed with iodoethane, a rapid reaction takes place to produce ethyllithium (37) and tert-butyl iodide (2-iodo-2-methylpropane). • The primary organolithium reagent (37) is more stable than the tertiary organolithium reagent (36), and the reaction shown favors formation of 37. • Because of this difference in reactivity and stability, when a tertiary organolithium reagent such as tert-butyllithium (36) reacts with a primary alkyl halide, a new organolithium reagent is formed if the product is more stable. • The reaction of 36 with a primary alkyl halide (mostly the iodide) is a very common method of producing organolithium reagents that are not commercially available. • This metal-halogen exchange reaction works best when the tertiary organolithium reagents reacts with a primary iodide (bromides and chlorides are less reactive), but the exchange reaction with secondary halides is much slower and often gives poor Li yields. I t-BuLi , pentane-ether 39 38 t-BuLi , pentane-ether Li I 40 41 8 Oganolithium Reagents are BASES • Organolithium reagents behave as carbanions, and they are very powerful bases. • If methyllithium (33) reacts with water, the conjugate base is LiOH (lithium hydroxide) and the conjugate acid is methane, which is very weak acid indeed. • The !– carbon of a C–Li bond is more basic than the !– carbon of a C–Mg bond. • Organolithium reagents are stronger bases than Grignard reagents. • Organolithium reagents are such strong bases that they react with the protons of very weak acids, some with pKa of >30. Li !+ Li CH2C3H7 + !" 28 H O H H CH2C3H7 + O H 9 Oganolithium Reagents are BASES • Organolithium reagents are such strong bases that they react with the protons of very weak acids, some with pKa of >30. BuLi , ether Me C C H Me 42 + usually drawn as BuLi , ether N C C: Li 43 N: Li H 44 N + H-Bu Li 45 Li H Li 36 + 39 H-Bu H Organocuprates 10 • It is possible to generate a different organometallic reagent from an initially formed organometallic reagent, and the new reagent may react directly with an alkyl halide. • When copper is added to an organolithium reagent, the coupling reaction is more facile that the similar reaction with Grignard reagents. • This is the reaction of an organolithium reagent with the copper CuBr or CuI. Both are cuprous salts, or Cu(I). • When an organolithium reagent (RLi) reacts with cuprous iiodide (CuI) in ether at –10°C, a reaction takes place to generate odide what is called an organocuprate, R2CuLi (46). what organocuprate 2 RLi + CuI ether , -10°C R2CuLi 46 11 Organocuprates • The reaction of alkyl halides and organocuprates is the preferred method for coupling an alkyl halide to an organometallic compound. Ph2CuLi Br Ph ether P h 49 P h 50 + C6H13CH2I 2 Li 28 47 Cu Li 2 –78°C ! 0°C C6H13 48 53% 12 25: Disconnections And Synthesis • Synthesis means choosing a molecule of fewer carbons as a starting material and building the molecule of interest by making the necessary carbon-carbon bonds, and incorporating the functional groups. • This chapter will focus on rudimentary techniques for assembling molecules and provide methodology to analyze a molecule and determine what smaller molecule(s) must be used for its synthesis. To begin, you should know: 13 • The concept of bond polarization. (chapter 3, section 3.7, chapter 5, section 5.4) • The concept of strong and weak covalent bonds. (chapter 7, section 7,2, 7.5) • The fundamental structure and nomenclature all functional groups in this book. (focus on chapters 4, 5, 14, 15, 20) • All of the functional group transformations presented in this book. (focus on chapters 10, 11, 12, 16, 17, 18, 19, 20, 21, 23) • All of the carbon-carbon bond forming reactions presented in this book. (focus on chapters 11, 14, 17, 19, 20, 21, and 23) • Mechanisms. (chapter 7, section 7.8 and chapters 10, 11, 12, 16, 17, 18, 19, 20, 21, 23) • All of the reagents used in this book. (chapters 10, 11, 12, 15, 17, 18, 19, 20, 21, 23) • The structure and bonding of organic molecules. (focus on chapters 3, 5) • The concept of isomers. (chapter 4, section 4.5, chapter 5) • The concept of stereoisomers, including regioisomers, enantiomers, and diastereomers. (chapter 9, section 9.1, 9.3, 9.4, 9.5, 9.6) When completed, you should know: 14 • The target is the molecule to be synthesized. The starting material is the molecule used to begin the synthesis. Disconnection is the process of mentally breaking bonds in a target to generate simpler fragments as new targets to be used in the synthesis. The disconnection approach to synthesis is sometimes called retrosynthetic analysis. • If a starting material is designated, try to identify the carbon atoms of the starting material in the target. The disconnections will occur at bonds connecting that fragment to l•c the rest of the molecule. • Assume that ionic reactions are used, and convert each disconnect fragment into a donor (nucleophilic) or acceptor (electrophilic) site, if possible based on the natural bond polarity of any heteroatoms that are present. A synthetic equivalent is the molecular fragment that correlates with the disconnect fragment in terms of the desired reactivity. • In most retrosynthetic analyses, the bond #- to the functional group and that $- to the functional group are the most important for disconnection. • If no starting material is designated, use retrosynthetic analysis to find a commercially available or readily prepared starting material. • Identify the relationship of functional groups and manipulate the functional group as required to complete the synthesis. • The most efficient synthesis is usually a convergent strategy rather than a consecutive strategy. • Disconnection of multi-functional targets requires a complete understanding of all reactions related to those functional groups. • When one group interferes with another, it may be protected. 15 Disconnection • If 1 is a target that must be prepared, several questions should be asked. • What is the starting material? What is the first chemical step? What reagents are used? How many chemical steps are required? • The target will be examined and then simplified it by a series of mental bondbreaking steps called disconnections. • The term disconnection implies a thought experiment that breaks a bond within a disconnection molecule to generate simpler fragments. • • If a bond is disconnected, a chemical process must be available to make that bond. • In other words, choosing a specific a disconnection points towards a bond that must be made by a known chemical reaction. disconnect bond "d" i j h i j b h a Ph g f Ph e b d 1 a c OH f g 2 e c 3 OH 16 Disconnection • Disconnection of bond d generates two smaller fragments 2 and 3 ("smaller" is defined as having fewer carbon atoms). • The disconnection has simplified the target. • Disconnection of bond d should point to a chemical reaction by which 1 may be prepared from simpler fragments. • This is the fundamental principle behind the disconnection process. • Note that the reverse arrow symbol (%) is used with the disconnection. disconnect bond "d" i j h i j b h a Ph g f Ph e b d 1 a c OH f g 2 e c 3 OH 17 Disconnection • Fragments 2 and 3 are not real because each carbon (marked in red) has only three bonds. • There must be a protocol that converts these fragments into real molecules. • Disconnection of the indicated bond in 4 can be correlated with two real molecules, 5 and 6. disconnect bond "d" i j h i j b h a Ph g f Ph e b d a 1 c f g c 2 OH R2 OH 3 O R1 HO R3 e 4 R2 R1 H 6 R3 5 18 Specific Starting Material • A synthetic problem requires that starting material 8 be converted to target 9. • The first step is to identify those carbons in structure 8 that are part of the structure of target 9. Close inspection shows that the carbon atoms highlighted in red and the OH unit in 9 correspond exactly to the carbon atoms and OH of 8. • The bonds connected to the highlighted carbons (the green bond and the blue bond) in 9 are disconnected because those bonds must be formed in the synthesis • This restriction leads specifically to bonds a and b. In other words, the retrosynthesis of 9 must be biased towards the designated starting material, 8. bb OH OH a 9 8 19 Specific Starting Material • These fragments are pieces of a molecule (call them disconnect products; sometimes they are called retrons). • In order to determine the reaction required for the synthesis, convert the disconnect fragments into real molecules. • Focus on translating the fragments into real molecules. This process will allow an evaluation of both chemical reaction, in the context of this specific synthesis. • This translation of disconnect fragments to real molecules involves the use of a synthetic equivalent. OH disconnect b b a 9 10 OH 11 disconnect a OH 12 13 ...
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This note was uploaded on 02/25/2012 for the course CHEM 244 taught by Professor Jardin,j during the Fall '08 term at UConn.

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